a73 Viral Infections
a73 Bacterial Infections
a73 Protozoan Diseases
a73 Diseases Caused by Parasitic Worms (Helminths)
a73 Emerging Infectious Diseases
Neisseria gonorrheae Attaching to Urethral Epithelial Cells
Immune Response to
Infectious Diseases
I
? ? ???????? ?? ?? ????????? ?? ????????? ?? ?
susceptible host, a series of coordinated events must
circumvent both innate and adaptive immunity. One
of the first and most important features of host innate
immunity is the barrier provided by the epithelial surfaces of
the skin and the lining of the gut. The difficulty of penetrat-
ing these epithelial barriers ensures that most pathogens
never gain productive entry into the host. In addition to pro-
viding a physical barrier to infection, the epithelia also pro-
duce chemicals that are useful in preventing infection. The
secretion of gastric enzymes by specialized epithelial cells
lowers the pH of the stomach and upper gastrointestinal
tract, and other specialized cells in the gut produce antibac-
terial peptides.
A major feature of innate immunity is the presence of the
normal gut flora, which can competitively inhibit the bind-
ing of pathogens to gut epithelial cells. Innate responses can
also block the establishment of infection. For example, the
cell walls of some gram-positive bacteria contain a peptido-
glycan that activates the alternative complement pathway,
resulting in the generation of C3b, which opsonizes bacteria
and enhances phagocytosis (see Chapter 13). Some bacteria
produce endotoxins such as LPS, which stimulate the pro-
duction of cytokines such as TNF-H9251, IL-1, and IL-6 by
macrophages or endothelial cells. These cytokines can acti-
vate macrophages. Phagocytosis of bacteria by macrophages
and other phagocytic cells is another highly effective line of
innate defense. However, some types of bacteria that com-
monly grow intracellularly have developed mechanisms that
allow them to resist degradation within the phagocyte.
Viruses are well known for the stimulation of innate
responses. In particular, many viruses induce the production
of interferons, which can inhibit viral replication by induc-
ing an antiviral response. Viruses are also controlled by NK
cells. As described in Chapter 14, NK cells frequently form
the first line of defense against viral infections.
Generally, pathogens use a variety of strategies to escape
destruction by the adaptive immune system. Many patho-
gens reduce their own antigenicity either by growing within
host cells, where they are sequestered from immune attack,
or by shedding their membrane antigens. Other pathogens
camouflage themselves by mimicking the surfaces of host
cells, either by expressing molecules with amino acid se-
quences similar to those of host cell-membrane molecules or
by acquiring a covering of host membrane molecules. Some
pathogens are able to suppress the immune response selec-
tively or to regulate it so that a branch of the immune system
is activated that is ineffective against the pathogen. Contin-
ual variation in surface antigens is another strategy that
enables a pathogen to elude the immune system. This anti-
genic variation may be due to the gradual accumulation of
mutations, or it may involve an abrupt change in surface
antigens.
Both innate and adaptive immune responses to patho-
gens provide critical defense, but infectious diseases, which
have plagued human populations throughout history, still
cause the death of millions each year. Although widespread
use of vaccines and drug therapy has drastically reduced
mortality from infectious diseases in developed countries,
such diseases continue to be the leading cause of death in the
Third World. It is estimated that over 1 billion people are
infected worldwide, resulting in more than 11 million deaths
every year (Figure 17-1). Despite these alarming numbers,
estimated expenditures for research on infectious diseases
prevalent in the Third World are less than 5% of total health-
research expenditures worldwide. Not only is this a tragedy
for these countries, but some of these diseases are begin-
ning to emerge or re-emerge in developed countries. For
chapter 17
example, some United States troops returned from the Per-
sian Gulf with leishmaniasis; cholera cases have recently
increased worldwide, with more than 100,000 cases reported
in KwaZulu-Natal, South Africa, during the summer of 2001;
and a new drug-resistant strain of Mycobacterium tuberculo-
sis is spreading at an alarming rate in the United States.
In this chapter, the concepts described in earlier chapters,
antigenicity (Chapter 3) and immune effector mechanisms
(Chapters 12–16), as well as vaccine development (which will
be considered in Chapter 18) are applied to selected infec-
tious diseases caused by viruses, bacteria, protozoa, and
helminths—the four main types of pathogens.
Viral Infections
A number of specific immune effector mechanisms, together
with nonspecific defense mechanisms, are called into play to
eliminate an infecting virus (Table 17-1). At the same time,
the virus acts to subvert one or more of these mechanisms to
prolong its own survival. The outcome of the infection de-
pends on how effectively the host’s defensive mechanisms
resist the offensive tactics of the virus.
The innate immune response to viral infection is primar-
ily through the induction of type I interferons (IFN-H9251 and
IFN-H9252) and the activation of NK cells. Double stranded RNA
(dsRNA) produced during the viral life cycle can induce the
expression of IFN-H9251 and IFN-H9252 by the infected cell. Macro-
phages, monocytes, and fibroblasts also are capable of syn-
thesizing these cytokines, but the mechanisms that induce
the production of type I interferons in these cells are not
completely understood. IFN-H9251 and IFN-H9252 can induce an
antiviral response or resistance to viral replication by bind-
ing to the IFN H9251/H9252 receptor. Once bound, IFN-H9251 and IFN-H9252
activate the JAK-STAT pathway, which in turn induces the
transcription of several genes. One of these genes encodes an
390 PART IV The Immune System in Health and Disease
Deaths in millions
4.0
3.0
2.5
2.0
1.5
1.0
0.5
0
Acute
respiratory
infections
(including
pneumonia and
influenza)
AIDS Malaria MeaslesTBDiarrheal
diseases
3.5
2.3
Over age five
1.1
0.9
1.5
2.2
Under age five
FIGURE 17-1 Leading infectious disease killers. Data collected and
compiled by the World Health Organization in 2000 for deaths in
1998. HIV-infected individuals who died of TB are included among
AIDS deaths.
TABLE 17-1 Mechanisms of humoral and cell-mediated immune responses to viruses
Response type Effector molecule or cell Activity
Humoral Antibody (especially, secretory IgA) Blocks binding of virus to host cells, thus
preventing infection or reinfection
IgG, IgM, and IgA antibody Blocks fusion of viral envelope with host-cells
plasma membrane
IgG and IgM antibody Enhances phagocytosis of viral particles
(opsonization)
IgM antibody Agglutinates viral particles
Complement activated by IgG or Mediates opsonization by C3b and lysis
IgM antibody of enveloped viral particles by membrane-
attack complex
Cell-mediated IFN-H9253 secreted by T
H
or T
C
cells Has direct antiviral activity
Cytotoxic T lymphocytes (CTLs) Kill virus-infected self-cells
NK cells and macrophages Kill virus-infected cells by antibody-
dependent cell-mediated cytotoxicity (ADCC)
enzyme known as 2H11032-5H11032-oligo-adenylate synthetase [2-5(A)
synthetase], which activates a ribonuclease (RNAse L) that
degrades viral RNA. Other genes activated by IFN-H9251/H9252 bind-
ing to its receptor also contribute to the inhibition of viral
replication. For example, IFN-H9251/H9252 binding induces a specific
protein kinase called dsRNA-dependent protein kinase (PKR),
which inactivates protein synthesis, thus blocking viral repli-
cation in infected cells (Figure 17-2).
The binding of IFN-H9251 and IFN-H9252 to NK cells induces lytic
activity, making them very effective in killing virally infected
cells. The activity of NK cells is also greatly enhanced by
IL-12, a cytokine that is produced very early in a response to
viral infection.
Many Viruses are Neutralized by Antibodies
Antibodies specific for viral surface antigens are often crucial
in containing the spread of a virus during acute infection and
in protecting against reinfection. Antibodies are particularly
effective in protecting against infection if they are localized at
the site of viral entry into the body. Most viruses express sur-
face receptor molecules that enable them to initiate infection
by binding to specific host-cell membrane molecules. For
example, influenza virus binds to sialic acid residues in cell-
membrane glycoproteins and glycolipids; rhinovirus binds to
intercellular adhesion molecules (ICAMs); and Epstein-Barr
virus binds to type 2 complement receptors on B cells. If anti-
body to the viral receptor is produced, it can block infection
altogether by preventing the binding of viral particles to host
cells. Secretory IgA in mucous secretions plays an important
role in host defense against viruses by blocking viral attach-
ment to mucosal epithelial cells. The advantage of the atten-
uated oral polio vaccine, considered in Chapter 18, is that it
induces production of secretory IgA, which effectively blocks
attachment of poliovirus along the gastrointestinal tract.
Viral neutralization by antibody sometimes involves
mechanisms that operate after viral attachment to host cells.
In some cases, antibodies may block viral penetration by
binding to epitopes that are necessary to mediate fusion of
the viral envelope with the plasma membrane. If the induced
antibody is of a complement-activating isotype, lysis of en-
veloped virions can ensue. Antibody or complement can also
agglutinate viral particles and function as an opsonizing
agent to facilitate Fc- or C3b-receptor–mediated phagocyto-
sis of the viral particles.
Cell-Mediated Immunity is Important
for Viral Control and Clearance
Although antibodies have an important role in containing
the spread of a virus in the acute phases of infection, they are
not usually able to eliminate the virus once infection has
occurred—particularly if the virus is capable of entering a
latent state in which its DNA is integrated into host chromo-
somal DNA. Once an infection is established, cell-mediated
immune mechanisms are most important in host defense. In
general, CD8
+
T
C
cells and CD4
+
T
H
1 cells are the main com-
ponents of cell-mediated antiviral defense, although in some
cases CD4
+
T
C
cells have also been implicated. Activated T
H
1
cells produce a number of cytokines, including IL-2, IFN-H9253,
and TNF, that defend against viruses either directly or indi-
rectly. IFN-H9253 acts directly by inducing an antiviral state in
cells. IL-2 acts indirectly by assisting in the recruitment of
CTL precursors into an effector population. Both IL-2 and
IFN-H9253 activate NK cells, which play an important role in host
defense during the first days of many viral infections until a
specific CTL response develops.
In most viral infections, specific CTL activity arises within
3–4 days after infection, peaks by 7–10 days, and then de-
clines. Within 7–10 days of primary infection, most virions
have been eliminated, paralleling the development of CTLs.
CTLs specific for the virus eliminate virus-infected self-cells
and thus eliminate potential sources of new virus. The role of
CTLs in defense against viruses is demonstrated by the abil-
ity of virus-specific CTLs to confer protection for the specific
virus on nonimmune recipients by adoptive transfer. The
viral specificity of the CTL as well can be demonstrated with
Immune Response to Infectious Diseases CHAPTER 17 391
IFN-α/β
IFN-α/β receptor
2-5(A) synthetase Protein kinase
PKR (inactive)
PKR (activated)
ATP 2-5(A)
Inactive
RNAse L
Degradation of
poly(A)mRNA
eIF2-GDP
(nonfunctional)
Phosphorylation
of eIF-2
Active
RNAse L
+ ATP and
dsRNA
INHIBITION OF PROTEIN SYNTHESIS
FIGURE 17-2 Induction of antiviral activity by IFN-H9251 and -H9252. These
interferons bind to the IFN receptor, which in turn induces the syn-
thesis of both 2-5(A) synthetase and protein kinase (PKR). The action
of of 2-5(A) synthetase results in the activation of RNAse L, which
can degrade mRNA. PKR inactivates the translation initiation factor
eIF-2 by phosphorylating it. Both pathways thus result in the inhibi-
tion of protein synthesis and thereby effectively block viral replication.
adoptive transfer: adoptive transfer of a CTL clone specific
for influenza virus strain X protects mice against influenza
virus X but not against influenza virus strain Y.
Viruses Can Evade Host Defense
Mechanisms
Despite their restricted genome size, a number of viruses
have been found to encode proteins that interfere at various
levels with specific or nonspecific host defenses. Presumably,
the advantage of such proteins is that they enable viruses to
replicate more effectively amidst host antiviral defenses. As
described above, the induction of IFN-H9251 and IFN-H9252 is a
major innate defense against viral infection, but some viruses
have developed strategies to evade the action of IFN-H9251/H9252.
These include hepatitis C virus, which has been shown to
overcome the antiviral effect of the interferons by blocking or
inhibiting the action of PKR (see Figure 17-2).
Another mechanism for evading host responses, utilized
in particular by herpes simplex viruses (HSV) is inhibition
of antigen presentation by infected host cells. HSV-1 and
HSV-2 both express an immediate-early protein (a protein
synthesized shortly after viral replication) called ICP47,
which very effectively inhibits the human transporter mole-
cule needed for antigen processing (TAP; see Figure 8-8).
Inhibition of TAP blocks antigen delivery to class I MHC re-
ceptors on HSV-infected cells, thus preventing presentation
of viral antigen to CD8
+
T cells. This results in the trapping
of empty class I MHC molecules in the endoplasmic reticu-
lum and effectively shuts down a CD8
+
T-cell response to
HSV-infected cells.
The targeting of MHC molecules is not unique to HSV.
Other viruses have been shown to down-regulate class I
MHC expression shortly after infection. Two of the best-
characterized examples, the adenoviruses and cytomegalo-
virus (CMV), use distinct molecular mechanisms to reduce
the surface expression of class I MHC molecules, again in-
hibiting antigen presentation to CD8
+
T cells. Some viruses—
CMV, measles virus, and HIV—have been shown to reduce
levels of class II MHC molecules on the cell surface, thus
blocking the function of antigen-specific antiviral helper
T cells.
Antibody-mediated destruction of viruses requires com-
plement activation, resulting either in direct lysis of the viral
particle or opsonization and elimination of the virus by
phagocytic cells. A number of viruses have strategies for evad-
ing complement-mediated destruction. Vaccinia virus, for
example, secretes a protein that binds to the C4b complement
component, inhibiting the classical complement pathway;
and herpes simplex viruses have a glycoprotein component
that binds to the C3b complement component, inhibiting
both the classical and alternative pathways.
A number of viruses escape immune attack by constantly
changing their antigens. In the influenza virus, continual
antigenic variation results in the frequent emergence of new
infectious strains. The absence of protective immunity to
these newly emerging strains leads to repeated epidemics of
influenza. Antigenic variation among rhinoviruses, the causa-
tive agent of the common cold, is responsible for our inabil-
ity to produce an effective vaccine for colds. Nowhere is anti-
genic variation greater than in the human immunodeficiency
virus (HIV), the causative agent of AIDS. Estimates suggest
that HIV accumulates mutations at a rate 65 times faster than
does influenza virus. Because of the importance of AIDS, a
section of Chapter 19 addresses this disease.
A large number of viruses evade the immune response by
causing generalized immunosuppression. Among these are
the paramyxoviruses that cause mumps, the measles virus,
Epstein-Barr virus (EBV), cytomegalovirus, and HIV. In
some cases, immunosuppression is caused by direct viral in-
fection of lymphocytes or macrophages. The virus can then
either directly destroy the immune cells by cytolytic mecha-
nisms or alter their function. In other cases, immunosup-
pression is the result of a cytokine imbalance. For example,
EBV produces a protein, called BCRF1, that is homologous to
IL-10; like IL-10, BCRF1 suppresses cytokine production by
the T
H
1 subset, resulting in decreased levels of IL-2, TNF, and
IFN-H9253.
Influenza Has Been Responsible for Some
of the Worst Pandemics in History
The influenza virus infects the upper respiratory tract and
major central airways in humans, horses, birds, pigs, and
even seals. In 1918–19, an influenza pandemic (worldwide
epidemic) killed more than 20 million people, a toll surpass-
ing the number of casualties in World War I. Some areas,
such as Alaska and the Pacific Islands, lost more than half of
their population during that pandemic.
PROPERTIES OF THE INFLUENZA VIRUS
Influenza viral particles, or virions, are roughly spherical or
ovoid in shape, with an average diameter of 90–100 nm. The
virions are surrounded by an outer envelope—a lipid bilayer
acquired from the plasma membrane of the infected host cell
during the process of budding. Inserted into the envelope are
two glycoproteins, hemagglutinin (HA) and neuraminidase
(NA), which form radiating projections that are visible in
electron micrographs (Figure 17-3). The hemagglutinin pro-
jections, in the form of trimers, are responsible for the
attachment of the virus to host cells. There are approximately
1000 hemagglutinin projections per influenza virion. The
hemagglutinin trimer binds to sialic acid groups on host-cell
glycoproteins and glycolipids by way of a conserved amino
acid sequence that forms a small groove in the hemagglu-
tinin molecule. Neuraminidase, as its name indicates, cleaves
N-acetylneuraminic (sialic) acid from nascent viral glyco-
proteins and host-cell membrane glycoproteins, an activity
that presumably facilitates viral budding from the infected
host cell. Within the envelope, an inner layer of matrix pro-
tein surrounds the nucleocapsid, which consists of eight dif-
392 PART IV The Immune System in Health and Disease
ferent strands of single-stranded RNA (ssRNA) associated
with protein and RNA polymerase (Figure 17-4). Each RNA
strand encodes one or more different influenza proteins.
Three basic types of influenza (A, B, and C), can be distin-
guished by differences in their nucleoprotein and matrix pro-
teins. Type A, which is the most common, is responsible for the
major human pandemics. Antigenic variation in hemagglu-
tinin and neuraminidase distinguishes subtypes of type A in-
fluenza virus. According to the nomenclature of the World
Health Organization, each virus strain is defined by its animal
host of origin (specified, if other than human), geographical
origin, strain number, year of isolation, and antigenic descrip-
tion of HA and NA (Table 17-2). For example, A/Sw/Iowa/
15/30 (H1N1) designates strain-A isolate 15 that arose in swine
in Iowa in 1930 and has antigenic subtypes 1 of HA and NA.
Notice that the H and N spikes are antigenically distinct in these
two strains. There are 13 different hemagglutinins and 9 neu-
raminidases among the type A influenza viruses.
The distinguishing feature of influenza virus is its vari-
ability. The virus can change its surface antigens so com-
pletely that the immune response to infection with the virus
that caused a previous epidemic gives little or no protection
against the virus causing a subsequent epidemic. The anti-
genic variation results primarily from changes in the hemag-
glutinin and neuraminidase spikes protruding from the viral
envelope (Figure 17-5). Two different mechanisms generate
antigenic variation in HA and NA: antigenic drift and anti-
genic shift. Antigenic drift involves a series of spontaneous
point mutations that occur gradually, resulting in minor
changes in HA and NA. Antigenic shift results in the sudden
emergence of a new subtype of influenza whose HA and pos-
sibly also NA are considerably different from that of the virus
present in a preceding epidemic.
The first time a human influenza virus was isolated was in
1934; this virus was given the subtype designation H0N1
(where H is hemagglutinin and N is neuraminidase). The
H0N1 subtype persisted until 1947, when a major antigenic
shift generated a new subtype, H1N1, which supplanted the
previous subtype and became prevalent worldwide until
1957, when H2N2 emerged. The H2N2 subtype prevailed for
the next decade and was replaced in 1968 by H3N2. Antigenic
shift in 1977 saw the re-emergence of H1N1. The most recent
antigenic shift, in 1989, brought the re-emergence of H3N2,
which remained dominant throughout the next several years.
However, an H1N1 strain re-emerged in Texas in 1995, and
current influenza vaccines contain both H3N2 and H1N1
strains. With each antigenic shift, hemagglutinin and neu-
raminidase undergo major sequence changes, resulting in
major antigenic variations for which the immune system
lacks memory. Thus, each antigenic shift finds the population
immunologically unprepared, resulting in major outbreaks of
influenza, which sometimes reach pandemic proportions.
Immune Response to Infectious Diseases CHAPTER 17 393
Matrix protein
Lipid bilayer
Hemagglutinin
Neuraminidase
Nucleocapsid
NS1, NS2
M1, M2
PB2
PB1
PA
HA
NP
NA
0 1020304050
Nanometers
FIGURE 17-3 Electron micrograph of influenza virus reveals roughly
spherical viral particles enclosed in a lipid bilayer with protruding
hemagglutinin and neuraminidase glycoprotein spikes. [Courtesy of
G. Murti, Department of Virology, St. Jude Children’s Research Hospital,
Memphis, Tenn.]
FIGURE 17-4 Schematic representation of influenza structure. The
envelope is covered with neuraminidase and hemagglutinin spikes. In-
side is an inner layer of matrix protein surrounding the nucleocapsid,
which consists of eight ssRNA molecules associated with nucleopro-
tein. The eight RNA strands encode ten proteins: PB1, PB2, PA, HA
(hemagglutinin), NP (nucleoprotein), NA (neuraminidase), M1, M2,
NS1, and NS2.
O.1 H9262m
Between pandemic-causing antigenic shifts, the influenza
virus undergoes antigenic drift, generating minor antigenic
variations, which account for strain differences within a sub-
type. The immune response contributes to the emergence
of these different influenza strains. As individuals infected
with a given influenza strain mount an effective immune
response, the strain is eliminated. However, the accumula-
tion of point mutations sufficiently alters the antigenicity of
some variants so that they are able to escape immune elimi-
nation (Figure 17-6a). These variants become a new strain of
influenza, causing another local epidemic cycle. The role of
antibody in such immunologic selection can be demon-
strated in the laboratory by mixing an influenza strain with a
monoclonal antibody specific for that strain and then cultur-
ing the virus in cells. The antibody neutralizes all unaltered
viral particles and only those viral particles with mutations
resulting in altered antigenicity escape neutralization and are
able to continue the infection. Within a short time in culture,
a new influenza strain can be shown to emerge.
Antigenic shift is thought to occur through genetic reas-
sortment between influenza virions from humans and from
various animals, including horses, pigs, and ducks (Figure
17-6b). The fact that influenza contains eight separate
strands of ssRNA makes possible the reassortment of the
RNA strands of human and animal virions within a single
cell infected with both viruses. Evidence for in vivo genetic
reassortment between influenza A viruses from humans and
domestic pigs was obtained in 1971. After infecting a pig
simultaneously with human Hong Kong influenza (H3N2)
and with swine influenza (H1N1), investigators were able to
recover virions expressing H3N1. In some cases, an apparent
antigenic shift may represent the re-emergence of a previous
strain that has remained hidden for several decades. In May
of 1977, a strain of influenza, A/USSR/77 (H1N1), appeared
that proved to be identical to a strain that had caused an epi-
demic 27 years earlier. The virus could have been preserved
over the years in a frozen state or in an animal reservoir.
When such a re-emergence occurs, the HA and NA antigens
expressed are not really new; however, they will be seen by
the immune system of anyone not previously exposed to
that strain (people under the age of twenty-seven in the 1977
epidemic, for example) as if they were new because no mem-
ory cells specific for these antigenic subtypes will exist in
the susceptible population. Thus, from an immunologic
point of view, the re-emergence of an old influenza A strain
394 PART IV The Immune System in Health and Disease
Amino acid change, %
NS2
5
Viral proteins
NS1M2M1NAHA1NPPAPB1PB2
61
69
10
15
20
25
30
FIGURE 17-5 Amino acid sequence variation in 10 influenza viral
proteins from two H3N2 strains and one H1N1 strain. The surface
glycoproteins hemagglutinin (HA1) and neuraminidase (NA) show
significant sequence variation; in contrast, the sequences of internal
viral proteins, such as matrix proteins (M1 and M2) and nucleopro-
tein (NP), are largely conserved. [Adapted from G. G. Brownlee, 1986,
in Options for the Control of Influenza, Alan R. Liss.]
TABLE 17-2
Some influenza A strains and
their hemagglutinin (H) and
neuraminidase (N) subtype
Antigenic
Species Virus strain designation subtype
Human A/Puerto Rico/8/34 H0N1
A/Fort Monmouth/1/47 H1N1
A/Singapore/1/57 H2N2
A/Hong Kong/1/68 H3N2
A/USSR/80/77 H1N1
A/Brazil/11/78 H1N1
A/Bangkok/1/79 H3N2
A/Taiwan/1/86 H1N1
A/Shanghai/16/89 H3N2
A/Johannesburg/33/95 H3N2
A/Wuhan/359/95 H3N2
A/Texas/36/95 H1N1
A/Hong Kong/156/97 H5N1
Swine A/Sw/Iowa/15/30 H1N1
A/Sw/Taiwan/70 H3N2
Horse (equine) A/Eq/Prague/1/56 H7N7
A/Eq/Miami/1/63 H3N8
Birds A/Fowl/Dutch/27 H7N7
A/Tern/South America/61 H5N3
A/Turkey/Ontario/68 H8N4
A/Chicken/Hong Kong/258/97 H5N1
can have the same effect as an antigenic shift that generates a
new subtype.
HOST RESPONSE TO INFLUENZA INFECTION
Humoral antibody specific for the HA molecule is produced
during an influenza infection. This antibody confers protec-
tion against influenza, but its specificity is strain-specific and
is readily bypassed by antigenic drift. Antigenic drift in the
HA molecule results in amino acid substitutions in several
antigenic domains at the molecule’s distal end (Figure 17-7).
Two of these domains are on either side of the conserved
sialic-acid–binding cleft, which is necessary for binding of
virions to target cells. Serum antibodies specific for these two
regions are important in blocking initial viral infectivity.
These antibody titers peak within a few days of infection and
then decrease over the next 6 months; the titers then plateau
and remain fairly stable for the next several years. This anti-
body does not appear to be required for recovery from in-
fluenza, as patients with agammaglobulinemia recover from
the disease. Instead, the serum antibody appears to play a sig-
nificant role in resistance to reinfection by the same strain.
When serum-antibody levels are high for a particular HA
molecule, both mice and humans are resistant to infection by
virions expressing that HA molecule. If mice are infected
with influenza virus and antibody production is experimen-
tally suppressed, the mice recover from the infection but
can be reinfected with the same viral strain. In addition to
humoral responses, CTLs can play a role in immune re-
sponses to influenza.
Bacterial Infections
Immunity to bacterial infections is achieved by means of
antibody unless the bacterium is capable of intracellular
growth, in which case delayed-type hypersensitivity has an
important role. Bacteria enter the body either through a
number of natural routes (e.g., the respiratory tract, the gas-
trointestinal tract, and the genitourinary tract) or through
normally inaccessible routes opened up by breaks in mucous
membranes or skin. Depending on the number of organisms
Immune Response to Infectious Diseases CHAPTER 17 395
Antigenic
driftVirus
Host
cell
Antigenic
shift
Human
influenza
Swine
influenza
(a)
(b)
FIGURE 17-6 Two mechanisms generate variations in influenza
surface antigens. (a) In antigenic drift, the accumulation of point mu-
tations eventually yields a variant protein that is no longer recognized
by antibody to the original antigen. (b) Antigenic shift may occur by re-
assortment of an entire ssRNA between human and animal virions in-
fecting the same cell. Only four of the eight RNA strands are depicted.
Tip/interface
Binding
cleft
Loop
Hinge
α helix
β pleated
sheet
FIGURE 17-7 Structure of hemagglutinin molecule. Sialic acid on
host cells interacts with the binding cleft, which is bounded by re-
gions—designated the loop and tip/interface—where antigenic drift
is prevalent (blue areas). Antibodies to these regions are important
in blocking viral infections. Continual changes in amino acid residues
in these regions allow the influenza virus to evade the antibody re-
sponse. Small red dots represent residues that exhibit a high degree
of variation among virus strains. [Adapted from D. C. Wiley et al.,
1981, Nature 289:373.]
Go to www.whfreeman.com/immunology Molecular Visualization
Viral Antigens See Introduction and Flu Virus Hemagglutinin.
entering and their virulence, different levels of host defense
are enlisted. If the inoculum size and the virulence are both
low, then localized tissue phagocytes may be able to eliminate
the bacteria with an innate, nonspecific defense. Larger in-
oculums or organisms with greater virulence tend to induce
an adaptive, specific immune response.
Immune Responses to Extracellular
and Intracellular Bacteria Can Differ
Infection by extracellular bacteria induces production of
humoral antibodies, which are ordinarily secreted by plasma
cells in regional lymph nodes and the submucosa of the res-
piratory and gastrointestinal tracts. The humoral immune
response is the main protective response against extracellular
bacteria. The antibodies act in several ways to protect the
host from the invading organisms, including removal of the
bacteria and inactivation of bacterial toxins (Figure 17-8).
Extracellular bacteria can be pathogenic because they induce
a localized inflammatory response or because they produce
toxins. The toxins, endotoxin or exotoxin, can be cytotoxic
but also may cause pathogenesis in other ways. An excellent
example of this is the toxin produced by diphtheria, which
exerts a toxic effect on the cell by blocking protein synthesis.
Endotoxins, such as lipopolysaccharides (LPS), are generally
components of bacterial cell walls, while exotoxins, such as
diphtheria toxin, are secreted by the bacteria.
Antibody that binds to accessible antigens on the surface
of a bacterium can, together with the C3b component of
complement, act as an opsonin that increases phagocytosis
and thus clearance of the bacterium (see Figure 17-8). In the
case of some bacteria—notably, the gram-negative organ-
isms—complement activation can lead directly to lysis of the
organism. Antibody-mediated activation of the complement
system can also induce localized production of immune
effector molecules that help to develop an amplified and
more effective inflammatory response. For example, the
complement split products C3a, C4a, and C5a act as anaphy-
latoxins, inducing local mast-cell degranulation and thus
vasodilation and the extravasation of lymphocytes and neu-
trophils from the blood into tissue space (see Figure 17-8).
Other complement split products serve as chemotactic fac-
tors for neutrophils and macrophages, thereby contributing
to the buildup of phagocytic cells at the site of infection.
Antibody to a bacteria toxin may bind to the toxin and neu-
tralize it; the antibody-toxin complexes are then cleared by
phagocytic cells in the same manner as any other antigen-
antibody complex.
While innate immunity is not very effective against intra-
cellular bacterial pathogens, intracellular bacteria can acti-
vate NK cells, which, in turn, provide an early defense against
these bacteria. Intracellular bacterial infections tend to in-
duce a cell-mediated immune response, specifically, delayed-
type hypersensitivity. In this response, cytokines secreted by
CD4
+
T cells are important—notably IFN-H9253, which activates
macrophages to kill ingested pathogens more effectively (see
Figure 14-15).
Bacteria Can Effectively Evade Host
Defense Mechanisms
There are four primary steps in bacterial infection:
a73
Attachment to host cells
a73
Proliferation
a73
Invasion of host tissue
a73
Toxin-induced damage to host cells
Host-defense mechanisms act at each of these steps, and
many bacteria have evolved ways to circumvent some of these
host defenses (Table 17-3).
Some bacteria have surface structures or molecules that
enhance their ability to attach to host cells. A number of
gram-negative bacteria, for instance, have pili (long hairlike
projections), which enable them to attach to the membrane
of the intestinal or genitourinary tract (Figure 17-9). Other
bacteria, such as Bordetella pertussis, secrete adhesion mole-
cules that attach to both the bacterium and the ciliated
epithelial cells of the upper respiratory tract.
Secretory IgA antibodies specific for such bacterial struc-
tures can block bacterial attachment to mucosal epithelial
cells and are the main host defense against bacterial attach-
ment. However, some bacteria (e.g., Neisseria gonorrhoeae,
Haemophilus influenzae, and Neisseria meningitidis) evade
the IgA response by secreting proteases that cleave secretory
IgA at the hinge region; the resulting Fab and Fc fragments
have a shortened half-life in mucous secretions and are not
able to agglutinate microorganisms.
Some bacteria evade the IgA response of the host by
changing these surface antigens. In N. gonorrhoeae, for ex-
ample, pilin, the protein component of the pili, has a highly
variable structure. Variation in the pilin amino acid sequence
is generated by gene rearrangements of its coding sequence.
The pilin locus consists of one or two expressed genes and
10–20 silent genes. Each gene is arranged into six regions
called minicassettes. Pilin variation is generated by a process
of gene conversion, in which one or more minicassettes from
the silent genes replace a minicassette of the expression gene.
This process generates enormous antigenic variation, which
may contribute to the pathogenicity of N. gonorrhoeae by
increasing the likelihood that expressed pili will bind firmly
to epithelial cells. In addition, the continual changes in the
pilin sequence allow the organism to evade neutralization
by IgA.
Some bacteria possess surface structures that serve to
inhibit phagocytosis. A classic example is Streptococcus pneu-
moniae, whose polysaccharide capsule prevents phagocytosis
very effectively. There are 84 serotypes of S. pneumoniae that
differ from one another by distinct capsular polysaccharides.
396 PART IV The Immune System in Health and Disease
Go to www.whfreeman.com/immunology Animation
Vaccine Strategies See Pathenogenesis
Immune Response to Infectious Diseases CHAPTER 17 397
VISUALIZING CONCEPTS
Mast cell
Opsonization and
phagocytosis
Anaphylatoxins mediate
mast cell degranulation
Complement–mediated lysis
Toxin neutralization
C3b
C3b
C3b
C3b
C3b
C3b
Toxin
Bacteria
Complement
activation
C3a, C4a, C5a
Mediators
Extravasation
Macrophage
Macrophage
LymphocyteNeutrophil
3
Chemotaxis5
2
4
1
FIGURE 17-8 Antibody-mediated mechanisms for combating
infection by extracellular bacteria. (1) Antibody neutralizes bacterial
toxins. (2) Complement activation on bacterial surfaces leads to
complement-mediated lysis of bacteria. (3) Antibody and the com-
plement split product C
3
b bind to bacteria, serving as opsonins to
increase phagocytosis. (4) C3a, C4a, and C5a, generated by antibody-
initiated complement activation, induce local mast cell degranulation,
releasing substances that mediate vasodilation and extravasation
of lymphocytes and neutrophils. (5) Other complement split prod-
ucts are chemotactic for neutrophils and macrophages.
During infection, the host produces antibody against the
infecting serotype. This antibody protects against reinfection
with the same serotype but will not protect against infection
by a different serotype. In this way, S. pneumoniae can cause
disease many times in the same individual. On other bacteria,
such as Streptococcus pyogenes, a surface protein projection
called the M protein inhibits phagocytosis. Some pathogenic
staphylococci are able to assemble a protective coat from host
proteins. These bacteria secrete a coagulase enzyme that pre-
cipitates a fibrin coat around them, shielding them from
phagocytic cells.
Mechanisms for interfering with the complement system
help other bacteria survive. In some gram-negative bacteria,
for example, long side chains on the lipid A moiety of the
cell-wall core polysaccharide help to resist complement-
mediated lysis. Pseudomonas secretes an enzyme, elastase,
that inactivates both the C3a and C5a anaphylatoxins, there-
by diminishing the localized inflammatory reaction.
A number of bacteria escape host defense mechanisms by
their ability to survive within phagocytic cells. Some, such as
Listeria monocytogenes, do this by escaping from the phago-
lysosome to the cytoplasm, which is a more favorable environ-
ment for their growth. Other bacteria, such as Mycobacterium
avium, block lysosomal fusion with the phagolysosome; and
some mycobacteria are resistant to the oxidative attack that
takes place within the phagolysosome.
Immune Responses Can Contribute
to Bacterial Pathogenesis
In some cases, disease is caused not by the bacterial pathogen
itself but by the immune response to the pathogen. As
described in Chapter 12, pathogen-stimulated overproduc-
tion of cytokines leads to the symptoms of bacterial septic
shock, food poisoning, and toxic-shock syndrome. For in-
stance, cell-wall endotoxins of some gram-negative bacteria
activate macrophages, resulting in release of high levels of
IL-1 and TNF-H9251, which can cause septic shock. In staphylo-
coccal food poisoning and toxic-shock syndrome, exotoxins
produced by the pathogens function as superantigens, which
can activate all T cells that express T-cell receptors with a par-
ticular V
H9252
domain (see Table 10-4). The resulting overpro-
duction of cytokines by activated T
H
cells causes many of the
symptoms of these diseases.
398 PART IV The Immune System in Health and Disease
TABLE 17-3 Host immune responses to bacterial infection and bacterial evasion mechanisms
Infection process Host defense Bacterial evasion mechanisms
Attachment to host Blockage of attachment by Secretion of proteases that cleave secretory IgA dimers
cells secretory IgA antibodies (Neisseria meningitidis, N. gonorrhoeae, Haemophilus influenzae)
Antigenic variation in attachment structures (pili of
N. gonorrhoeae)
Proliferation Phagocytosis (Ab- and Production of surface structures (polysaccharide capsule, M protein,
C3b-mediated opsonization) fibrin coat) that inhibit phagocytic cells
Mechanisms for surviving within phagocytic cells
Induction of apoptosis in macrophages (Shigella flexneri)
Complement-mediated lysis and Generalized resistance of gram-positive bacteria to complement-
localized inflammatory response mediated lysis
Insertion of membrane-attack complex prevented by long side
chain in cell-wall LPS (some gram-negative bacteria)
Invasion of host tissues Ab-mediated agglutination Secretion of elastase that inactivates C3a and C5a (Pseudomonas)
Toxin-induced damage Neturalization of toxin by antibody Secretion of hyaluronidase, which enhances bacterial invasiveness
to host cells
FIGURE 17-9 Electron micrograph of Neisseria gonorrhoeae at-
taching to urethral epithelial cells. Pili (P) extend from the gonococ-
cal surface and mediate the attachment. [From M. E. Ward and P. J.
Watt, 1972, J. Inf. Dis. 126:601.]
The ability of some bacteria to survive intracellularly with-
in infected cells can result in chronic antigenic activation of
CD4
+
T cells, leading to tissue destruction by a cell-mediated
response with the characteristics of a delayed-type hypersen-
sitivity reaction (see Chapter 14). Cytokines secreted by these
activated CD4
+
T cells can lead to extensive accumulation
and activation of macrophages, resulting in formation of a
granuloma. The localized concentrations of lysosomal en-
zymes in these granulomas can cause extensive tissue necro-
sis. Much of the tissue damage seen with M. tuberculosis is
due to a cell-mediated immune response.
Diphtheria (Corynebacterium diphtheriae)
May Be Controlled by Immunization with
Inactivated Toxoid
Diphtheria is the classic example of a bacterial disease caused
by a secreted exotoxin to which immunity can be induced by
immunization with an inactivated toxoid. The causative
agent, a gram-positive, rodlike organism called Corynebac-
terium diphtheriae, was first described by Klebs in 1883 and
was shown a year later by Loeffler to cause diphtheria in
guinea pigs and rabbits. Autopsies on the infected animals
revealed that, while bacterial growth was limited to the site of
inoculation, there was widespread damage to a variety of
organs, including the heart, liver, and kidneys. This finding
led Loeffler to speculate that the neurologic and cardiologic
manifestations of the disease were caused by a toxic sub-
stance elaborated by the organism.
Loeffler’s hypothesis was validated in 1888, when Roux
and Yersin produced the disease in animals by injecting them
with a sterile filtrate from a culture of C. diphtheriae. Two
years later, von Behring showed that an antiserum to the
toxin was able to prevent death in infected animals. He pre-
pared a toxoid by treating the toxin with iodine trichloride
and demonstrated that it could induce protective antibodies
in animals. However, the toxoid was still quite toxic and
therefore unsuitable for use in humans. In 1923, Ramon
found that exposing the toxin to heat and formalin rendered
it nontoxic but did not destroy its antigenicity. Clinical trials
showed that formaldehyde-treated toxoid conferred a high
level of protection against diphtheria.
As immunizations with the toxoid increased, the number
of cases of diphtheria decreased rapidly. In the 1920s, there
were approximately 200 cases of diphtheria per 100,000 pop-
ulation in the United States. In 1989, the Centers for Disease
Control reported only three cases of diphtheria in the entire
United States. Recently in the former Soviet Union, there has
been an alarming epidemic of diphtheria due to a reduction
in vaccinations.
Natural infection with C. diphtheriae occurs only in hu-
mans. The disease is spread from one individual to another
by airborne respiratory droplets. The organism colonizes the
nasopharyngeal tract, remaining in the superficial layers of
the respiratory mucosa. Growth of the organism itself causes
little tissue damage, and only a mild inflammatory reaction
develops. The virulence of the organism is due completely to
its potent exotoxin. The toxin causes destruction of the
underlying tissue, resulting in the formation of a tough fibri-
nous membrane (“pseudomembrane”) composed of fibrin,
white blood cells, and dead respiratory epithelial cells. The
membrane itself can cause suffocation. The exotoxin also is
responsible for widespread systemic manifestations. Pro-
nounced myocardial damage (often leading to congestive
heart failure) and neurologic damage (ranging from mild
weakness to complete paralysis) are common.
The exotoxin that causes diphtheria symptoms is encoded
by the tox gene carried by phage H9252. Within some strains of
C. diphtheriae, phage H9252 can exist in a state of lysogeny, in
which the H9252-prophage DNA persists within the bacterial cell.
Only strains that carry lysogenic phage H9252 are able to produce
the exotoxin. The diphtheria exotoxin contains two disulfide-
linked chains, a binding chain and toxin chain. The binding
chain interacts with ganglioside receptors on susceptible
cells, facilitating internalization of the exotoxin. Toxicity re-
sults from the inhibitory effect of the toxin chain on protein
synthesis. The diphtheria exotoxin is extremely potent; a sin-
gle molecule has been shown to kill a cell. Removal of the
binding chain prevents the exotoxin from entering the cell,
thus rendering the exotoxin nontoxic. As described in Chap-
ter 4, an immunotoxin can be prepared by replacing the
binding chain with a monoclonal antibody specific for a
tumor-cell surface antigen; in this way the toxin chain can be
targeted to tumor cells (see Figure 4-23).
Today, diphtheria toxoid is prepared by treating diphthe-
ria toxin with formaldehyde. The reaction with formalde-
hyde cross-links the toxin, resulting in an irreversible loss in
its toxicity while enhancing its antigenicity. The toxoid is
administered together with tetanus toxoid and inactivated
Bordetella pertussis in a combined vaccine that is given to
children beginning at 6–8 weeks of age. Immunization with
the toxoid induces the production of antibodies (antitoxin),
which can bind to the toxin and neutralize its activity. Be-
cause antitoxin levels decline slowly over time, booster doses
are recommended at 10-year intervals to maintain antitoxin
levels within the protective range. Interestingly, antibodies
specific for epitopes on the binding chain of the diphtheria
exotoxin are critical for toxin neutralization because these
antibodies block internalization of the active toxin chain.
Tuberculosis (Mycobacterium tuberculosis) Is
Primarily Controlled by CD4
+
T Cells
Tuberculosis is the leading cause of death in the world from a
single infectious agent, killing about 3 million individuals
every year and accounting for 18.5% of all deaths in adults
between the ages of 15 and 59. About 1.79 billion people,
roughly one-third of the world’s population, are infected with
the causative agent M. tuberculosis and are at risk of develop-
ing the disease. Long thought to have been eliminated as a
Immune Response to Infectious Diseases CHAPTER 17 399
public health problem in the United States, tuberculosis re-
emerged in the early 1990s, particularly in the inner cities and
in areas where HIV-infection levels are high (see the last sec-
tion of this chapter). In 2000, approximately 17,000 individu-
als were diagnosed with tuberculosis in the United States.
Although several Mycobacterium species can cause tuber-
culosis, M. tuberculosis is the principal causative agent. This
organism is spread easily, and pulmonary infection usually
results from inhalation of small droplets of respiratory secre-
tions containing a few bacilli. The inhaled bacilli are ingested
by alveolar macrophages and are able to survive and multiply
intracellularly by inhibiting formation of phagolysosomes.
When the infected macrophages lyse, as they eventually do,
large numbers of bacilli are released. A cell-mediated re-
sponse involving CD4
+
T cells, which is required for immu-
nity to tuberculosis, may be responsible for much of the tis-
sue damage in the disease. CD4
+
T-cell activity is the basis for
the tuberculin skin test to the purified protein derivative
(PPD) from M. tuberculosis (see Chapter 14).
Upon infection with M. tuberculosis, the most common
clinical pattern, termed pulmonary tuberculosis, appears in
about 90% of those infected. In this pattern, CD4
+
T cells are
activated within 2–6 weeks after infection, inducing the infil-
tration of large numbers of activated macrophages. These
cells wall off the organism inside a granulomatous lesion
called a tubercle (Figure 17-10). A tubercle consists of a few
small lymphocytes and a compact collection of activated
macrophages, which sometimes differentiate into epithelioid
cells or multinucleated giant cells. The massive activation of
macrophages that occurs within tubercles often results in the
concentrated release of lytic enzymes. These enzymes destroy
nearby healthy cells, resulting in circular regions of necrotic
tissue, which eventually form a lesion with a caseous (cheese-
like) consistency (see Figure 17-10). As these caseous lesions
heal, they become calcified and are readily visible on x-rays,
where they are called Ghon complexes.
Because the activated macrophages suppress proliferation
of the phagocytosed bacilli, infection is contained. Cytokines
produced by CD4
+
T cells (T
H
1 subset) play an important
role in the response by activating macrophages, so that they
are able to kill the bacilli or inhibit their growth. The role of
IFN-H9253 in the immune response to mycobacteria has been
demonstrated with knockout mice lacking IFN-H9253. These mice
died when they were infected with an attenuated strain of
mycobacteria (BCG), whereas IFN-H9253
+
normal mice survive.
Recent studies have revealed high levels of IL-12 in the
pleural effusions of tuberculosis patients. The high levels
of IL-12, produced by activated macrophages, are not sur-
prising, given the decisive role of IL-12 in stimulating T
H
1-
mediated responses (see Figure 12-12). In mouse models of
tuberculosis, IL-12 has been shown to increase resistance to
the disease. Not only does IL-12 stimulate development of
T
H
1 cells, but it also may contribute to resistance by inducing
the production of chemokines that attract macrophages to
the site of infection. When IL-12 is neutralized by antibody to
IL-12, granuloma formation in tuberculous mice is blocked.
The CD4
+
T-cell–mediated immune response mounted
by the majority of people exposed to M. tuberculosis thus
controls the infection and later protects against reinfection.
However, about 10% of individuals infected with M. tuber-
culosis follow a different clinical pattern: the disease pro-
gresses to chronic pulmonary tuberculosis or extrapulmonary
tuberculosis. This progression may occur years after the pri-
mary infection. In this clinical pattern, accumulation of large
concentrations of mycobacterial antigens within tubercles
leads to extensive and continual chronic CD4
+
T-cell activa-
tion and ensuing macrophage activation. The resulting high
concentrations of lytic enzymes cause the necrotic caseous
lesions to liquefy, creating a rich medium that allows the tuber-
cle bacilli to proliferate extracellularly. Eventually the lesions
rupture, and the bacilli disseminate in the lung and/or
are spread through the blood and lymphatic vessels to the
pleural cavity, bone, urogenital system, meninges, peritoneum,
or skin.
Tuberculosis is treated with several drugs used in combina-
tion, including isoniazid, rifampin, streptomycin, pyrazina-
mide, and ethambutol. The combination therapy of isoniazid
and rifampin has been particularly effective. The intracellular
growth of M. tuberculosis makes it difficult for drugs to reach
the bacilli. For this reason, drug therapy must be continued for
at least 9 months to eradicate the bacteria. Some patients with
tuberculosis do not exhibit any clinical symptoms, and some
patients with symptoms begin to feel better within 2–4 weeks
400 PART IV The Immune System in Health and Disease
T
H
1
cell
Activated
macrophages
Macrophage
with bacilli
Activated
macrophages
Caseous
center
Bacilli
FIGURE 17-10 A tubercle formed in pulmonary tuberculosis.
[Modified from A. M. Dannenberg, 1993, Hosp. Prac. ( Jan. 15):51.]
after treatment begins. To avoid the side effects associated with
the usual antibiotic therapy, many patients, once they feel
better, stop taking the medications long before the recom-
mended treatment period is completed. Because briefer treat-
ment may not eradicate organisms that are somewhat resistant
to the antibiotics, a multidrug-resistant strain can emerge.
Noncompliance with required treatment regimes, one of the
most troubling aspects of the large number of current tuber-
culosis cases, clearly compromises efforts to contain the spread
of the disease.
Presently, the only vaccine for M. tuberculosis is an attenu-
ated strain of M. bovis called BCG (Bacillus Calmette-Guerin).
The vaccine appears to provide fairly effective protection
against extrapulmonary tuberculosis but has been inconsis-
tent against pulmonary tuberculosis. In different studies, BCG
has provided protection in anywhere from 0% to 80% of vac-
cinated individuals; in some cases, BCG vaccination has even
increased the risk of infection. Moreover, after BCG vaccina-
tion, the tuberculin skin test cannot be used as an effective
monitor of exposure to M. tuberculosis. Because of the variable
effectiveness of the BCG vaccine and the inability to monitor
for exposure with the skin test after vaccination, this vaccine is
not used in the United States. However, the alarming increase
in multidrug-resistant strains has stimulated renewed efforts
to develop a more effective tuberculosis vaccine.
Protozoan Diseases
Protozoans are unicellular eukaryotic organisms. They are
responsible for several serious diseases in humans, includ-
ing amoebiasis, Chagas’ disease, African sleeping sickness,
malaria, leishmaniasis, and toxoplasmosis. The type of im-
mune response that develops to protozoan infection and the
effectiveness of the response depend in part on the location of
the parasite within the host. Many protozoans have life-cycle
stages in which they are free within the bloodstream, and it is
during these stages that humoral antibody is most effective.
Many of these same pathogens are also capable of intracellular
growth; during these stages, cell-mediated immune reactions
are effective in host defense. In the development of vaccines for
protozoan diseases, the branch of the immune system that is
most likely to confer protection must be carefully considered.
Malaria (Plasmodium Species) Infects
600 Million People Worldwide
Malaria is one of the most devastating diseases in the world
today, infecting nearly 10% of the world population and
causing 1–2 million deaths every year. Malaria is caused by
various species of the genus Plasmodium, of which P. falci-
parum is the most virulent and prevalent. The alarming
development of multiple-drug resistance in Plasmodium and
the increased resistance of its vector, the Anopheles mosquito,
to DDT underscore the importance of developing new stra-
tegies to hinder the spread of malaria.
PLASMODIUM LIFE CYCLE AND PATHOGENESIS
OF MALARIA
Plasmodium progresses through a remarkable series of devel-
opmental and maturational stages in its extremely complex
life cycle. Female Anopheles mosquitoes, which feed on blood
meals, serve as the vector for Plasmodium, and part of the
parasite’s life cycle takes place within the mosquito. (Because
male Anopheles mosquitoes feed on plant juices, they do not
transmit Plasmodium.)
Human infection begins when sporozoites, one of the
Plasmodium stages, are introduced into an individual’s blood-
stream as an infected mosquito takes a blood meal (Figure
17-11). Within 30 min, the sporozoites disappear from the
Immune Response to Infectious Diseases CHAPTER 17 401
Sporozoites
Liver
Merozoites
Gametocytes
In
mosquito
gut
RBC
FIGURE 17-11 The life cycle of Plasmodium. Sporozoites enter the
bloodstream when an infected mosquito takes a blood meal. The
sporozoites migrate to the liver, where they multiply, transforming
liver hepatocytes into giant multinucleate schizonts, which release
thousands of merozoites into the bloodstream. The merozoites in-
fect red blood cells, which eventually rupture, releasing more mero-
zoites. Eventually some of the merozoites differentiate into male and
female gametocytes, which are ingested by a mosquito and differen-
tiate into gametes. The gametes fuse to form a zygote that differenti-
ates to the sporozoite stage within the salivary gland of the mosquito.
blood as they migrate to the liver, where they infect hepato-
cytes. Sporozoites are long, slender cells that are covered by
a 45-kDa protein called circumsporozoite (CS) antigen,
which appears to mediate their adhesion to hepatocytes. The
binding site on the CS antigen is a conserved region in the
carboxyl-terminal end (called region II) that has a high degree
of sequence homology with known cell-adhesion molecules.
Within the liver, the sporozoites multiply extensively and
undergo a complex series of transformations that culminate
in the formation and release of merozoites in about a week. It
has been estimated that a liver hepatocyte infected with a sin-
gle sporozoite can release 5,000–10,000 merozoites. The re-
leased merozoites infect red blood cells, initiating the symp-
toms and pathology of malaria. Within a red blood cell,
merozoites replicate and undergo successive differentiations;
eventually the cell ruptures and releases new merozoites,
which go on to infect more red blood cells. Eventually some
of the merozoites differentiate into male and female gameto-
cytes, which may be ingested by a female Anopheles mosquito
during a blood meal. Within the mosquito’s gut, the male and
female gametocytes differentiate into gametes that fuse to
form a zygote, which multiplies and differentiates into sporo-
zoites within the salivary gland. The infected mosquito is
now set to initiate the cycle once again.
The symptoms of malaria are recurrent chills, fever, and
sweating. The symptoms peak roughly every 48 h, when suc-
cessive generations of merozoites are released from infected
red blood cells. An infected individual eventually becomes
weak and anemic and shows splenomegaly. The large num-
bers of merozoites formed can block capillaries, causing
intense headaches, renal failure, heart failure, or cerebral
damage—often with fatal consequences. There is speculation
that some of the symptoms of malaria may be caused not by
Plasmodium itself but instead by excessive production of
cytokines. This hypothesis stemmed from the observation
that cancer patients treated in clinical trials with recombi-
nant tumor necrosis factor (TNF) developed symptoms that
mimicked malaria. The relation between TNF and malaria
symptoms was studied by infecting mice with a mouse-
specific strain of Plasmodium, which causes rapid death by
cerebral malaria. Injection of these mice with antibodies to
TNF was shown to prevent the rapid death.
HOST RESPONSE TO PLASMODIUM
INFECTION
In regions where malaria is endemic, the immune response
to Plasmodium infection is poor. Children less than 14 years
old mount the lowest immune response and consequently
are most likely to develop malaria. In some regions, the child-
hood mortality rate for malaria reaches 50%, and worldwide
the disease kills about a million children a year. The low im-
mune response to Plasmodium among children can be
demonstrated by measuring serum antibody levels to the
sporozoite stage. Only 22% of the children living in endemic
areas have detectable antibodies to the sporozoite stage,
whereas 84% of the adults have such antibodies. Even in
adults, the degree of immunity is far from complete, how-
ever, and most people living in endemic regions have lifelong
low-level Plasmodium infections.
A number of factors may contribute to the low levels of
immune responsiveness to Plasmodium. The maturational
changes from sporozoite to merozoite to gametocyte allow
the organism to keep changing its surface molecules, result-
ing in continual changes in the antigens seen by the immune
system. The intracellular phases of the life cycle in liver cells
and erythrocytes also reduce the degree of immune activa-
tion generated by the pathogen and allow the organism to
multiply while it is shielded from attack. Furthermore, the
most accessible stage, the sporozoite, circulates in the blood
for only about 30 min before it infects liver hepatocytes; it is
unlikely that much immune activation can occur in such a
short period of time. And even when an antibody response
does develop to sporozoites, Plasmodium has evolved a way
of overcoming that response by sloughing off the surface CS-
antigen coat, thus rendering the antibodies ineffective.
DESIGN OF MALARIA VACCINES
An effective vaccine for malaria should maximize the most
effective immune defense mechanisms. Unfortunately, little
is known of the roles that humoral and cell-mediated
responses play in the development of protective immunity to
this disease. Current approaches to design of malaria vac-
cines focus largely on the sporozoite stage. One experimental
vaccine, for example, consists of Plasmodium sporozoites at-
tenuated by x-irradiation. In one study, nine volunteers were
repeatedly immunized by the bite of P. falciparum–infected,
irradiated mosquitoes. Later challenge by the bites of mos-
quitoes infected with virulent P. falciparum revealed that six
of the nine recipients were completely protected. These re-
sults are encouraging, but translating these findings into mass
immunization remains problematic. Sporozoites do not grow
well in cultured cells, so an enormous insectory would be
required to breed mosquitoes in which to prepare enough
irradiated sporozoites to vaccinate just one small village.
Current vaccine strategies are aimed at producing syn-
thetic subunit vaccines consisting of epitopes that can be rec-
ognized by T cells and B cells. While no effective vaccine has
been developed, this is an active area of investigation.
African Sleeping Sickness
(Trypanosoma Species)
Two species of African trypanosomes, which are flagellated
protozoans, can cause sleeping sickness, a chronic, debilitat-
ing disease transmitted to humans and cattle by the bite of the
tsetse fly. In the bloodstream, a trypanosome differentiates
into a long, slender form that continues to divide every 4–6 h.
The disease progresses through several stages, beginning with
an early (systemic) stage in which trypanosomes multiply in
the blood and progressing to a neurologic stage in which the
402 PART IV The Immune System in Health and Disease
parasite infects the central nervous system, causing menin-
goencephalitis and eventually the loss of consciousness.
As parasite numbers increase after infection, an effective
humoral antibody response develops to the glycoprotein
coat, called variant surface glycoprotein (VSG), that covers
the trypanosomal surface (Figure 17-12). These antibodies
eliminate most of the parasites from the bloodstream, both
by complement-mediated lysis and by opsonization and
Immune Response to Infectious Diseases CHAPTER 17 403
VISUALIZING CONCEPTS
(a)
Millions of trypanosomes
per milliliter of blood
1.5
Variant 3
Variant 4
Variant 2
Variant 1
28 302726 2925
0.5
0
1.0
Approximate time after tsetse fly bite, weeks
Antibodies to variant 3
Antibodies to variant 2
Antibodies to variant 1
Duplication and translocation
to expression site
VSG
1
(b)
VSG
2
VSG
3
VSG
4
VSG
n
3′
Expression site
5′
VSG
1
VSG
1VSG
1
Duplication and translocation
to expression site
VSG
1
VSG
2
VSG
3
VSG
4
VSG
n
VSG
2
3′
Expression site
5′
VSG
2
VSG
2VSG
2
VSG
1
VSG
2
VSG
3
VSG
4
VSG
n
VSG
3
3′
Expression site
5′
VSG
3
VSG
3
VSG
3
VSG
1
FIGURE 17-12 (a) Successive waves of parasitemia after infection
with Trypanosoma result from antigenic shifts in the parasite’s vari-
ant surface glycoprotein (VSG). Each variant that arises is unaffected
by the humoral antibodies induced by the previous variant. (b) Anti-
genic shifts in trypanosomes occur by the duplication of gene seg-
ments encoding variant VSG molecules and their translocation to an
expression site located close to the telomere. [Part (a) adapted from
J. Donelson, 1988, The Biology of Parasitism, Alan R. Liss.]
subsequent phagocytosis. However, about 1% of the organ-
isms, which bear an antigenically different VSG, escape the
initial antibody response. These surviving organisms now
begin to proliferate in the bloodstream, and a new wave of
parasitemia is observed. The successive waves of parasitemia
reflect a unique mechanism of antigenic shift by which the
trypanosomes can evade the immune response to their gly-
coprotein antigens. This process is so effective that each new
variant that arises in the course of a single infection is able to
escape the humoral antibodies generated in response to the
preceding variant, so that waves of parasitemia recur (Figure
17-12a).
Several unusual genetic processes generate the extensive
variation in trypanosomal VSG that enables the organism to
escape immunologic clearance. An individual trypanosome
carries a large repertoire of VSG genes, each encoding a dif-
ferent VSG primary sequence. Trypanosoma brucei, for ex-
ample, contains more than 1000 VSG genes in its genome,
clustered at multiple chromosomal sites. A trypanosome
expresses only a single VSG gene at a time. Activation of a
VSG gene results in duplication of the gene and its transposi-
tion to a transcriptionally active expression site (ES) at the
telomeric end of specific chromosomes (Figure 17-12b).
Activation of a new VSG gene displaces the previous gene
from the telomeric expression site. A number of chromo-
somes in the trypanosome have transcriptionally active
expression sites at the telomeric ends, so that a number of
VSG genes can potentially be expressed, but unknown con-
trol mechanisms limit expression to a single VSG expression
site at a time.
There appears to be some order in the VSG variation dur-
ing infection. Each new variant arises not by clonal out-
growth from a single variant cell but instead from the growth
of multiple cells that have activated the same VSG gene in the
current wave of parasite growth. It is not known how this
process is regulated among individual trypanosomes. The
continual shifts in epitopes displayed by the VSG make the
development of a vaccine for African sleeping sickness ex-
tremely difficult.
Leishmaniasis Is a Useful Model for
Demonstrating Differences in Host
Responses
The protozoan parasite Leishmania major provides a power-
ful and illustrative example of how host responses can differ
between individuals. These differences can lead to either
clearance of the parasite or fatality from the infection. Leish-
mania is a protozoan that lives in the phagosomes of macro-
phages. Resistance to the infection correlates well with the
production of IFN-H9253 and the development of a T
H
1 re-
sponse. Elegant studies in mice have demonstrated that
strains that are resistant to Leishmania develop a T
H
1 re-
sponse and produce IFN-H9253 upon infection. Such strains of
mice become highly susceptible to Leishmania-induced fatal-
ity if they lose either IFN-H9253 or the IFN-H9253 receptor, further
underscoring the importance of IFN-H9253 in containing the
infection. A few strains of mice, such as BALB/c, are highly
susceptible to Leishmania, and these animals frequently suc-
cumb to infection. These mice mount a T
H
2-type response to
Leishmania infection; they produce high levels of IL-4 and
essentially no IFN-H9253. Thus, one difference between an effec-
tive and an ineffective defense against the parasite is the
development of a T
H
1 response or a T
H
2 response. Recent
studies demonstrate that one difference between the resistant
strains of mice and BALB/c is that a small restricted subset of
BALB/c CD4
+
T cells are capable of recognizing a particular
epitope on L. major, and this subset produces high levels of
IL-4 early in the response to the parasite. This skews the
response toward a predominantly T
H
2 type. Understanding
how these different T-helper responses affect the outcome of
infection could provide a more rational approach to the de-
sign of effective treatments and successful vaccines for other
pathogens.
Diseases Caused by Parasitic
Worms (Helminths)
Unlike protozoans, which are unicellular and often grow
within human cells, helminths are large, multicellular organ-
isms that reside in humans but do not ordinarily multiply
there and are not intracellular pathogens. Although hel-
minths are more accessible to the immune system than pro-
tozoans, most infected individuals carry few of these para-
sites; for this reason, the immune system is not strongly
engaged and the level of immunity generated to helminths is
often very poor.
Parasitic worms are responsible for a wide variety of dis-
eases in both humans and animals. More than a billion peo-
ple are infected with Ascaris, a parasitic roundworm that
infects the small intestine, and more than 300 million people
are infected with Schistosoma, a trematode worm that causes
a chronic debilitating infection. Several helminths are impor-
tant pathogens of domestic animals and invade humans who
ingest contaminated food. These helminths include Taenia, a
tapeworm of cattle and pigs, and Trichinella, the roundworm
of pigs that causes trichinosis.
Several Schistosoma species are responsible for the
chronic, debilitating, and sometimes fatal disease schistoso-
miasis (formerly known as bilharzia). Three species, S. man-
soni, S. japonicum, and S. haematobium, are the major
pathogens in humans, infecting individuals in Africa, the
Middle East, South America, the Caribbean, China, South-
east Asia, and the Philippines. A rise in the incidence of schis-
tosomiasis in recent years has paralleled the increasing
worldwide use of irrigation, which has expanded the habitat
of the freshwater snail that serves as the intermediate host for
schistosomes.
404 PART IV The Immune System in Health and Disease
Infection occurs through contact with free-swimming
infectious larvae, called cercariae, which are released from an
infected snail at the rate of 300–3000 per day. When cercariae
contact human skin, they secrete digestive enzymes that help
them to bore into the skin, where they shed their tails and are
transformed into schistosomules. The schistosomules enter
the capillaries and migrate to the lungs, then to the liver, and
finally to the primary site of infection, which varies with the
species. S. mansoni and S. japonicum infect the intestinal
mesenteric veins; S. haematobium infects the veins of the uri-
nary bladder. Once established in their final tissue site, schis-
tosomules mature into male and female adult worms. The
worms mate and the females produce at least 300 spiny eggs
a day. Unlike protozoan parasites, schistosomes and other
helminths do not multiply within their hosts. The eggs pro-
duced by the female worm do not mature into adult worms
in humans; instead, some of them pass into the feces or urine
and are excreted to infect more snails. The number of worms
in an infected individual increases only through repeated ex-
posure to the free-swimming cercariae, and so most infected
individuals carry rather low numbers of worms.
Most of the symptoms of schistosomiasis are initiated by
the eggs. As many as half of the eggs produced remain in the
host, where they invade the intestinal wall, liver, or bladder
and cause hemorrhage. A chronic state can then develop in
which the adult worms persist and the unexcreted eggs in-
duce cell-mediated delayed-type hypersensitive reactions,
resulting in large granulomas that are gradually walled off by
fibrous tissue. Although the eggs are contained by the forma-
tion of the granuloma, often the granuloma itself obstructs
the venous blood flow to the liver or bladder.
Although an immune response does develop to the schis-
tosomes, in most individuals it is not sufficient to eliminate
the adult worms, even though the intravascular sites of schis-
tosome infestation should make the worm an easy target for
immune attack. Instead, the worms survive for up to 20 years.
The schistosomules would appear to be the forms most sus-
ceptible to attack, but because they are motile, they can evade
the localized cellular buildup of immune and inflammatory
cells. Adult schistosome worms also have several unique
mechanisms that protect them from immune defenses. The
adult worm has been shown to decrease the expression of
antigens on its outer membrane and also to enclose itself in a
glycolipid and glycoprotein coat derived from the host,
masking the presence of its own antigens. Among the anti-
gens observed on the adult worm are the host’s own ABO
blood-group antigens and histocompatibility antigens! The
immune response is, of course, diminished by this covering
made of the host’s self-antigens, which must contribute to
the lifelong persistence of these organisms.
The relative importance of the humoral and cell-
mediated responses in protective immunity to schistosomia-
sis is controversial. The humoral response to infection with
S. mansoni is characterized by high titers of antischistosome
IgE antibodies, localized increases in mast cells and their sub-
sequent degranulation, and increased numbers of eosino-
phils (Figure 17-13, top). These manifestations suggest that
cytokines produced by a T
H
2-like subset are important for
the immune response: IL-4, which induces B cells to class-
switch to IgE production; IL-5, which induces bone-marrow
precursors to differentiate into eosinophils; and IL-3, which
(along with IL-4) stimulates growth of mast cells. Degranula-
tion of mast cells releases mediators that increase the infiltra-
tion of such inflammatory cells as macrophages and eosino-
phils. The eosinophils express Fc receptors for IgE and
IgG and bind to the antibody-coated parasite. Once bound
to the parasite, an eosinophil can participate in antibody-
dependent cell-mediated cytotoxicity (ADCC), releasing me-
diators from its granules that damage the parasite (see Figure
14-12). One eosinophil mediator, called basic protein, is par-
ticularly toxic to helminths.
Immunization studies with mice, however, suggest that
this humoral IgE response may not provide protective im-
munity. When mice are immunized with S. mansoni vaccine,
the protective immune response that develops is not an IgE
response, but rather a T
H
1 response characterized by IFN-H9253
production and macrophage accumulation (Figure 17-13,
bottom). Furthermore, inbred strains of mice with deficien-
cies in mast cells or IgE develop protective immunity from
vaccination, whereas inbred strains with deficiencies in cell-
mediated CD4
+
T-cell responses fail to develop protective
immunity in response to the vaccine. These studies suggest
that the CD4
+
T-cell response may be the most important in
immunity to schistosomiasis. It has been suggested that the
ability to induce an ineffective T
H
2-like response may have
evolved in schistosomes as a clever defense mechanism to
ensure that T
H
2 cells produced sufficient levels of IL-10 to
inhibit protective immunity mediated by the T
H
1-like subset
in the CD4
+
T response.
Antigens present on the membrane of cercariae and
young schistosomules are promising vaccine components
because these stages appear to be most susceptible to im-
mune attack. Injecting mice and rats with monoclonal anti-
bodies to cercariae and young schistosomules passively
transferred resistance to infection with live cercariae. When
these protective antibodies were used in affinity columns
to purify schistosome membrane antigens from crude mem-
brane extracts, it was found that mice immunized and
boosted with these purified antigens exhibited increased
resistance to a later challenge with live cercariae. Schisto-
some cDNA libraries were then established and screened
with the protective monoclonal antibodies to identify those
cDNAs encoding surface antigens. Experiments using
cloned cercariae or schistosomule antigens are presently
under way to assess their ability to induce protective immu-
nity in animal models. However, in developing an effective
vaccine for schistosomiasis, a fine line separates a beneficial
immune response, which at best limits the parasite load,
from a detrimental response, which in itself may become
pathologic.
Immune Response to Infectious Diseases CHAPTER 17 405
Emerging Infectious Diseases
A cursory glance at the current offerings in your local book-
store or video rental store brings into focus the preoccupa-
tion of the public and the press with new infectious agents.
Several times a year, it seems, we hear about a new virus or
bacterium that arises in a particular location and causes
severe illness or death in a population. Newly described
pathogens are referred to as emerging pathogens. Some of
the emerging pathogens that have been described since the
early 1970s appear in Table 17-4. These new pathogens are
thought to have emerged within the recent past. HIV is an
example of a newly emerged pathogen.
In other instances, diseases that were no longer causing
widespread infection suddenly began to infect an ever-larger
number of individuals. These are referred to as “re-emerging”
406 PART IV The Immune System in Health and Disease
VISUALIZING CONCEPTS
C3b
B
a
s
ic
p
ro
tei
n
Neutrophil
Mast cell
Eosinophil
Macrophage
Plasma cell
ECF
C3a
C5a
C
C3b
Adult worm
C
C3a
C5a
Mast cell
T
DTH
Mediators
IgE
NCF
Inflammation
Mediators
Platelets
PAF
PAF
Chemotaxis
IFN-γ
FIGURE 17-13 Overview of the immune response generated
against Schistosoma mansoni. The response includes an IgE hu-
moral component (top) and a cell-mediated component involv-
ing CD4
+
T cells (bottom). C = complement; ECF = eosinophil
chemotactic factor; NCF = neutrophil chemotactic factor; PAF =
platelet-activating factor.
infectious diseases. The re-emergence of these diseases
should not be surprising if we consider that bacteria can
adapt to living in almost any environment. If they can adapt
to living at the high temperatures of the thermal vents deep
within the oceans, it is not difficult to accept that they can
evolve to evade antimicrobial drugs. (An additional risk from
intentionally disseminated diseases is discussed in the Clini-
cal Focus.)
Tuberculosis is a well-known re-emerging disease. Fifteen
years ago, public health officials were convinced that tuber-
culosis would soon disappear as a major health consideration
in the United States. Then, because of a number of events,
including the AIDS epidemic, thousands of infected individ-
uals developed TB strains resistant to the conventional bat-
tery of antibiotics. These individuals then passed on the
newly emerged, antibiotic-resistant strains of M. tuberculosis
to others. While the rate of infection with M. tuberculosis in
the United States increased sharply during the early part of
the 1990s, by 1995 the incidence had begun to decline again.
However, the worldwide incidence of the disease is still in-
creasing, and the World Health Organization predicts that,
between 1998 and 2020, one billion more people will become
infected and over 70 million will die from this disease if pre-
ventive measures are not adopted.
Another re-emerging disease is diphtheria. This disease
was almost non-existent throughout Europe in recent years
because of vaccination; in 1994, however, scattered cases were
reported in some of the republics of the former Soviet Union.
By 1995, there were over 50,000 cases reported in the same
region, and thousands died from diphtheria infection. The
social upheaval and instability that came with the breakup of
the Soviet Union was almost certainly a major factor in the
re-emergence of this disease, because of the resultant lapses
in public health measures—perhaps most important was the
loss of immunization programs. Since 1995, immunization
programs have been re-established and the trend has re-
versed, with only 13,687 cases of diphtheria reported in Rus-
sian republics in 1996, 6932 in 1998, and 1573 in 2000.
Other diseases have appeared seemingly from nowhere
and, as far as we know, are new pathogens. These include
Immune Response to Infectious Diseases CHAPTER 17 407
TABLE 17-4 Emerging pathogens recognized since 1973
Year Pathogen Disease
1973 Rotavirus Major cause of infantile diarrhea globally
1974 Hepatitis C Non-A, non-B hepatitis commonly transmitted via transfusions
1976 Cryptosporidium parvum Acute chronic diarrhea
1977 Ebola virus Ebola haemorrhagic fever
Legionella pneumophilia Legionnaires’ disease
Hantavirus Haemorrhagic fever with renal syndrome
Campylobacter jejuni Enteric diseases distributed globally
1980 Human T-lymphotrophic virus I (HTLV-1) T-cell lymphoma
1981 Toxin-producing strains of Toxic shock syndrome
Staphylococcus aureus
1982 Escherichia coli 0157:H7 Haemorrhagic colitis
HTLV-II Hairy cell leukemia
Borrelia burgdorferi Lyme disease
1983 HIV AIDS
Helicobacter pylori Peptic ulcers
1988 Hepatitis E Enteric non-A, non-B hepatitis
1990 Guanarito virus Venezuelan haemorrhagic fever
1991 Encephalitozzon hellem Conjunctivitis, disseminated disease
1992 Vibrio cholerae 0139 New strain of epidemic cholera
Bartonella henselae Cat scratch disease
1994 Sabia virus Brazilian haemorrhagic fever
1995 Human herpes virus-8 Associated with Kaposi sarcoma in AIDS patients
1996 TSE causing agent New variant of Creutzfeldt-Jakob disease (mad cow disease)
1997 Influenza A subtype H5N1 Avian influenza
1999 Influenza A subtype H9N2 New strain of human influenza
Nipah virus Encephalitis
West Nile virus Encephalitis
SOURCE: Adapted from M. F. Good et. al., 1988, Annual Review of Immunology, Vol. 6.
such pathogens as the widely publicized Ebola virus and
Legionella pneumophilia, the bacterial causative agent for
Legionnaires’ disease. Ebola was first recognized after an out-
break in Africa, in 1976. By 1977, the virus that causes this
disease had been isolated and classified as a filovirus, a type of
RNA virus that includes Marburg virus, a close relative of
Ebola. Ebola causes a particularly severe haemorrhagic fever
that kills more than 50% of those infected. Because of the
408 PART IV The Immune System in Health and Disease
spread of the virus requires direct contact
with infected fluids. More worrisome are
pathogens that can be spread by aerosol
contact, such as anthrax, and toxins that
can be added to food or water supplies,
such as botulinum toxin.
It is ironic that one of the most feared
bioterrorism agents is smallpox, the tar-
get of the first vaccine. Smallpox is caused
by the virus Variola major; 30% or more of
those infected with this virus die within a
month of exposure. Survivors may be hor-
ribly scarred. Smallpox can spread rapidly,
even before symptoms are visible. As de-
scribed in Chapter 1, the vaccine for small-
pox is a virus (Vaccinia) related to variola,
which in most cases causes a localized
pustule that resolves within 3 weeks.
Smallpox disappeared as a consequence
of widespread vaccination—the last re-
ported case of natural infection was in
1977. As the disease was eradicated, vac-
cination was discontinued. In the United
States, vaccination ceased in 1972. Pro-
duction of the vaccine ceased and the re-
maining doses were put into storage.
Reasons for discontinuing smallpox
vaccination include side effects that affect
approximately 40 individuals per million
vaccinees. These can be life threatening
and take the form of encephalitis or dis-
seminated skin infection. In addition, re-
cently vaccinated individuals can spread
the virus to others, especially those with
compromised immunity. The occasional
negative reactions to vaccinia can be
treated by the administration of immu-
noglobulin isolated from sera of persons
previously vaccinated, but this so-called
Vaccina IG, or VIG, is no longer produced
and little remains available. Facing the
threat of smallpox as a bioterrorism agent
means that vaccination must be reconsid-
ered. It is unlikely that the vaccine pro-
duced today will be the same one used
earlier. Vaccine was produced by infection
of the scarified skin of calves and virus
was collected by scraping the infected
area. Most likely a new vaccine candidate
will be produced under controlled condi-
tions in a tissue-cultured cell line that is
certified free of any contaminating viruses.
Furthermore, the actual virus used may be
a more highly attenuated form of vaccinia.
Stocks of VIG must be replenished before
a mass vaccination effort is begun.
Most of the viruses on the select
agent list are not easy to disseminate.
Agents of bioterrorism prepared in a
form that allows easy dispersal are re-
ferred to as weaponized. While nightmare
scenarios include customized viral
agents engineered in the laboratory, the
more likely weaponized pathogens are
bacteria. An accidental release of anthrax
(Bacillus anthracis) in Sverdlovsk in the
former Soviet Union infected 79 per-
sons, of whom 68 died, pointing to the
deadly potential of this organism. In late
2001, mail containing anthrax (see the
accompanying figure) infected a number
of persons in multiple postal centers as
the letters progressed to their destina-
tions, giving a glimpse of how widely and
rapidly a bioweapon might be spread
through modern infrastructure.
Bacillus anthracis is a common veteri-
nary pathogen, and like smallpox was the
subject of early vaccine efforts, in this case
by Louis Pasteur. Human infection was
found mainly in those working with hair or
hides from animals, especially goats. In-
fection occurs via three different routes:
a73
Inhalation causes severe flu-like
illness with high mortality unless
diagnosed and treated immediately
The use of human patho-
gens as weapons has a long history. Lord
Jeffery Amherst used smallpox against
native American populations before the
Revolutionary War, and there are reports
of attempts to spread plague and
anthrax in both the distant and recent
past. A few years ago, members of a dis-
sident cult in Oregon introduced salmo-
nella into the salad bars of several
restaurants in an attempt cause sickness
and death. The more recent discovery of
anthrax spores mailed to congressmen
and news offices accelerates our interest
in possible agents of bioterrorism.
Pathogens and toxins with potential
for use as weapons are called “select
agents” and include bacteria, bacterial
toxins, and certain viruses (see table). The
threat from such agents depends on both
the severity of the disease it causes and
the ease with which it can be dissemi-
nated. For example, Ebola virus causes a
fulminating hemorraghic disease, but
CLINICAL FOCUS
The Threat of Infection
from Potential Agents
of Bioterrorism
Category A agents of bioterrorism
Anthrax (Bacillus anthracis)
Botulism (Clostridium botulinum toxin)
Plague (Yersinia pestis)
Smallpox (Variola major)
Tularemia (Francisella tularensis)
Viral hemorrhagic fevers
(filoviruses [e.g., Ebola, Marburg]
and arenaviruses [e.g., Lassa,
Machupo])
severity of disease and the rapid progression to death after
the initial appearance of symptoms, this virus has received a
great deal of attention. However, while the risk of death is
very high if you are infected with Ebola, it is fairly easy to
control the spread of the virus. Through isolation of infected
individuals, hospital workers and medical personnel can be
protected. In such ways, the spread of Ebola virus has been
contained during the two most recent outbreaks.
Immune Response to Infectious Diseases CHAPTER 17 409
used as bioweapons. Primate studies sug-
gest that inhalation of 2500 to 55,000
spores will cause fatal disease, although
the number is controversial. Victims may
have flu-like symptoms; a chest x-ray will
reveal a characteristic widening of the me-
diastinum, and blood smears will show
gram-positive bacilli. Since prompt diag-
nosis and treatment is required for sur-
vival it is essential that medical personnel
recognize the disease.
A vaccine has been developed for an-
thrax, but its use has been limited to the
military. The present preparation is a fil-
trate from cultures of a non-spore-forming
strain of B. anthracis. Newly proposed vac-
cines take advantage of the information
gained from basic studies of the mecha-
nism used by the organism to infect target
cells, as well as our understanding of the
structure and function of anthrax-derived
proteins. The major protein involved in in-
fection is the so-called protective antigen,
or PA, which pairs with either edema factor
(EF) or lethal factor (LF) to cause produc-
tive infection. Antibodies that target the
binding site on PA for either LF or EF are
being developed as the next generation of
vaccines against anthrax.
The threat from select agents of bioter-
rorism, like that from emerging diseases,
is being addressed by careful attention
to unusual infection events, and by in-
creased study of agents that lend them-
selves to weaponization. Research to
determine the efficacy of various treat-
ments and the windows of immunity that
result from administration of antitoxins
have risen to top priority in the U.S. fol-
lowing the events of September 11, 2001.
with antibiotics such as penicillin,
doxycycline or ciprofloxacin.
a73
Cutaneous exposure results in skin
lesions with characteristic black
deep eschar. Cutaneous anthrax has
a 20% mortality if untreated, but
usually responds to antibiotics.
a73
Gastrointestinal exposure results in
ulcers in the ileum or cecum, bloody
diarrhea, and sepsis, and is nearly
always fatal because of difficulty in
diagnosis.
B. anthracis is particularly deadly be-
cause the bacillus forms spores that are
quite stable to heat, dryness, sunlight, and
other factors that normally limit pathogen
viability. It is relatively simple to induce
spore formation, and it is spores that are
Letters to congressmen and news agencies that contained anthrax spores.
Courtesy of the Federal Bureau of Investigation.
Another emerging disease recently described is Legion-
naires’ disease, a virulent pneumonia first reported in
221 individuals who had attended an American Legion con-
vention in Philadelphia in 1976. Of the 221 afflicted, 34 died
from the infection. The organism causing the disease was not
known, but further investigation led to the identification of a
bacterium that was named Legionella pneumophilia. This
bacterium proliferates in cool, damp areas and can be found
in the condensing units of large commercial air-conditioning
systems. The air-conditioning system can produce an aerosol
that contains the bacteria, thus spreading the infection
throughout the area served by the unit. This was determined
to be the source of the bacteria at the 1976 convention in
Philadelphia. Because the hazard of such aerosols is now rec-
ognized, improved design of air-conditioning and plumbing
systems has greatly reduced the incidence of the disease.
In 1999, a new virus emerged in the Western Hemisphere.
West Nile virus was first isolated in Uganda in 1937, but until
recently it was not found outside Africa and western Asia. In
1999, West Nile virus was found in the New York City metro-
politan area and by summer 2002, incidence of West Nile virus
was reported in all but a few states in the Northwest, indicat-
ing a rapid spread of this virus in a short period of time. West
Nile virus belongs to a group of viruses known as flaviruses, a
group of viruses spread by insects, usually mosquitoes. The
most common reservoir of the virus is birds. Crows are partic-
ularly sensitive to infection by this virus. Mosquitoes bite an
infected bird and, most commonly, the virus-infected mos-
quito passes the virus to another bird. However, on occasion,
the mosquito bites a human, infecting that individual with the
virus. Since West Nile is not contagious between humans, it
cannot be spread among human populations. In all but a small
proportion of humans, West Nile infection does not cause dis-
ease. Only in individuals with compromised immune func-
tion is the virus a health hazard. Because this virus can cross
the blood–brain barrier in compromised individuals, it can
cause life threatening encephalitis or meningitis and this is
the usual cause of death. Between 1999 and 2001, West Nile
caused 18 deaths and sickened 131 others. By September 6,
2002, 954 cases of West Nile had been reported to CDC and
43 people had died in the year 2002. These statistics indicate
that West Nile is spreading and is a virus to monitor carefully.
Current public health control mechanisms include education
of the public regarding mosquito control.
Why are these new diseases emerging and others re-
emerging? One reason suggested by public-health officials is
the crowding of the world’s poorest populations into very
small places within huge cities. Another factor is the great
increase in international travel; it is now easy to traverse the
globe in a very short time, making it possible for an individual
to become infected on one continent and then spread the dis-
ease to another continent tens of thousands of miles distant.
Other features of modern life that may contribute include
mass distribution of food, which exposes large populations to
potentially contaminated food, and unhygienic food prepara-
tion. The World Health Organization and the U. S. Center for
Disease Control both actively monitor new infections and
work together closely to detect and identify new infectious
agents and to provide up-to-date information for travelers to
parts of the world where such agents may pose a risk.
SUMMARY
a73
Innate immune responses form the initial defense against
pathogens. These include physical barriers, such as skin, as
well as the nonspecific production of complement compo-
nents and certain cytokines in response to infection by var-
ious pathogens.
a73
The immune response to viral infections involves both
humoral and cell-mediated components. Antibody to a
viral receptor can block viral infections of host cells. How-
ever, a number of viruses, including influenza, are able to
mutate their receptor molecules and thus evade the
humoral antibody response (see Figure 17-6). Once a viral
infection has been established, cell-mediated immunity
appears to be more important than humoral.
a73
The immune response to extracellular bacterial infections
is generally mediated by antibody. Antibody can induce
localized production of immune effector molecules of the
complement system, thus facilitating development of an
inflammatory response. Antibody can also activate com-
plement-mediated lysis of the bacterium, neutralize tox-
ins, and serve as an opsonin to increase phagocytosis.
Some bacteria secrete protease enzymes that cleave IgA
dimers, thus reducing the effectiveness of IgA in the
mucous secretions. Other bacteria escape phagocytosis by
producing surface capsules or proteins that inhibit adher-
ence to phagocytes, by secreting toxins that kill phagocytes,
or by their ability to survive within phagocytes. Host de-
fense against intracellular bacteria depends largely on
CD4
+
T-cell–mediated responses.
a73
Both humoral and cell-mediated immune responses have
been implicated in immunity to protozoan infections. In
general, humoral antibody is effective against blood-borne
stages of the protozoan life-cycle, but once protozoans have
infected host cells, cell-mediated immunity is necessary. Pro-
tozoans escape the immune response through several mech-
anisms. Some—notably, Trypanosoma brucei—are covered
by a glycoprotein coat that is constantly changed by a genetic-
switch mechanism (see Figure 17-12). Others (including
Plasmodium, the causative agent of malaria) slough off their
glycoprotein coat after antibody has bound to it.
a73
Helminths are large parasites that normally do not multi-
ply within cells. Because few of these organisms are carried
by an affected individual, immune-system exposure to
helminths is limited; consequently, only a low level of im-
munity is induced. Although helminths generally are at-
tacked by antibody-mediated defenses, these may be inef-
fective. A cell-mediated response by CD4
+
T cells plays a
critical role in the response to Schistosoma.
410 PART IV The Immune System in Health and Disease
a73
Emerging and re-emerging pathogens include some that
are newly described and others that had been thought to be
controlled by public-health practices. Factors leading to
the emergence of such pathogens include increased travel
and intense crowding of some populations.
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USEFUL WEB SITES
http://www.cdc.gov/ncidod/
National Center for Infectious Diseases home page—a superb
site for monitoring emerging diseases. This is a subdivision of
the Centers for Disease Control (CDC), and links to CDC are
found at this site.
http://www.niaid.nih.gov/
National Institute of Allergy and Infectious Diseases home
page—NIAID is the NIH institute that sponsors research in
infectious diseases, and its Web site provides a number of
links to other relevant sites.
http://www.who.int/
World Health Organization home page—the international
organization that monitors infectious diseases worldwide.
http://www.hopkins-biodefense.org/
The Johns Hopkins University Center for Civilian Biodefense
Strategies; in particular, the link entitled “Dark Winter: A
bioterrorism exercise” is excellent.
Study Questions
CLINICAL FOCUS QUESTION VIG is used to treat individuals who
display complications following administration of the smallpox
vaccine. Where is VIG obtained and why is it frequently an effec-
tive treatment?
1. The effect of the MHC on the immune response to peptides of
the influenza virus nucleoprotein was studied in H-2
b
mice
that had been previously immunized with live influenza viri-
ons. The CTL activity of primed lymphocytes was determined
by in vitro CML assays using H-2
k
fibroblasts as target cells.
The target cells had been transfected with different H-2
b
class
I MHC genes and were infected either with live influenza or
incubated with nucleoprotein synthetic peptides. The results
of these assays are shown in the table below.
a. Why was there no killing of the target cells in system A
even though the target cells were infected with live
influenza?
b. Why was a CTL response generated to the nucleoprotein
in system C, even though it is an internal viral protein?
Immune Response to Infectious Diseases CHAPTER 17 411
Go to www.whfreeman.com/immunology Self-Test
Review and quiz of key terms
c. Why was there a good CTL response in system C to pep-
tide 365–380, whereas there was no response in system D
to peptide 50–63?
d. If you were going to develop a synthetic peptide vaccine
for influenza in humans, how would these results ob-
tained in mice influence your design of a vaccine?
2. Describe the nonspecific defenses that operate when a
disease-producing microorganism first enters the body.
3. Describe the various specific defense mechanisms that the
immune system employs to combat various pathogens.
4. What is the role of the humoral response in immunity to
influenza?
5. Describe the unique mechanisms each of the following
pathogens has for escaping the immune response: (a)
African trypanosomes, (b) Plasmodium species, and (c)
influenza virus.
6. M. F. Good and coworkers analyzed the effect of MHC hap-
lotype on the antibody response to a malarial circumsporo-
zoite (CS) peptide antigen in several recombinant congenic
mouse strains. Their results are shown in the table below.
a. Based on the results of this study, which MHC mole-
cule(s) serve(s) as restriction element(s) for this peptide
antigen?
b. Since antigen recognition by B cells is not MHC
restricted, why is the humoral antibody response influ-
enced by the MHC haplotype?
7. Fill in the blanks in the following statements.
a. The current vaccine for tuberculosis consists of an atten-
uated strain of M. bovis called .
b. Variation in influenza surface proteins is generated by
and .
c. Variation in pilin, which is expressed by many gram-
negative bacteria, is generated by the process of .
d. The mycobacteria causing tuberculosis are walled off in
granulomatous lesions called , which contain a
small number of and many .
e. The diphtheria vaccine is a formaldehyde-treated prepa-
ration of the exotoxin, called a .
f. A major contribution to nonspecific host defense against
viruses is provided by and .
g. The primary host defense against viral and bacterial
attachment to epithelial surfaces is .
h. Two cytokines of particular importance in the response
to infection with M. tuberculosis are , which stim-
ulates development of T
H
1 cells, and , which pro-
motes activation of macrophages.
8. Discuss the factors that contribute to the emergence of new
pathogens or the re-emergence of pathogens previously
thought to be controlled in human populations.
412 PART IV The Immune System in Health and Disease
H-2 alleles Antibody
response to
Strain K IA IE S D CS peptide
B10.BR kkkkk <1
B10.A (4R) kkbbb <1
B10.HTT sskkd <1
B10.A (5R) bbkdd 67
B10 bbbbb 73
B10.MBR bkkkq <1
SOURCE: Adapted from M. F. Good et al., 1988, Annu. Rev. Immunol. 6:633.
CTL activity
of influenza-
primed H-2
b
Target cell lymphocytes
(H-2
k
fibroblast) Test antigen (% lysis)
(A) Untransfected Live influenza 0
(B) Transfected Live influenza 60
with class I D
b
(C) Transfected Nucleoprotein 50
with class I D
b
peptide 365–380
(D) Transfected Nucleoprotein 2
with class I D
b
peptide 50–63
(E) Transfected Nucleoprotein 0.5
with class I K
b
peptide 365–380
(F) Transfected Nucleoprotein 1
with class I K
b
peptide 50–63