Bacterial Infection and Immunity
Xiao-Kui GUO
Symbioses
? Commensalism,one
partner benefits and the
other is neither harmed
nor benefited,
? Mutualism,both
partners benefit,
? Parasitism,one partner
benefits at the expense of
the other,
Role of the resident flora
? Members of the resident flora in the intestinal tract
synthesize vitamin K and aid in the absorption of
nutrients,
? Members of the resident flora on mucous membranes
and skin may prevent colonization by pathogens and
possible disease through ―bacterial interference‖,
? The normal flora may antagonize other bacteria
through the production of substances which inhibit or
kill nonindigenous species,
? The normal flora stimulates the development of
certain tissues,i.e.,the caecum and certain lymphatic
tissues (Peyer's patches) in the GI tract
? The normal flora stimulate the production of cross-
reactive antibodies,
? Hospital acquired infection,Infections acquired during hospital stays,
? Pathgen,A microorganism capable of causing sisease,
? Nonpathogen,A microorganism that does not cause disease; may be part of the normal flora,
? Opportunistic pathogen,An agent capable of causing disease only when the host’s
resistance is impaired (ie,when the patient is ―immunocompromised‖),
? Pathogenicity,The ability of an infectious agent to cause disease
? Virulence,The quantitative ability of an agent to cause disease,Virulent agents cause disease
when introduced into the host in small numbers,Virulence involves invasion and toxigenicity,
LD 50 (age /sex /health /route of entry,etc )
? LD50,The number of pathogens required to cause lethal disease in half of the exposed hosts is called an LD50,
? ID50,The number of pathogens required to cause disease (or,at least,infection) in half of
the exposed hosts is called the ID50
? Adherence(adhesion,attachment),the process by which bacteria stick to the surfaces of host cells,
Once bacteria have entered the body,adherence is a major initial step in the infection process,The terms
adherence,adhesion,and attachment are often used interchangeably,
? Invasion,The process whereby bacteria,animal parasites,fungi,and viruses enter host cells or
tissues and spread in the body,
? Toxigenicity,The ability of a microorganism to produce a toxin that contributes to the
development of disease,
? Koch’s Postulates
? Molecular Koch’s
Postulates
? Molecular Guidelines for
Establishing Microbial
Disease Causation
Koch's postulates
? Isolated
– diseased not healthy
people
? Growth
– pure culture
? Induce disease
– susceptible animals
? Re-isolated
– susceptible animals
Pathogenesis
? Pathogenesis is a multi-factorial process which
depends on the immune status of the host,the
nature of the species or strain (virulence
factors) and the number of organisms in the
initial exposure,
Source of infection
? Exogenous infection, patient,carrier,diseased
animal or animal carrier,
? Endogenous condition, most are normal flora,
cause infection under abnormal condition,
? Airborne droplets
? Food
? Water
? Sexual contact
Transmission ? Respiratory
? Gastroenteric
? Genitourinary tract
? closely contact
? insect bitting
? blood transfusion
? Parenteral route
? Mucous membranes
Routes of
infection
According to
infectious sites
? Local infection
? Generalized or systemic
infection
1,Toxemia, is the presence of
exotoxins in the blood,
2,Endotoxemia, is the presence
of endotoxins in the blood,
3,Bacteremia, is an invasion of
the bloodstream by bacteria,
4,Septicemia, illness that occurs
when poisonous substances
(toxins) produced by certain
bacteria enter the bloodstream,
5,Pyemia, is caused by pyogenic
microorganisms in the blood,
? Inapparent or subclinical
infection
? Latent infection
? Apparent infection, cause
apparent clinic syndrome
? Carrier state,carrier
According to
infectious state
Environmental signals often control the expression of the virulence genes,
Common signals include:Temperrature/Iron availability, C diphtheriae
/low ion/Osmolality /Growth phase/pH/Specific ions
BACTERIAL VIRULENCE FACTORS
1,Adherence Factors
1,Tissue tropism,
2,Species specificity,
3,Genetic specificity within a species,
? Hydrophobic interactions
? Electrostatic attractions
? Atomic and molecular vibrations resulting from
fluctuating dipoles of similar frequencies
? Brownian movement
? Recruitment and trapping by biofilm polymers
interacting with the bacterial glycocalyx (capsule)
Adhesion
adhesin
EPITHELIUM
receptor
BACTERIUM
fibronectin
lipoteichoic acid
F-protein
mannose
Type 1
galactose
– glycolipids
– glycoproteins
P
E,coli fimbriae
2,Invasion of host cells & tissues
3,Toxins ? Exotoxins
? Endotoxins
Exotoxins
? Produce in vitro cause food poisoning,botulin,
staphylococcal enterotoxin,etc,
? Produce in vivo,
Systematic toxic effects, e.g,diphtheria,
tetanus,and streptococcal erythrogenic toxins,
Local toxic effects, e.g,cholera,and toxigenic
E,coli enterotoxins,
Active Binding
A
Cell surface
B
? Antibodies (anti-toxins)
neutralize
– vaccination
Endotoxins
? LPS Lipopolysaccharide,
core or backbone of CHO
side chains of CHO,"O" antigen
Lipid A
? Cell wall lysis required
? formaldehyde and heat resistant
? poor antigen as free molecule
? Endotoxin effects
? Fever-pyrogen 1 microgram/ kg
? Leukopenia and leukocytosis necrosis
? Shwartzman phenomenon and
disseminated intravascular coagulation
(DIC),
? Endotoxemia and shock
? Lethal 1 milligram/ kg Identification,
Limulcyte assay
? Non-specific inflammation,
? Cytokine release
? Complement activation
? B cell mitogens
? Polyclonal B cell activators
? Adjuvants
Peptidoglycan of Gram-
positive bacteria
? May yield many of the same biologic
activities as LPS,
4,Enzymes
? Tissue-degrading
enzymes
? IgA1 proteases,
split IgA1,an
important secretory
antibody on
mucosal surfaces,
and inactivate its
antibody activity,
1,H,influenzae
2,S,pneumoniae
3,N,gonorrhoeae
4,N,meningitidis
? Some pathogens evade
phagocytosis or leukocyte
microbicidal mechanisms by
adsorbing normal host
components to their surfaces,
A few bacteria produce
soluble factors or toxins that
inhibit chemotaxis by
leukocytes and thus evade
phagocytosis,
5,Antiphagocytic
factors
Antiphagocytic Substances
? 1,Polysaccharide capsules of S,pneumoniae,Haemophilus influenzae,
Treponema pallidum ; B,anthracis and Klebsiella pneumoniae,
? 2,M protein and fimbriae of Group A streptococci
? 3,Surface slime (polysaccharide) produced as a biofilm by Pseudomonas
aeruginosa
? 4,O polysaccharide associated with LPS of E,coli
? 5,K antigen (acidic polysaccharides) of E,coli or the analogous Vi
antigen of Salmonella typhi
? 6,Cell-bound or soluble Protein A produced by Staphylococcus aureus,Protein A
attaches to the Fc region of IgG and blocks the cytophilic (cell-binding) domain of the Ab,
Thus,the ability of IgG to act as an opsonic factor is inhibited,and opsonin-mediated
ingestion of the bacteria is blocked,
Protein A inhibits phagocytosis
immunoglobulin Protein A
Fc receptor
BACTERIUM
PHAGOCYTE
r r r
peptidoglycan
Complement fibrinogen
M protein
M protein inhibits phagocytosis
6,Intracellular
pathogenicity
Some bacteria live and
grow within
polymorphonuclear cells,
macrophages,or
monocytes by avoiding
entry into phagolysosomes
and living within the
cytosol of the phagocyte,
preventing phagosome-
lysosome fusion and living
within the phagosome,or
being resistant to lysosomal
enzymes and surviving
within the phagolysosome,
7,Antigenic heterogeneity
? Antigenic type of bacteria may be a marker for
virulence,related to the clonal nature of pathogens,
though it may not actually be the virulence factor,
? Some bacteria may make frequent shifts in the
antigenic form of their surface structures in vitro
and presumably in vivo,allowing the bacteria to
evade the host’s immune system,
Bacterial siderophores compete effectively for
Fe3+ bound to lactoferrin and transferrin,
8,The requirement for iron
? For the host,the iron
metabolism denies
pathogenic bacteria an
adequate source of iron for
growth,
? For the bacteria,they have
developed several methods
to obtain sufficient iron for
essential metabolism,e.g.,
the low-affinity iron
assimilation system or the
high-affinity iron
assimilation systems,
Development of the Immune
System
ery pl
mye
neu mφ
lym
nk
thy
CD8+
CD4+
CTL
TH2
TH1
Components of the Immune
System
Humoral Cellular Humoral Cellular
Specific Nonspecific
complement,
interferon,
TNF etc,
macrophages,
neutrophils
T cells; other
effectors cells antibodies
Balance between Infection and
Immunity
infection immunity
Bolus of infection x virulence
immunity Disease =
Response to Infection
infection
x
disease
Innate
immunity
adaptive
immunity
no
disease
? Beneficial,
? Protection from Invaders
? Elimination of Altered Self
? Detrimental,
? Discomfort (inflammation)
? Damage to self (autoimmunity)
Significance of the Immune System
Innate Immunity Adaptive Immunity
Components of Innate and Adaptive
Immunity
skin,gut Villi,lung cilia,etc
many protein and
non-protein secretions
phagocytes,NK cell
eosinophils,K cells
physical barriers
soluble factors
cells
none
Immunoglobulins
(antibody)
T and B lymphocytes
Chemotactic response to inflammatory stimulus Macrophage Attacking E.coli (SEM x8,800)
Adaptive Immunity
Innate Immunity Adaptive Immunity
Characteristics of Innate and
Adaptive Immunity
No Immunologic
memory
Antigen independent
No time lag
Not antigen specific
Antigen dependent
A lag period
Antigen specific
Development
of memory
? Immunity of extracellular bacterial infection,
antibodies (IgG,IgM,SIgA); phagocytes
(neutrophils); complement; humoral immunity
mainly,
? Immunity of intracellular bacterial infection,
cell-mediated immunity (delayed-type
hypersensitivity,DTH response (DTH) involving
TH1and macrophages) mainly,
INADEQUATE IMMUNE RESPONSES
TO INFECTIOUS AGENTS
? Causes immune suppression—an example is infection with
HIV,which alters T cell immunity and allows further
infection with opportunistic pathogens,
? Release toxins that function as superantigens,initially
stimulating large numbers of T cells to proliferate but,
because of the release of cytokines from T cells,ultimately
suppressing the immune response and allowing the
pathogen to multilply,
? Evade the immune defenses by altering their antigenic
structure—an example is that influenza virus undergoes
antigenic variation by two mutational mechanisms called
antigenic shift and antigenic drift that creat new antigenic
phenotypes which evade the host’s current immunity and
allow reinfection with the virus,
Xiao-Kui GUO
Symbioses
? Commensalism,one
partner benefits and the
other is neither harmed
nor benefited,
? Mutualism,both
partners benefit,
? Parasitism,one partner
benefits at the expense of
the other,
Role of the resident flora
? Members of the resident flora in the intestinal tract
synthesize vitamin K and aid in the absorption of
nutrients,
? Members of the resident flora on mucous membranes
and skin may prevent colonization by pathogens and
possible disease through ―bacterial interference‖,
? The normal flora may antagonize other bacteria
through the production of substances which inhibit or
kill nonindigenous species,
? The normal flora stimulates the development of
certain tissues,i.e.,the caecum and certain lymphatic
tissues (Peyer's patches) in the GI tract
? The normal flora stimulate the production of cross-
reactive antibodies,
? Hospital acquired infection,Infections acquired during hospital stays,
? Pathgen,A microorganism capable of causing sisease,
? Nonpathogen,A microorganism that does not cause disease; may be part of the normal flora,
? Opportunistic pathogen,An agent capable of causing disease only when the host’s
resistance is impaired (ie,when the patient is ―immunocompromised‖),
? Pathogenicity,The ability of an infectious agent to cause disease
? Virulence,The quantitative ability of an agent to cause disease,Virulent agents cause disease
when introduced into the host in small numbers,Virulence involves invasion and toxigenicity,
LD 50 (age /sex /health /route of entry,etc )
? LD50,The number of pathogens required to cause lethal disease in half of the exposed hosts is called an LD50,
? ID50,The number of pathogens required to cause disease (or,at least,infection) in half of
the exposed hosts is called the ID50
? Adherence(adhesion,attachment),the process by which bacteria stick to the surfaces of host cells,
Once bacteria have entered the body,adherence is a major initial step in the infection process,The terms
adherence,adhesion,and attachment are often used interchangeably,
? Invasion,The process whereby bacteria,animal parasites,fungi,and viruses enter host cells or
tissues and spread in the body,
? Toxigenicity,The ability of a microorganism to produce a toxin that contributes to the
development of disease,
? Koch’s Postulates
? Molecular Koch’s
Postulates
? Molecular Guidelines for
Establishing Microbial
Disease Causation
Koch's postulates
? Isolated
– diseased not healthy
people
? Growth
– pure culture
? Induce disease
– susceptible animals
? Re-isolated
– susceptible animals
Pathogenesis
? Pathogenesis is a multi-factorial process which
depends on the immune status of the host,the
nature of the species or strain (virulence
factors) and the number of organisms in the
initial exposure,
Source of infection
? Exogenous infection, patient,carrier,diseased
animal or animal carrier,
? Endogenous condition, most are normal flora,
cause infection under abnormal condition,
? Airborne droplets
? Food
? Water
? Sexual contact
Transmission ? Respiratory
? Gastroenteric
? Genitourinary tract
? closely contact
? insect bitting
? blood transfusion
? Parenteral route
? Mucous membranes
Routes of
infection
According to
infectious sites
? Local infection
? Generalized or systemic
infection
1,Toxemia, is the presence of
exotoxins in the blood,
2,Endotoxemia, is the presence
of endotoxins in the blood,
3,Bacteremia, is an invasion of
the bloodstream by bacteria,
4,Septicemia, illness that occurs
when poisonous substances
(toxins) produced by certain
bacteria enter the bloodstream,
5,Pyemia, is caused by pyogenic
microorganisms in the blood,
? Inapparent or subclinical
infection
? Latent infection
? Apparent infection, cause
apparent clinic syndrome
? Carrier state,carrier
According to
infectious state
Environmental signals often control the expression of the virulence genes,
Common signals include:Temperrature/Iron availability, C diphtheriae
/low ion/Osmolality /Growth phase/pH/Specific ions
BACTERIAL VIRULENCE FACTORS
1,Adherence Factors
1,Tissue tropism,
2,Species specificity,
3,Genetic specificity within a species,
? Hydrophobic interactions
? Electrostatic attractions
? Atomic and molecular vibrations resulting from
fluctuating dipoles of similar frequencies
? Brownian movement
? Recruitment and trapping by biofilm polymers
interacting with the bacterial glycocalyx (capsule)
Adhesion
adhesin
EPITHELIUM
receptor
BACTERIUM
fibronectin
lipoteichoic acid
F-protein
mannose
Type 1
galactose
– glycolipids
– glycoproteins
P
E,coli fimbriae
2,Invasion of host cells & tissues
3,Toxins ? Exotoxins
? Endotoxins
Exotoxins
? Produce in vitro cause food poisoning,botulin,
staphylococcal enterotoxin,etc,
? Produce in vivo,
Systematic toxic effects, e.g,diphtheria,
tetanus,and streptococcal erythrogenic toxins,
Local toxic effects, e.g,cholera,and toxigenic
E,coli enterotoxins,
Active Binding
A
Cell surface
B
? Antibodies (anti-toxins)
neutralize
– vaccination
Endotoxins
? LPS Lipopolysaccharide,
core or backbone of CHO
side chains of CHO,"O" antigen
Lipid A
? Cell wall lysis required
? formaldehyde and heat resistant
? poor antigen as free molecule
? Endotoxin effects
? Fever-pyrogen 1 microgram/ kg
? Leukopenia and leukocytosis necrosis
? Shwartzman phenomenon and
disseminated intravascular coagulation
(DIC),
? Endotoxemia and shock
? Lethal 1 milligram/ kg Identification,
Limulcyte assay
? Non-specific inflammation,
? Cytokine release
? Complement activation
? B cell mitogens
? Polyclonal B cell activators
? Adjuvants
Peptidoglycan of Gram-
positive bacteria
? May yield many of the same biologic
activities as LPS,
4,Enzymes
? Tissue-degrading
enzymes
? IgA1 proteases,
split IgA1,an
important secretory
antibody on
mucosal surfaces,
and inactivate its
antibody activity,
1,H,influenzae
2,S,pneumoniae
3,N,gonorrhoeae
4,N,meningitidis
? Some pathogens evade
phagocytosis or leukocyte
microbicidal mechanisms by
adsorbing normal host
components to their surfaces,
A few bacteria produce
soluble factors or toxins that
inhibit chemotaxis by
leukocytes and thus evade
phagocytosis,
5,Antiphagocytic
factors
Antiphagocytic Substances
? 1,Polysaccharide capsules of S,pneumoniae,Haemophilus influenzae,
Treponema pallidum ; B,anthracis and Klebsiella pneumoniae,
? 2,M protein and fimbriae of Group A streptococci
? 3,Surface slime (polysaccharide) produced as a biofilm by Pseudomonas
aeruginosa
? 4,O polysaccharide associated with LPS of E,coli
? 5,K antigen (acidic polysaccharides) of E,coli or the analogous Vi
antigen of Salmonella typhi
? 6,Cell-bound or soluble Protein A produced by Staphylococcus aureus,Protein A
attaches to the Fc region of IgG and blocks the cytophilic (cell-binding) domain of the Ab,
Thus,the ability of IgG to act as an opsonic factor is inhibited,and opsonin-mediated
ingestion of the bacteria is blocked,
Protein A inhibits phagocytosis
immunoglobulin Protein A
Fc receptor
BACTERIUM
PHAGOCYTE
r r r
peptidoglycan
Complement fibrinogen
M protein
M protein inhibits phagocytosis
6,Intracellular
pathogenicity
Some bacteria live and
grow within
polymorphonuclear cells,
macrophages,or
monocytes by avoiding
entry into phagolysosomes
and living within the
cytosol of the phagocyte,
preventing phagosome-
lysosome fusion and living
within the phagosome,or
being resistant to lysosomal
enzymes and surviving
within the phagolysosome,
7,Antigenic heterogeneity
? Antigenic type of bacteria may be a marker for
virulence,related to the clonal nature of pathogens,
though it may not actually be the virulence factor,
? Some bacteria may make frequent shifts in the
antigenic form of their surface structures in vitro
and presumably in vivo,allowing the bacteria to
evade the host’s immune system,
Bacterial siderophores compete effectively for
Fe3+ bound to lactoferrin and transferrin,
8,The requirement for iron
? For the host,the iron
metabolism denies
pathogenic bacteria an
adequate source of iron for
growth,
? For the bacteria,they have
developed several methods
to obtain sufficient iron for
essential metabolism,e.g.,
the low-affinity iron
assimilation system or the
high-affinity iron
assimilation systems,
Development of the Immune
System
ery pl
mye
neu mφ
lym
nk
thy
CD8+
CD4+
CTL
TH2
TH1
Components of the Immune
System
Humoral Cellular Humoral Cellular
Specific Nonspecific
complement,
interferon,
TNF etc,
macrophages,
neutrophils
T cells; other
effectors cells antibodies
Balance between Infection and
Immunity
infection immunity
Bolus of infection x virulence
immunity Disease =
Response to Infection
infection
x
disease
Innate
immunity
adaptive
immunity
no
disease
? Beneficial,
? Protection from Invaders
? Elimination of Altered Self
? Detrimental,
? Discomfort (inflammation)
? Damage to self (autoimmunity)
Significance of the Immune System
Innate Immunity Adaptive Immunity
Components of Innate and Adaptive
Immunity
skin,gut Villi,lung cilia,etc
many protein and
non-protein secretions
phagocytes,NK cell
eosinophils,K cells
physical barriers
soluble factors
cells
none
Immunoglobulins
(antibody)
T and B lymphocytes
Chemotactic response to inflammatory stimulus Macrophage Attacking E.coli (SEM x8,800)
Adaptive Immunity
Innate Immunity Adaptive Immunity
Characteristics of Innate and
Adaptive Immunity
No Immunologic
memory
Antigen independent
No time lag
Not antigen specific
Antigen dependent
A lag period
Antigen specific
Development
of memory
? Immunity of extracellular bacterial infection,
antibodies (IgG,IgM,SIgA); phagocytes
(neutrophils); complement; humoral immunity
mainly,
? Immunity of intracellular bacterial infection,
cell-mediated immunity (delayed-type
hypersensitivity,DTH response (DTH) involving
TH1and macrophages) mainly,
INADEQUATE IMMUNE RESPONSES
TO INFECTIOUS AGENTS
? Causes immune suppression—an example is infection with
HIV,which alters T cell immunity and allows further
infection with opportunistic pathogens,
? Release toxins that function as superantigens,initially
stimulating large numbers of T cells to proliferate but,
because of the release of cytokines from T cells,ultimately
suppressing the immune response and allowing the
pathogen to multilply,
? Evade the immune defenses by altering their antigenic
structure—an example is that influenza virus undergoes
antigenic variation by two mutational mechanisms called
antigenic shift and antigenic drift that creat new antigenic
phenotypes which evade the host’s current immunity and
allow reinfection with the virus,
