Lecture 8 BIOL 533 1
Microbial Interference with
Host Defenses
BIOL 533
Lecture 8
Medical Microbiology
Lecture 8 BIOL 533 2
Overall Strategies
? Defense against complement
? Subversion of phagocytosis
? Subversion of immune responses
Lecture 8 BIOL 533 3
General Aspects
? Pathogen finds itself in hostile territory
– Host fights back and usually—but not
always—wins
? Host’s defenses are interrelated and so are
organism’s countermeasures
Lecture 8 BIOL 533 4
General Aspects
– Given organism sometimes has numerous
different virulence factors
? Does not have to harm tissue to be called
virulence factor,although many do
? Have to determine precise role of each factor if a
large number are involved
– Not always sure in vitro situation is same as in
disease state
Lecture 8 BIOL 533 5
Defense Against Complement
? Overall strategies
– Inhibit complement activation
? Mask activating substances
– Capsule
– IgA antibodies
– Cover up target of complement membrane
attack complex
Lecture 8 BIOL 533 6
Defense Against Complement
? Overall strategies,continued
– Appropriate inhibitor to activation to surface
– Inactivate complement chemotaxin C5a
Lecture 8 BIOL 533 7
Prevent Complement Activation
? Masking surface components that activate
by the alternative pathway
– Capsules
? Murein of S,aureus good activator,but is covered
by capsule
? Capsules rich in sialic acid of Group B streptococci
and strains of E,coli
Lecture 8 BIOL 533 8
Prevent Complement Activation
– IgA antibodies
? Meningococci get coated with IgA antibody
– Does not activate complement
– Prevents other Ab that can activate from reaching
surface of cell
Lecture 8 BIOL 533 9
Prevent Complement Activation
? Cost of having capsule— antigenic
– Elicits activation by primary pathway
? Defend better against immediate defenses than
later ones
Lecture 8 BIOL 533 10
Prevent Complement Activation
? Cover up target of membrane attack
complex (outer membrane)
– Gram—,such as Salmonella or E,coli
? Smooth strains with long ‘0’ antigen polysaccharide
chain do not allow access of mac while rough
strains (with little or no ‘0’ antigen) do
– Correlates with pathogenicity
Lecture 8 BIOL 533 11
Subversion of Phagocytosis
? Overall strategies
– Inhibition of phagocyte recruitment
– Microbial killing of phagocytes
– Escape of ingestion
Lecture 8 BIOL 533 12
Subversion of Phagocytosis
? Overall strategies,continued
– Survival inside phagocytes
? Escape into the cytoplasm
? Inhibition of lysosome and phagosome fusion
? Resistance to lysosomal enzymes
? Inhibition of phagocyte oxidative pathway
– Antibody effects (host counters)
Lecture 8 BIOL 533 13
Subversion of Phagocytosis
? General aspects
– Being inside cell is not necessarily bad for an
organism
? Powerful strategy is to grow within nonphagocytic
cell
– Shielded from antibodies and drugs
Lecture 8 BIOL 533 14
Subversion of Phagocytosis
? Inhibition of phagocyte recruitment
– Direct inhibition of neutrophil motility and
chemotaxis
? Bordetella pertussis produces toxins
– Adenylate cyclase toxin
? Increase cyclic AMP in neutrophils
? Leads to paralysis
– Pertussis toxin
? Impairs migration of monocytes
Lecture 8 BIOL 533 15
Subversion of Phagocytosis
? Microbial killing of phagocytes
– Leukocidins (exotoxins) kill neutrophils and
macrophages
? Can work at distance or after ingestion
? Typical producers are highly invasive bacteria
– Pseudomonas,staphylococci,group A streptococci,gas
gangrene clostridia
Lecture 8 BIOL 533 16
Subversion of Phagocytosis
? Escaping ingestion
– Naked capsule is effective (pneumococci)
? Opsonized bacteria not as effective
– Countering opsonization by complement
components or Ab
? Any mechanism inhibits
– Activation of complement
– Synthesis or activity of Ab
Lecture 8 BIOL 533 17
Subversion of Phagocytosis
? Escaping ingestion,continued
– Countering opsonization when antibodies are
present
? Staphylococci and streptococci
– Make surface component (protein A)
– Binds to IgG molecules by the wrong end (Fc region)
? Cannot act as opsonins because Fc region not free to
bind to Fc receptors on phagocytic cells
? Not known if antiphagocytic defense is relevant to
disease process
Lecture 8 BIOL 533 18
Subversion of Phagocytosis
? Survival inside phagocytes
– Escape into cytoplasm
? Rickettsia (Rocky Mountain Spotted Fever) or
trypanosomes of Chagas’ disease cross membrane
of phagosome to enter cytoplasm
– Since lysosomes do not secrete contents into cytoplasm,
organism is safe
– How they enter cytoplasm is not known for certain
? Possess surface-bound phospholipase,which may
weaken membrane
Lecture 8 BIOL 533 19
Subversion of Phagocytosis
? Survival inside phagocytes,continued
– Inhibition of lysosome and phagosome fusion
– Examples—bacteria that cause,
? Tuberculosis
? Psittacosis
? Legionnaire’s disease
Lecture 8 BIOL 533 20
Subversion of Phagocytosis
– Mechanism of tuberculosis
? Induced by complex glycolipids (sulfatides)—not
certain
? Facts,
– Inhibition must be due to modification of phagosome
membrane
– Microorganism might contribute by compounds secreted
or present on the surface
Lecture 8 BIOL 533 21
Subversion of Phagocytosis
? Survival inside phagocytes,continued
– Resistance to lysosomal enzymes—survive in
phagolysosome (pH as low as 4)
? Leishmania (protozoa)—resistance may be due to,
– Resistant cell surfaces
– Excretion of enzyme inhibitors
Lecture 8 BIOL 533 22
Subversion of Phagocytosis
? Survival inside phagocytes,continued
– Inhibition of phagocyte’s oxidative pathway
? Bacillus of Legionnaire’s disease
– Inhibits hexose-monophosphate shunt and oxygen
consumption in neutrophils
? Reduces respiratory burst for killing microbes
? Staphylococci—produces catalase that degrades
hydrogen peroxide necessary for oxidative killing
Lecture 8 BIOL 533 23
Subversion of Phagocytosis
? Survival inside phagocytes,continued
– Antibody effects,host counters parasite
? Sometimes help host guard against microbial
survival measures
– Antibodies do not prevent entry into cells,but inhibit
subsequent effects
? Rickettsia coated with antibody cannot pass through
membrane into cytoplasm
? Antibodies against Legionnella prevent inhibition of
phagolysosomal fusion
Lecture 8 BIOL 533 24
Subversion of Immune Response
? Immunosuppression,general aspects
– Host becomes susceptible to other infections
and survival probability is lessened
Lecture 8 BIOL 533 25
Subversion of Immune Response
? AIDS—infects T4 inducer-helper
lymphocytes
– Depletion of cells leads to collapse of immune
system
? Reduction in circulating lymphocytes
? Impaired delayed hypersensitivity
? Defective responses of T cells to Ag
? Reduction in T-cell numbers cytotoxic for tumor
cells and virus infected cells
Lecture 8 BIOL 533 26
Subversion of Immune Response
– B cell function is also impaired
? Reduced production of specific Ig
? Increased chaotic production of nonspecific Ig
Lecture 8 BIOL 533 27
Subversion of Immune Response
? Other immunosuppressive viruses,
Measles
– Tuberculosis more common after widespread
measles outbreaks
– Infected T cells in vitro do not die
? Lose certain functions,including ability to mount
delayed hypersensitivity response
Lecture 8 BIOL 533 28
Subversion of Immune Response
– Infected B cells in vitro
? Stop synthesizing and releasing Ig
– Primary effect on B cells
? Not secondary to action of virus on T cells or
macrophage
Lecture 8 BIOL 533 29
Subversion of Immune Response
? Other immunosuppressive viruses,
Hepatitis B and influenza
– Impair function of lymphoid cells without
causing major structural damage
? Immune suppression as a result of
inhibition of synthesis of lymphokines
– Leishmanias (protozoa)
Lecture 8 BIOL 533 30
Subversion of Immune Response
– Leishmanias (protozoa)—when grown in
macrophage
? Suppress secretion of interleukin-1
– Important for initiating series of inflammatory and
immunological reactions important for the eradication of
the organism
– Also explains T cell unresponsiveness
? Suppresses capacity of macrophage to make class I
and class II products of major histocompatibility
locus (MHC)
? Potential for marked suppression of cell-mediated
immunity
Lecture 8 BIOL 533 31
Subversion of Immune Response
? Final thoughts
– Infection of lymphocytes is not immuno-
suppressive in nature
? Large number of organisms infect lymphoreticular
tissues,but do not cause global disturbances to
host immunity
– Bacteria that cause typhoid fever or brucellosis live in
lymph nodes for long period of time
? Do not induce noticeable immune suppression
Lecture 8 BIOL 533 32
Subversion of Immune Response
? Frequent changing of antigenic coats
(antigenic variation)
– Examples of bacteria,viruses,and protozoa
? Trypanosomes (protozoa)
? Gonococci
? Borrelia (recurrent fever)
? Influenza viruses
Lecture 8 BIOL 533 33
Subversion of Immune Response
? Trypanosoma brucei
(causative agent of sleeping sickness)
– Infects blood of interstitial fluids of animals
and man
? Exposed to circulating Ab
Lecture 8 BIOL 533 34
Subversion of Immune Response
? Trypanosoma brucei,continued
– Covered with thick protein coat (variable
surface glycoprotein)
? Undergoes antigenic shifts during infection
– Have several hundred genes that encode different
antigens,but express only one at a time
Lecture 8 BIOL 533 35
Subversion of Immune Response
? Trypanosoma brucei,continued
? When antibodies against one type are made,
– Number of parasites in blood drops
– Soon replaced by new antigenic type
– Can be many successive waves of antigenic changes in a
single host
? Protective immunity does not function well
Lecture 8 BIOL 533 36
Subversion of Immune Response
? Gonococcus and its adhesin
– Periodic change in
? Pilin (protein fimbriae; attach to cells)
? Major outer membrane proteins
Lecture 8 BIOL 533 37
Subversion of Immune Response
? Antigenic variation among influenza
viruses—major obstacle to effective
vaccine (year after year)
– Definitions
? Antigenic drift—minor changes that occur every
2 to 3 years
? Antigenic shift—major changes that occur about
every 10 years
Lecture 8 BIOL 533 38
Subversion of Immune Response
? Antigenic variation,continued
– Mechanism involves two proteins
? Hemagglutinin-binds to cell receptors
? Neuraminidase-changes receptors
Lecture 8 BIOL 533 39
Subversion of Immune Response
? Proteolysis of antibodies
– Make extracellular proteases that inactivate
secretory IgA antibody (major Ab type on
human mucosal surfaces; subclasses I and II)
? Cleave only subclass I at hinge region to leave
complete by inactive peptide fragments
– Examples,
? Gonococci,meningococci,Haemophilus influenzae,
and some pathogenic dental streptococci
Lecture 8 BIOL 533 40
Subversion of Immune Response
? Proteolysis of antibodies,continued
– Specificity of IgA1 proteases from different
bacteria
? Highly specific for subclass I
? Biochemical and genetic differences that suggest
property evolved independently
– Presence in fluids and tissues
? Active form in infected tissues and fluids
Lecture 8 BIOL 533 41
Subversion of Immune Response
? Proteolysis of antibodies,continued
– Possible relationship to pathogenicity;
suggested,not proven
? Nonpathogeic relatives lack these proteases
– Fabulation (cleavage with Fab fragment
attached)
? Ag unavailable for binding with intact antibody
molecules
? May serve to protect some organisms against Ab
Lecture 8 BIOL 533 42
Subversion of Immune Response
? Other viral survival strategies,
general aspects
– Chronic infection—evade host defenses longer
Lecture 8 BIOL 533 43
Subversion of Immune Response
? Herpes infection
– Do not usually enter extracellular fluid,but
pass among cells through cytoplasmic bridges
– Can also be latent (reside within nerve cells
but do not multiply)
? In these circumstances,not affect by antibodies,
cell-mediated immunity,or interferon
? Survive for long periods of time,then later
reactivate (perhaps when defenses are lower)
Lecture 8 BIOL 533 44
Lecture 8
? Questions?
? Comments?
? Assignments..,
Microbial Interference with
Host Defenses
BIOL 533
Lecture 8
Medical Microbiology
Lecture 8 BIOL 533 2
Overall Strategies
? Defense against complement
? Subversion of phagocytosis
? Subversion of immune responses
Lecture 8 BIOL 533 3
General Aspects
? Pathogen finds itself in hostile territory
– Host fights back and usually—but not
always—wins
? Host’s defenses are interrelated and so are
organism’s countermeasures
Lecture 8 BIOL 533 4
General Aspects
– Given organism sometimes has numerous
different virulence factors
? Does not have to harm tissue to be called
virulence factor,although many do
? Have to determine precise role of each factor if a
large number are involved
– Not always sure in vitro situation is same as in
disease state
Lecture 8 BIOL 533 5
Defense Against Complement
? Overall strategies
– Inhibit complement activation
? Mask activating substances
– Capsule
– IgA antibodies
– Cover up target of complement membrane
attack complex
Lecture 8 BIOL 533 6
Defense Against Complement
? Overall strategies,continued
– Appropriate inhibitor to activation to surface
– Inactivate complement chemotaxin C5a
Lecture 8 BIOL 533 7
Prevent Complement Activation
? Masking surface components that activate
by the alternative pathway
– Capsules
? Murein of S,aureus good activator,but is covered
by capsule
? Capsules rich in sialic acid of Group B streptococci
and strains of E,coli
Lecture 8 BIOL 533 8
Prevent Complement Activation
– IgA antibodies
? Meningococci get coated with IgA antibody
– Does not activate complement
– Prevents other Ab that can activate from reaching
surface of cell
Lecture 8 BIOL 533 9
Prevent Complement Activation
? Cost of having capsule— antigenic
– Elicits activation by primary pathway
? Defend better against immediate defenses than
later ones
Lecture 8 BIOL 533 10
Prevent Complement Activation
? Cover up target of membrane attack
complex (outer membrane)
– Gram—,such as Salmonella or E,coli
? Smooth strains with long ‘0’ antigen polysaccharide
chain do not allow access of mac while rough
strains (with little or no ‘0’ antigen) do
– Correlates with pathogenicity
Lecture 8 BIOL 533 11
Subversion of Phagocytosis
? Overall strategies
– Inhibition of phagocyte recruitment
– Microbial killing of phagocytes
– Escape of ingestion
Lecture 8 BIOL 533 12
Subversion of Phagocytosis
? Overall strategies,continued
– Survival inside phagocytes
? Escape into the cytoplasm
? Inhibition of lysosome and phagosome fusion
? Resistance to lysosomal enzymes
? Inhibition of phagocyte oxidative pathway
– Antibody effects (host counters)
Lecture 8 BIOL 533 13
Subversion of Phagocytosis
? General aspects
– Being inside cell is not necessarily bad for an
organism
? Powerful strategy is to grow within nonphagocytic
cell
– Shielded from antibodies and drugs
Lecture 8 BIOL 533 14
Subversion of Phagocytosis
? Inhibition of phagocyte recruitment
– Direct inhibition of neutrophil motility and
chemotaxis
? Bordetella pertussis produces toxins
– Adenylate cyclase toxin
? Increase cyclic AMP in neutrophils
? Leads to paralysis
– Pertussis toxin
? Impairs migration of monocytes
Lecture 8 BIOL 533 15
Subversion of Phagocytosis
? Microbial killing of phagocytes
– Leukocidins (exotoxins) kill neutrophils and
macrophages
? Can work at distance or after ingestion
? Typical producers are highly invasive bacteria
– Pseudomonas,staphylococci,group A streptococci,gas
gangrene clostridia
Lecture 8 BIOL 533 16
Subversion of Phagocytosis
? Escaping ingestion
– Naked capsule is effective (pneumococci)
? Opsonized bacteria not as effective
– Countering opsonization by complement
components or Ab
? Any mechanism inhibits
– Activation of complement
– Synthesis or activity of Ab
Lecture 8 BIOL 533 17
Subversion of Phagocytosis
? Escaping ingestion,continued
– Countering opsonization when antibodies are
present
? Staphylococci and streptococci
– Make surface component (protein A)
– Binds to IgG molecules by the wrong end (Fc region)
? Cannot act as opsonins because Fc region not free to
bind to Fc receptors on phagocytic cells
? Not known if antiphagocytic defense is relevant to
disease process
Lecture 8 BIOL 533 18
Subversion of Phagocytosis
? Survival inside phagocytes
– Escape into cytoplasm
? Rickettsia (Rocky Mountain Spotted Fever) or
trypanosomes of Chagas’ disease cross membrane
of phagosome to enter cytoplasm
– Since lysosomes do not secrete contents into cytoplasm,
organism is safe
– How they enter cytoplasm is not known for certain
? Possess surface-bound phospholipase,which may
weaken membrane
Lecture 8 BIOL 533 19
Subversion of Phagocytosis
? Survival inside phagocytes,continued
– Inhibition of lysosome and phagosome fusion
– Examples—bacteria that cause,
? Tuberculosis
? Psittacosis
? Legionnaire’s disease
Lecture 8 BIOL 533 20
Subversion of Phagocytosis
– Mechanism of tuberculosis
? Induced by complex glycolipids (sulfatides)—not
certain
? Facts,
– Inhibition must be due to modification of phagosome
membrane
– Microorganism might contribute by compounds secreted
or present on the surface
Lecture 8 BIOL 533 21
Subversion of Phagocytosis
? Survival inside phagocytes,continued
– Resistance to lysosomal enzymes—survive in
phagolysosome (pH as low as 4)
? Leishmania (protozoa)—resistance may be due to,
– Resistant cell surfaces
– Excretion of enzyme inhibitors
Lecture 8 BIOL 533 22
Subversion of Phagocytosis
? Survival inside phagocytes,continued
– Inhibition of phagocyte’s oxidative pathway
? Bacillus of Legionnaire’s disease
– Inhibits hexose-monophosphate shunt and oxygen
consumption in neutrophils
? Reduces respiratory burst for killing microbes
? Staphylococci—produces catalase that degrades
hydrogen peroxide necessary for oxidative killing
Lecture 8 BIOL 533 23
Subversion of Phagocytosis
? Survival inside phagocytes,continued
– Antibody effects,host counters parasite
? Sometimes help host guard against microbial
survival measures
– Antibodies do not prevent entry into cells,but inhibit
subsequent effects
? Rickettsia coated with antibody cannot pass through
membrane into cytoplasm
? Antibodies against Legionnella prevent inhibition of
phagolysosomal fusion
Lecture 8 BIOL 533 24
Subversion of Immune Response
? Immunosuppression,general aspects
– Host becomes susceptible to other infections
and survival probability is lessened
Lecture 8 BIOL 533 25
Subversion of Immune Response
? AIDS—infects T4 inducer-helper
lymphocytes
– Depletion of cells leads to collapse of immune
system
? Reduction in circulating lymphocytes
? Impaired delayed hypersensitivity
? Defective responses of T cells to Ag
? Reduction in T-cell numbers cytotoxic for tumor
cells and virus infected cells
Lecture 8 BIOL 533 26
Subversion of Immune Response
– B cell function is also impaired
? Reduced production of specific Ig
? Increased chaotic production of nonspecific Ig
Lecture 8 BIOL 533 27
Subversion of Immune Response
? Other immunosuppressive viruses,
Measles
– Tuberculosis more common after widespread
measles outbreaks
– Infected T cells in vitro do not die
? Lose certain functions,including ability to mount
delayed hypersensitivity response
Lecture 8 BIOL 533 28
Subversion of Immune Response
– Infected B cells in vitro
? Stop synthesizing and releasing Ig
– Primary effect on B cells
? Not secondary to action of virus on T cells or
macrophage
Lecture 8 BIOL 533 29
Subversion of Immune Response
? Other immunosuppressive viruses,
Hepatitis B and influenza
– Impair function of lymphoid cells without
causing major structural damage
? Immune suppression as a result of
inhibition of synthesis of lymphokines
– Leishmanias (protozoa)
Lecture 8 BIOL 533 30
Subversion of Immune Response
– Leishmanias (protozoa)—when grown in
macrophage
? Suppress secretion of interleukin-1
– Important for initiating series of inflammatory and
immunological reactions important for the eradication of
the organism
– Also explains T cell unresponsiveness
? Suppresses capacity of macrophage to make class I
and class II products of major histocompatibility
locus (MHC)
? Potential for marked suppression of cell-mediated
immunity
Lecture 8 BIOL 533 31
Subversion of Immune Response
? Final thoughts
– Infection of lymphocytes is not immuno-
suppressive in nature
? Large number of organisms infect lymphoreticular
tissues,but do not cause global disturbances to
host immunity
– Bacteria that cause typhoid fever or brucellosis live in
lymph nodes for long period of time
? Do not induce noticeable immune suppression
Lecture 8 BIOL 533 32
Subversion of Immune Response
? Frequent changing of antigenic coats
(antigenic variation)
– Examples of bacteria,viruses,and protozoa
? Trypanosomes (protozoa)
? Gonococci
? Borrelia (recurrent fever)
? Influenza viruses
Lecture 8 BIOL 533 33
Subversion of Immune Response
? Trypanosoma brucei
(causative agent of sleeping sickness)
– Infects blood of interstitial fluids of animals
and man
? Exposed to circulating Ab
Lecture 8 BIOL 533 34
Subversion of Immune Response
? Trypanosoma brucei,continued
– Covered with thick protein coat (variable
surface glycoprotein)
? Undergoes antigenic shifts during infection
– Have several hundred genes that encode different
antigens,but express only one at a time
Lecture 8 BIOL 533 35
Subversion of Immune Response
? Trypanosoma brucei,continued
? When antibodies against one type are made,
– Number of parasites in blood drops
– Soon replaced by new antigenic type
– Can be many successive waves of antigenic changes in a
single host
? Protective immunity does not function well
Lecture 8 BIOL 533 36
Subversion of Immune Response
? Gonococcus and its adhesin
– Periodic change in
? Pilin (protein fimbriae; attach to cells)
? Major outer membrane proteins
Lecture 8 BIOL 533 37
Subversion of Immune Response
? Antigenic variation among influenza
viruses—major obstacle to effective
vaccine (year after year)
– Definitions
? Antigenic drift—minor changes that occur every
2 to 3 years
? Antigenic shift—major changes that occur about
every 10 years
Lecture 8 BIOL 533 38
Subversion of Immune Response
? Antigenic variation,continued
– Mechanism involves two proteins
? Hemagglutinin-binds to cell receptors
? Neuraminidase-changes receptors
Lecture 8 BIOL 533 39
Subversion of Immune Response
? Proteolysis of antibodies
– Make extracellular proteases that inactivate
secretory IgA antibody (major Ab type on
human mucosal surfaces; subclasses I and II)
? Cleave only subclass I at hinge region to leave
complete by inactive peptide fragments
– Examples,
? Gonococci,meningococci,Haemophilus influenzae,
and some pathogenic dental streptococci
Lecture 8 BIOL 533 40
Subversion of Immune Response
? Proteolysis of antibodies,continued
– Specificity of IgA1 proteases from different
bacteria
? Highly specific for subclass I
? Biochemical and genetic differences that suggest
property evolved independently
– Presence in fluids and tissues
? Active form in infected tissues and fluids
Lecture 8 BIOL 533 41
Subversion of Immune Response
? Proteolysis of antibodies,continued
– Possible relationship to pathogenicity;
suggested,not proven
? Nonpathogeic relatives lack these proteases
– Fabulation (cleavage with Fab fragment
attached)
? Ag unavailable for binding with intact antibody
molecules
? May serve to protect some organisms against Ab
Lecture 8 BIOL 533 42
Subversion of Immune Response
? Other viral survival strategies,
general aspects
– Chronic infection—evade host defenses longer
Lecture 8 BIOL 533 43
Subversion of Immune Response
? Herpes infection
– Do not usually enter extracellular fluid,but
pass among cells through cytoplasmic bridges
– Can also be latent (reside within nerve cells
but do not multiply)
? In these circumstances,not affect by antibodies,
cell-mediated immunity,or interferon
? Survive for long periods of time,then later
reactivate (perhaps when defenses are lower)
Lecture 8 BIOL 533 44
Lecture 8
? Questions?
? Comments?
? Assignments..,
