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Medical Microbiology. Microbial Interference with Host Defenses. BIOL 533 Lecture 8. Overall Strategies. Defense against complement Subversion of phagocytosis Subversion of immune responses. General Aspects. Pathogen finds itself in hostile territory

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overall strategies
Overall Strategies
  • Defense against complement
  • Subversion of phagocytosis
  • Subversion of immune responses
general aspects
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
general aspects4
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
defense against complement
Defense Against Complement
  • Overall strategies
    • Inhibit complement activation
      • Mask activating substances
        • Capsule
        • IgA antibodies
    • Cover up target of complement membrane attack complex
defense against complement6
Defense Against Complement
  • Overall strategies, continued
    • Appropriate inhibitor to activation to surface
    • Inactivate complement chemotaxin C5a
prevent complement activation
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
prevent complement activation8
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
prevent complement activation9
Prevent Complement Activation
  • Cost of having capsule— antigenic
    • Elicits activation by primary pathway
      • Defend better against immediate defenses than later ones
prevent complement activation10
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
subversion of phagocytosis
Subversion of Phagocytosis
  • Overall strategies
    • Inhibition of phagocyte recruitment
    • Microbial killing of phagocytes
    • Escape of ingestion
subversion of phagocytosis12
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)
subversion of phagocytosis13
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
subversion of phagocytosis14
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
subversion of phagocytosis15
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
subversion of phagocytosis16
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
subversion of phagocytosis17
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
subversion of phagocytosis18
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
subversion of phagocytosis19
Subversion of Phagocytosis
  • Survival inside phagocytes, continued
    • Inhibition of lysosome and phagosome fusion
    • Examples—bacteria that cause:
      • Tuberculosis
      • Psittacosis
      • Legionnaire’s disease
subversion of phagocytosis20
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
subversion of phagocytosis21
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
subversion of phagocytosis22
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
subversion of phagocytosis23
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
subversion of immune response
Subversion of Immune Response
  • Immunosuppression: general aspects
    • Host becomes susceptible to other infections and survival probability is lessened
subversion of immune response25
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
subversion of immune response26
Subversion of Immune Response
  • B cell function is also impaired
    • Reduced production of specific Ig
    • Increased chaotic production of nonspecific Ig
subversion of immune response27
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
subversion of immune response28
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
subversion of immune response29
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)
subversion of immune response30
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
subversion of immune response31
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
subversion of immune response32
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
subversion of immune response33
Subversion of Immune Response
  • Trypanosoma brucei (causative agent of sleeping sickness)
    • Infects blood of interstitial fluids of animals and man
      • Exposed to circulating Ab
subversion of immune response34
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
subversion of immune response35
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
subversion of immune response36
Subversion of Immune Response
  • Gonococcus and its adhesin
    • Periodic change in
      • Pilin (protein fimbriae; attach to cells)
      • Major outer membrane proteins
subversion of immune response37
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
subversion of immune response38
Subversion of Immune Response
  • Antigenic variation, continued
    • Mechanism involves two proteins
      • Hemagglutinin-binds to cell receptors
      • Neuraminidase-changes receptors
subversion of immune response39
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
subversion of immune response40
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
subversion of immune response41
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
subversion of immune response42
Subversion of Immune Response
  • Other viral survival strategies: general aspects
    • Chronic infection—evade host defenses longer
subversion of immune response43
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
Lecture 8
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