Microbial Interference with Host Defenses

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Microbial Interference with Host Defenses
Medical Microbiology

• BIOL 533
• Lecture 8

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Overall Strategies

• Defense against complement
• Subversion of phagocytosis
• Subversion of immune responses

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General Aspects

• Pathogen finds itself in hostile territory
• Host fights back and usuallybut not alwayswins
• Hosts defenses are interrelated and so are
  organisms countermeasures

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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

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Defense Against Complement

• Overall strategies
• Inhibit complement activation
• Mask activating substances
• Capsule
• IgA antibodies
• Cover up target of complement membrane attack
  complex

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Defense Against Complement

• Overall strategies, continued
• Appropriate inhibitor to activation to surface
• Inactivate complement chemotaxin C5a

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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

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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

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Prevent Complement Activation

• Cost of having capsule antigenic
• Elicits activation by primary pathway
• Defend better against immediate defenses than
  later ones

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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

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Subversion of Phagocytosis

• Overall strategies
• Inhibition of phagocyte recruitment
• Microbial killing of phagocytes
• Escape of ingestion

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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)

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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

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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

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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

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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

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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

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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

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Subversion of Phagocytosis

• Survival inside phagocytes, continued
• Inhibition of lysosome and phagosome fusion
• Examplesbacteria that cause
• Tuberculosis
• Psittacosis
• Legionnaires disease

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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

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Subversion of Phagocytosis

• Survival inside phagocytes, continued
• Resistance to lysosomal enzymessurvive in
  phagolysosome (pH as low as 4)
• Leishmania (protozoa)resistance may be due to
• Resistant cell surfaces
• Excretion of enzyme inhibitors

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Subversion of Phagocytosis

• Survival inside phagocytes, continued
• Inhibition of phagocytes oxidative pathway
• Bacillus of Legionnaires disease
• Inhibits hexose-monophosphate shunt and oxygen
  consumption in neutrophils
• Reduces respiratory burst for killing microbes
• Staphylococciproduces catalase that degrades
  hydrogen peroxide necessary for oxidative killing

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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

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Subversion of Immune Response

• Immunosuppression general aspects
• Host becomes susceptible to other infections and
  survival probability is lessened

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Subversion of Immune Response

• AIDSinfects 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

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Subversion of Immune Response

• B cell function is also impaired
• Reduced production of specific Ig
• Increased chaotic production of nonspecific Ig

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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

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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

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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)

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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

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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

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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

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Subversion of Immune Response

• Trypanosoma brucei (causative agent of
  sleeping sickness)
• Infects blood of interstitial fluids of animals
  and man
• Exposed to circulating Ab

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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

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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

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Subversion of Immune Response

• Gonococcus and its adhesin
• Periodic change in
• Pilin (protein fimbriae attach to cells)
• Major outer membrane proteins

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Subversion of Immune Response

• Antigenic variation among influenza virusesmajor
  obstacle to effective vaccine (year after year)
• Definitions
• Antigenic driftminor changes that occur every
  2 to 3 years
• Antigenic shiftmajor changes that occur about
  every 10 years

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Subversion of Immune Response

• Antigenic variation, continued
• Mechanism involves two proteins
• Hemagglutinin-binds to cell receptors
• Neuraminidase-changes receptors

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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

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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

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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

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Subversion of Immune Response

• Other viral survival strategies general
  aspects
• Chronic infectionevade host defenses longer

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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)

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Lecture 8

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