introduction to host microbe interactions l.
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Introduction to Host-Microbe Interactions. Normal Flora. More bacterial than human cells in the body provide some nutrients (vitamin K) stimulate immune system, immunity can be cross-reactive against certain pathogens

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Introduction to Host-Microbe Interactions

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normal flora
Normal Flora
  • More bacterial than human cells in the body
    • provide some nutrients (vitamin K)
    • stimulate immune system, immunity can be cross-reactive against certain pathogens
    • Prevent colonization by potential pathogens (antibiotic-associated colitis, Clostridium difficile)
types of pathogens
Types of Pathogens
  • Primary Pathogens
    • Cause disease upon infection, not normally associated with host
      • Plague (Yersinia pestis), influenza virus
  • Opportunistic Pathogens
    • Cause disease under some circumstances, sometime members of normal flora
      • Pseudomonas, Candida albicans
progression of disease
Progression of Disease
  • Transmission: infectious dose from 10-106 organisms
  • Incubation period: few days (common cold)-weeks (hepatitis A)-months (rabies)
  • Convalescence:
    • Clearing (Strep throat, S. pyogenes)
    • Latency (Chicken pox, tuberculosis, cold sores)
koch s postulates
Koch’s Postulates
  • Proposed by Robert Koch
  • Conclude that a microbe causes a particular disease
  • Must fulfill four postulates
  • 1. Microorganism must be present in every case of the disease
  • 2. Organism must be grown in pure culture from disease hosts
  • 3. Produce the same disease from the pure culture
  • 4. Organism recovered from experimentally infected hosts
molecular postulates
Molecular Postulates
  • Describe virulence factors
  • Four postulates
  • 1. Virulence gene or its product must be present
  • 2. Virulence gene must transform a non-pathogen into a pathogen
  • 3. Virulence gene must be expressed during disease process
  • 4. Antibodies against gene products are protective
establishing an infection
Establishing an Infection
  • 1. Encounter:
    • fecal-oral (cholera)
    • human-human (tuberculosis)
    • animal-human (rabies)
    • vector-borne (plague, lyme disease)
    • environmental contact (anthrax)
establishing an infection10
Establishing an Infection
  • 2. Adherence
    • Prevents early clearance
    • Often bind host tissues via pili
    • Specificity can determine host range of pathogen
establishing an infection13
Establishing an Infection
  • 3. Colonization: multiplication and maintainance
    • Competition with normal flora
    • Resist:
      • bile
      • stomach acid
      • peristalsis
      • skin secretions
      • IgA (mucosal antibodies)
      • compete with host for iron
establishing an infection14
Establishing an Infection
  • 4. Molecule Delivery
    • Affects target cell structure and host response
invasion breaching anatomical barriers
Invasion:Breaching Anatomical Barriers
  • Find new niche with few competitors
  • Gain access to rich nutrient supply
  • 1. Skin: tough barrier, rely on wounds or insect vectors
  • 2. Crossing mucous membrane (e.g. intestinal epithelial cells)
zippering model of invasion
Zippering-model of invasion

Tight ligand-receptor interactions direct uptake

“one at a time” uptake

ruffling method of invasion
Ruffling method of invasion

General induced cellular response

Can lead to co-invasion of other bacteria in close proximity

m cell invasion
M cell Invasion
  • M cells are a portal to the immune system
  • Important site of “antigen sampling”
  • Some pathogens use phagocytic nature of M cells to access deeper tissues by transcytosis
avoiding the host defenses
Avoiding the Host Defenses
  • 1. Hiding within host cells
    • Avoid exposure to host antibodies if remain intracellular
    • Access to rich source of nutrients
cell to cell spreading
Cell-to-cell Spreading

Shigella and Listeria species lyse out of


-assemble actin at pole

-actin propels them into

neighboring cell

“convergent evolution”

“molecular mimicry”

avoiding the host defenses24
Avoiding the Host Defenses
  • 2. Avoiding complement killing
    • Complement factors in blood serum can assemble into MAC “membrane attach complex” that are bactericidal
    • C3b is first component of complex to bind
    • Some bacteria bind factors that regulate C3b activity, prevent MAC assembly
      • “serum-resistance”
avoiding the host defenses26
Avoiding the Host Defenses
  • 3. Avoiding phagocytosis
    • Innate immune cells engulf (phagocytose) and kill microorganisms with degradative enzymes
    • Block signaling molecule production or degrade them after production
      • C5a cleaved by C5a peptidase of Strep pyogenes (strep throat)
avoiding the host defenses28
Avoiding the Host Defenses
  • 3. Avoiding phagocytosis
    • Capsule production on surface of bacteria: capsule leads to C3b inactivation-”serum resistance”
    • M protein of Streptococcus: also inactivates C3b
    • Fc receptors: bind antibodies and orient dangerous end away from bacteria
      • Found in Streptococcus (Protein G) and Staphylococcus (Protein A)
survival strategies within phagocytes
Survival Strategies within Phagocytes
  • A niche without competitors
  • Phagosomal escape: lyse out of vacuole and grow in cytoplasm of host cell
    • Shigella and Listeria
survival strategies within phagocytes31
Survival Strategies within Phagocytes
  • Blocking lysosomal fusion: prevent delivery of degradative enzymes to bacterial compartment
    • Mycobacterium (tuberculosis)
    • Salmonella (food poisoning or typhoid fever)
    • Legionella (Legionnaire’s disease)
survival strategies within phagocytes33
Survival Strategies within Phagocytes
  • Surviving lysosomal fusion:
    • Coxiella
    • Legionella
avoiding antibodies
Avoiding Antibodies
  • 1. IgA protease: cleaves Ab’s found in mucosal secretions (Neisseria gonorrhoeae)
  • 2. Antigenic variation: turning pili On and Off, or switching to new pilus
  • 3. Mimicking the host: look like self-antigens
    • Streptococcus pyogenes has capsule of hyaluronic acid, also made by host tissues
damage to host disease
Damage to Host (Disease)
  • 1. Exotoxins
    • May require prior colonization (cholera)
    • May cause food poisoning even in absence of organism
      • Botulism or Staphylococcus aureus toxin
    • Immune system often target toxin for neutralizing Ab’s
      • Vaccine against toxin
    • A-B toxins: A is catalytic subunit, B binds host cells
damage to host disease38
Damage to Host (Disease)
  • 2. Membrane-damaging toxins
    • Hemolysins
      • Cause cell-lysis: Streptolysin O
    • Phospholipases
      • Cleave lipids in membranes: Clostridium perfringens
        • Gas gangrene
damage to host disease39
Damage to Host (Disease)
  • 3. Superantigens
    • Hyperstimulate the immune system
      • 1/5 T cells stimulated rather than 1/10,000
      • Fever, nausea, diarrhea, vomiting
    • Leads to shock
      • Organ failure, circulatory collapse
    • Cause of toxic shock syndrome (TSST)
      • Staphylococcus aureus and Streptococcus pyogenes
damage to host disease41
Damage to Host (Disease)
  • 4. Endotoxins (attached to cell)
    • LPS, in the outer leaflet of Gram negative bacteria
      • Lipid A is toxic if organisms enter bloodstream
        • Massive immune cell infiltration
        • Activation of coagulation
      • Intravenous fluids are screened for Lipid A
damage due to the immune system
Damage due to the Immune System
  • Inflammation: bacterial meningitis
    • Neisseria meningitis
  • Antigen-Ab complexes
    • Settle in kidney or joints
      • Glomerulonephritis from S. pyogenes
  • Cross-reactive Ab’s
    • Ab’s against pathogen may cross-react with host tissues
      • Accute rheumatic fever, complication of Strep throat