Transcript Document

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
– Prevent colonization by potential pathogens
(antibiotic-associated colitis, Clostridium
difficile)
Potential Colonization Sites
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
• 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
• 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
• Describe virulence factors
• Four postulates
• 1. Virulence gene or its product must be
present
• 2. Virulence gene must transform a nonpathogen into a pathogen
• 3. Virulence gene must be expressed
during disease process
• 4. Antibodies against gene products are
protective
Establishing an Infection
• 1. Encounter:
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fecal-oral (cholera)
human-human (tuberculosis)
animal-human (rabies)
vector-borne (plague, lyme disease)
environmental contact (anthrax)
Establishing an Infection
• 2. Adherence
– Prevents early clearance
– Often bind host tissues via pili
– Specificity can determine host range of
pathogen
Establishing an Infection
• 3. Colonization: multiplication and maintainance
– Competition with normal flora
– Resist:
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bile
stomach acid
peristalsis
skin secretions
IgA (mucosal antibodies)
compete with host for iron
Establishing an Infection
• 4. Molecule
Delivery
– Affects target
cell structure
and host
response
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
Tight ligand-receptor interactions direct uptake
“one at a time” uptake
Ruffling method of invasion
General induced
cellular response
Can lead to coinvasion of other
bacteria in close
proximity
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
• 1. Hiding within host cells
– Avoid exposure to host antibodies if remain
intracellular
– Access to rich source of nutrients
Cell-to-cell Spreading
Shigella and Listeria
species lyse out of
vacuole
-assemble actin at pole
-actin propels them into
neighboring cell
“convergent evolution”
“molecular mimicry”
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 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 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
• A niche without competitors
• Phagosomal escape: lyse out of vacuole and
grow in cytoplasm of host cell
– Shigella and Listeria
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 Phagocytes
• Surviving lysosomal fusion:
– Coxiella
– Legionella
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 selfantigens
– Streptococcus pyogenes has capsule of
hyaluronic acid, also made by host tissues
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 (Disease)
• 2. Membrane-damaging toxins
– Hemolysins
• Cause cell-lysis: Streptolysin O
– Phospholipases
• Cleave lipids in membranes: Clostridium perfringens
– Gas gangrene
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 (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
• 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