Host-Pathogen Interactions

Symbiosis Commensual Mutualistic Parasitic

Normal microbiota DYNAMIC! Resident vs transient Protective functions: – Block attachment – Consume nutrients – Produce antibiotics

Normal microbiota Other beneficial functions? – Digestion and absorption of nutrients – Production of vitamins and fatty acids – Stimulation and regulation of the immune system

Normal microbiota Can also become opportunistic pathogens – Injury to normal mucosal or skin surfaces – Antibiotic use

Colonization 2 possible outcomes: – Symbiosis – commensual or mutualistic – Infection = parasitic symbiosis Infection: – Subclinical vs infectious disease – Primary vs secondary infection – Opportunist vs primary pathogen

What determines outcome of infection? Host defenses Predisposing infection Pathogenicity Infectious dose

Establishing infection Adherence – Pili, capsules, cell wall components – binding to receptors on host cells Colonization – Compete for iron, nutrients – Resist opsonization – Resist resident microbiota’s antimicrobials Invasion/translocation – Type III secretion systems – Directed uptake – Exploitation of antigen sampling processes

Type III Secretion System Pore-forming protein inserted in host cell membrane = type III translocon aka“injectisome” – bacterial proteins = virulence factors are injected into host cell cytoplasm

Exploitation of antigen sampling processes

Avoiding host defenses Hide in cells Avoid complement- mediated killing Avoid phagocytosis Survive in phagocytes Avoid antibodies

Avoiding phagocytosis: Don’t get seen, don’t get recognized or don’t get caught – C5a peptidase – C3b binding sites: capsules, M protein – Membrane damaging toxins – Fc receptors

Surviving in phagocytes Escape from phagosome Block fusion of the phagosome and lysosome Survive in the phagolysosome

Avoiding antibodies IgA protease Antigenic variation Molecular mimicry

Disease: damage to host Damage caused by bacterial exotoxins – Proteins synthesized by bacteria – Highly specific interactions with host cells – Highly immunogenic Toxoids Antitoxin

Disease: damage to host Damage caused by the immune response – Inflammation – Immune complex deposition – Cross-reaction of antibodies with host tissues

Types of exotoxins: functional/target tissue classification Enterotoxins: bind to receptors on enterocytes; alter function but do not kill target cells Neurotoxins: target cells in peripheral nervous system, interfere with nerve signal transduction (↑ or ↓) Cytotoxins: receptors may be present on a single cell type or many cell types; toxin is lethal to target cells

Types of exotoxins: structural/mechanistic classification A-B toxins – Inhibit protein synthesis – Interfere with cell signaling systems Membrane- damaging toxins Superantigens

Diseases caused by A-B type exotoxins Cytotoxins – Anthrax: Bacillus anthracis – lethal toxin, edema toxin (A-B toxins) – Pertussus (whooping cough): Bordetella pertussis – pertussis toxin (A-B toxin) – Diphtheria: Corynebacterium diphtheriae – diphtheria toxin – Hemolytic uremic syndrome: Escherichia coli O157:H7 – Bacillary dysentery: Shigella dysenteriae (and less severe forms caused by other Shigella species)

Diseases caused by A-B type exotoxins Enterotoxins – Cholera: Vibrio cholerae – Traveler’s diarrhea: many possible etiologies, but most cases are caused by enterotoxigenic strains of Escherichia coli

Diseases caused by A-B type exotoxins Neurotoxins – Botulism: – Clostridium botulinum – Tetanus: – Clostridium tetani

Diseases caused by membrane-damaging exotoxins Gas gangrene: Clostridium perfingens Strep throat: Streptococcus pyogenes Abscesses – pyogenic bacteria (many)

Diseases caused by superantigens Some foodborne intoxications Toxic shock syndromes Autoimmune disease, i.e. rheumatoid arthritis

Anthrax Etiologic agent: Bacillus anthracis Toxins: edema toxin (protective antigen + edema factor) and lethal toxin (protective antigen + lethal factor) Toxin type: A-B toxins B component of both = protective antigen A component of edema toxin = edema factor A component of lethal toxin = lethal factor Target cell: many cells, many mammals – receptor =highly conserved

Diphtheria Etiologic agent: Corynebacterium diphtheriae Toxin: diphtheria toxin Toxin type: A-B toxin Cell type with receptor: many human cells Toxin is encoded by a bacterial phage (virus)

Botulism Etiologic agent: Clostridium botulinum = G+ rod; obligate anaerobe; widespread Toxin: BoNTs Toxin type: A-B toxins Target cell: motor nerves at NM junction – people and dogs most suscecptible Effect: blocks release of acetylcholine = excitatory neurotransmitter → no nerve signal transmission → flaccid paralysis

Tetanus Etiologic agent: Clostridium tetani = G+ rod; obligate anaerobe; widespread Toxin: TeTx Toxin type: A-B toxin Target cell: spinal cord – receptors are highly conserved but susceptibiltiy is variable; people & horses most susceptible Effect: blocks release of GABA and glycine = inhibitory neurotransmitters → spastic or rigid paralysis

Cholera Etiologic agent: Vibrio cholerae Toxin: cholera toxin Toxin type: A-B toxin Cell type with receptor: human enterocytes Effect: secretion of Cl - ; H 2 O and Na + follow = severe watery diarrhea

Superantigens Bind directly to the outside of MHC-II molecules and the TCRs Activate many T4- lymphocytes A specific TCR is not required for activation.

Endotoxin Non-specific: triggers innate immune response; no antibody to endotoxin is produced Effect on cells is widespread A component of all (and only) Gram-negative bacteria

Viral pathogenesis Binding to host cells Invasion of host cells Interference with host defenses Regulation of apoptosis