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

AnthraxEtiologic agent: Bacillus anthracisToxins: edema toxin (protective antigen + edema factor) and lethal toxin

(protective antigen + lethal factor)Toxin type: A-B toxins

B component of both = protective antigenA component of edema toxin = edema factorA component of lethal toxin = lethal factor

Target cell: many cells, many mammals – receptor =highly conserved

Diphtheria

Etiologic agent: Corynebacterium diphtheriae

Toxin: diphtheria toxinToxin type: A-B toxinCell type with receptor:

many human cellsToxin is encoded by a

bacterial phage (virus)

BotulismEtiologic agent: Clostridium

botulinum = G+ rod; obligate anaerobe; widespread

Toxin: BoNTsToxin type: A-B toxinsTarget cell: motor nerves at NM

junction – people and dogs most suscecptible

Effect: blocks release of acetylcholine = excitatory neurotransmitter → no nerve signal transmission → flaccid paralysis

TetanusEtiologic agent: Clostridium tetani =

G+ rod; obligate anaerobe; widespread

Toxin: TeTxToxin type: A-B toxinTarget 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

CholeraEtiologic agent: Vibrio

choleraeToxin: cholera toxinToxin type: A-B toxinCell type with receptor:

human enterocytesEffect: secretion of Cl-;

H2O 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