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 complementmediated 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
• Membranedamaging 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-;
H2O and Na+ follow =
severe watery
diarrhea
Superantigens
• Bind directly to the
outside of MHC-II
molecules and the TCRs
• Activate many T4lymphocytes
• 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