Transcript bacterial Pathogenesis

Bacterial Pathogenesis
Infectious disease - cycle of biological
interactions. Most interventions in preventing
infectious disease do not directly involve the
physician. By understanding the complete
process of bacterial pathogenesis, you will be
better equipped to aid in intervention and
prevention at the numerous steps other than by
administering antibiotics or vaccines.
A. Definitions and concepts
1. Disease - damage caused by presence of microorganisms or
their products
2. Infection - presence of bacteria in or on the body (note that
some use this term synonymously with disease)
3. Colonization - presence of microorganisms at a site (some
infer no damage)
4. Carrier state - inapparent infection (colonization) with a
pathogen
5. Pathogen - any organism that has the potential to cause
disease
6. Overt (primary) vs. Opportunistic pathogens
a. overt pathogens have a high probability of causing
disease in an otherwise healthy host
b. opportunistic pathogens have a low probability and
usually require a debilitated or compromised host
B. Normal flora
1. Definition - frequently found on or within the body of
healthy persons
2. They can cause disease under the right conditions
(endogenous infection/disease)
3. Some tissues, organs are dense with normal flora, others are
normally sterile
a. colonized sites
i. alimentary/intestinal tract
ii. upper respiratory tract
iii. distal genitourinary tract
iv. skin
b. normally sterile sites
i. blood
ii. CSF
iii. interstitial fluid and spaces
iv. lymph
4.
a.
b.
c.
Normal flora and disease
breach of tissues/barriers
endocarditis with oral streptococci
peritonitis after bowel trauma
5.
a.
b.
c.
Protective effects of normal flora
priming immune system - specific (natural antibodies)
exclusion of pathogens from colonized surfaces (crowded bar)
production of nutrients - vitamin K
6. Considerations of normal flora in medicine
a. Manipulations that enable normal flora to cause disease
(surgery, chemotherapy, antibiotic use)
b. presence of bacteria doesn't always mean disease is
ongoing
C. Functions/stages of pathogens/disease
1. encounter
2. entry
3. spread (+/-)
4. multiplication
5. evasion of host defenses
6. damage
7. move to new host (+/-)
1. Encounter
a. Exogenous vs. endogenous infection and normal flora
b. sources: food, water, air, body fluids (sex, etc.), insects,
animals, fomites (things)
c. Is there a reservoir in other animals or in the environment?
d. Can we eliminate the source or reservoir?
2. Entry - where in/on the body do we initially contact the
bacteria
a. surface of skin
b. mucosal membrane open to outside
i. ingestion
ii. inhalation
iii. sex
c. direct inoculation (trauma, bite, injection, surgery)
d. virulence function - adherence
i. mucosal surface with moving fluid, bacteria must stick or be
washed away
ii. specific ligand-receptor interactions - not glue
iii. virulence factors
► structures: pili/fimbriae, fibrillae
► surface proteins
► extracellular matrix polysaccharide and
lipoteichoic
acid of oral streptococci
3. Spread - movement from surface through tissues and
body
a. not all bacteria spread to cause disease
b. bacteria cannot penetrate intact skin
c. mucosal surface is usually first barrier
d. virulence functions
i. cellular invasion - invading into host cells - intracellular
► professional phagocytes (macrophages and PMN) by
phagocytosis
► non-professional phagocytes (epithelial cells, endothelial
cells, hepatocytes, etc.) - bacterial mediated endocytosis
resulting in a phagosome/endosome (can involve type III
secreted proteins - injected into host cell affecting actin
polymerization)
► some bacteria escape the phagosome into the cytoplasm
ii. tissue invasion - through tissues, either through cell or
between cells
► degrade extracellular matrix
► disrupt tight junctions
e. use of host cells to move through blood or lymph (intracellular
pathogens)
4. Multiplication
a. don’t encounter enough bacteria to cause damage and disease
without their increase in number in your body
b. variety of nutritional environments in the body
i. intestinal lumen, blood, urine
ii. intracellular bacteria- cytoplasm vs. phagolysosome
c. inoculum size and disease
► threshold for bacterial inoculum to replicate to high enough
numbers to cause disease
d. incubation period
► how long it takes the inoculum to result in clinical damage
e. acquisition of Fe from transferrin, lactoferrin, or other Febinding proteins (e.g. siderophores as virulence factors)
5. Evasion of host defenses
► consider where the bacteria are and which defenses they
will encounter
a. Complement - beyond mucosal surface
i. functions
►opsonization - C3b
►lysis of gram-negatives - C5-9 (Membrane Attack Complex
[MAC])
►inflammation - C3a, C5a
ii. virulence mechanisms for evasion
►do not bind and/or activate complement - polysaccharide
capsules
► cause inhibition of activation and amplification cascade bind factor H (M protein of streptococci)
►keep activation away from membrane - smooth LPS
►degrade complement - secrete proteases
b. Phagocytes - beyond mucosal surface
i. EXTRACELLULAR vs. INTRACELLULAR pathogens
ii. extracellular antiphagocytic functions
►inhibit recruitment - inhibit complement, cytokines
►kill the phagocytes - toxins
►prevent phagocytosis - prevent opsonization, prevent
binding (carbohydrate capsules)
iii. intracellular pathogen functions
►inhibit phagosome-lysosome fusion
►escape phago(lyso)some into cytoplasm
►inhibit oxidative burst
►resist antimicrobial functions
c. Antibodies
i. antigenic mimicry - surface components look like host
►polysialic acid capsule of Neisseria meningitidis
ii. antigenic cloaking - bind host proteins to bacterial surface
►protein A of Staphylococcus aureus
iii. antigenic variation - change antigenic composition
►pili of Neisseria gonorrhoea
iv. antigenic variety -numerous serological types among strains
in the world (each strain is antigenically stable)
►M protein of Streptococcus pyogenes
v. degrade antibodies
►IgAse of Haemophilus influenzae
d. Cell-mediated immunity
►alter host response from cell-mediated (Th1) to antibody (Th2)
response - Mycobacterium leprae
6. Damage
a. cytotoxicity (kill host cells: necrosis vs. apoptosis
[programmed cell death])
i. from outside - toxins
ii. from inside - intracellular growth
iii. apoptosis - type III secreted (injected) proteins
b. pharmacology/physiology (alter host cell function) toxins
c. host immune/inflammatory response (host causes damage
to itself)
i. nonspecific: inflammation, abscess, cytokines
ii. specific immune response: antibodies (Rheumatic fever Streptococcus pyogenes), cell-mediated (Reiter’s syndrome bacterial heat shock proteins)
d. Toxins
i. Endotoxin vs. Exotoxin
ii. Endotoxin (LPS) from gram-negatives only
►damage is caused by host through macrophages producing
cytokines (TNF-α, IL-1, IL-6)
iii. Exotoxins (proteins)
►several have A-B motif - A=active portion, B=binding portion
►lytic (lyse host cells - creating pores or lipase activity)
►cytotoxic (kill cells by altering functions, e.g., protein
synthesis)
►pharmacological (alter host cell function, e.g., cAMP levels)
►extracellular enzymes (degrade extracellular matrix, e.g.,
DNAse, hyaluronidase)
►superantigens (stimulate host T cell responses in antigenindependent manner (binding to Vβ of T cell receptor) resulting
in cytokine cascade - similar to endotoxin)
►type III secreted proteins (injected into host cell) - induce
apoptosis, affect actin polymerization
7. Spread to new host
a. completes the cycle to lead to new encounter - step 1
b. not all pathogens spread to new human host (e.g.,
Legionella pneumophila)
c. not all pathogens are contagious - humans may be dead
end hosts
d. most bacterial pathogens are contagious - some examples
of how:
i. fecal-oral
ii. sexually transmitted
iii. droplet spread (respiration)
iv. skin-skin
v. fomite
vi. vertical - in utero, at birth