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 products2. 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 disease6. 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 flora1. Definition - frequently found on or within the body of healthy persons2. 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 sitesi. alimentary/intestinal tractii. upper respiratory tractiii. distal genitourinary tractiv. skin

b. normally sterile sitesi. bloodii. CSFiii. interstitial fluid and spacesiv. lymph

4. Normal flora and diseasea. breach of tissues/barriersb. endocarditis with oral streptococcic. peritonitis after bowel trauma

5. Protective effects of normal floraa. priming immune system - specific (natural antibodies) b. exclusion of pathogens from colonized surfaces (crowded bar)c. production of nutrients - vitamin K

6. Considerations of normal flora in medicinea. 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. encounter2. entry3. spread (+/-)4. multiplication5. evasion of host defenses6. damage7. 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 bacteriaa. surface of skinb. mucosal membrane open to outside

i. ingestionii. inhalationiii. 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 glueiii. 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 bodya. not all bacteria spread to cause diseaseb. bacteria cannot penetrate intact skinc. mucosal surface is usually first barrierd. 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 bodyi. intestinal lumen, blood, urineii. 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 Fe-binding 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 surfacei. 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 surfacei. 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. Antibodiesi. antigenic mimicry - surface components look like host ►polysialic acid capsule of Neisseria meningitidisii. antigenic cloaking - bind host proteins to bacterial surface ►protein A of Staphylococcus aureusiii. antigenic variation - change antigenic composition ►pili of Neisseria gonorrhoeaiv. antigenic variety -numerous serological types among strains in the world (each strain is antigenically stable) ►M protein of Streptococcus pyogenesv. degrade antibodies ►IgAse of Haemophilus influenzae

d. Cell-mediated immunity►alter host response from cell-mediated (Th1) to antibody (Th2) response - Mycobacterium leprae

6. Damagea. cytotoxicity (kill host cells: necrosis vs. apoptosis [programmed cell death])

i. from outside - toxinsii. from inside - intracellular growthiii. 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, cytokinesii. specific immune response: antibodies (Rheumatic fever -

Streptococcus pyogenes), cell-mediated (Reiter’s syndrome - bacterial heat shock proteins)

d. Toxinsi. Endotoxin vs. Exotoxinii. 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 antigen-independent 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 hosta. 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-oralii. sexually transmittediii. droplet spread (respiration)iv. skin-skinv. fomitevi. vertical - in utero, at birth