Lecture 9&10: Pathogenesis

Question 1

Obligate intracell bacteria

Answer 1

• Chlamydia spp
• Mycobacterium leprae
• Rickettsia spp

Question 2

Facultative intracell bacteria

Answer 2

• Brucella spp.
• Bordetella pertussis
• E, coli (some)
• GBS
• Legionella spp.
• Listeria monocytogenes
• Neisseria gonorrhoeae (meningitides)
• Salmonella spp.
• Shigella spp.
• Yersinia spp.

Question 3

2nd step of pathogenesis: attachment/adherence

Answer 3

• necessary for colonization (particular site)

Requires:

• host cell receptors
• microbial surface components (adhesins/ligands)

Defined by:

• ability to adhere (interaction)
• favourable environment (pH, nutrients, etc…)
• presence/absence of normal microflora (commensals)

Question 4

Tissue tropism/Specificity

Answer 4

• Strep. mutans: enamel (dental plaque)
• Strep salviarius: tongue epithelial cells
• Campylobacter spp.: intestinal mucosa
• B. pertussis: upper respiratory tract epithelium
• S. aureus: nasal membranes

Question 5

Adhesins

Answer 5

Pili & fimbriae (bacteria)

• may be coordinated w/ othr virulence factors: cholera toxin, Toxin Coregulated Pilus A (TcpA)
• Ex. in E. coli Type I pili (ligand) interacts w/ GM1 ganglioside in intestinal epithelium (receptor)

Afimbrial adhesins (bacteria & fungi)

• Lipoteichoic acid
• LPS or LOS
• Mannans in C. albicans

Question 6

3rd step of pathogenesis: Invasion

Answer 6

Invasins (bacterial & fungal)

• interact w/ specific cell receptors, induce endocytosis

Host cell cytoskeleton rearrangement

• Internalin A: usually injected into host cell -> membrane ruffling
• Ex. L. monocytogenes, Shigella

Question 7

4th step of pathogenesis: evasion of immune response

Answer 7

• capsules (complement & phagcytic killing): Ex. H. influenzae produce polyribose ribitol phosphate
• complement-binding proteins (complement): Ex1. P. aeruginosa produce Elastase inactivating C3b & C5a; Ex2. S. pyogenes produce C5a peptidase which degrades C5a and inhibits phagocyte chemotaxis
• proteases (complement)
• host cell mimicry (complement): Ex. Strep. pyogenes produce Hyaluronic acid, Ex2. N. meningitidis produce capsule w/ sialic acid and mimics host cells
• Type III secretion systems (phagocytic killing)
• intracell parasitism (phagocytic killing)
• interfere w/ MHC function and Ag processing
• Ig-binding/inactivating proteins
• Antigenic variation

Question 8

Evasion of phagocyte destruction

Answer 8

1. inhibit phagosome-lysosome fusion (L. pneumophilia)
2. escape phagolysosome (L. monocytogenes)
3. inactivate oxygen radicals or degradative enzymes (S. aureus)
4. production of surface components (H. capsulatum)

Question 9

Evasion of macrophages & leukocytes

Answer 9

• solution: toxins to kill macrophages & leukocytes
• leukocidins -> kill neutrophils and macrophages
• alters phospholipid metabolism by ADP-ribosylation of a protein controllling phosphatidylinositol -> disruption of cell activities
• typical produces = highly invasive bacteria
• Panton-valentine Leukocidin (phage-encoded) produced by Staphylococci

Question 10

Evasion mechanisms

Answer 10

• engulfing
• degradation
• toxins to prevent antigen processing and presentation
• evasion of Ab
• Ig-binding/inactivating proteins: Ex. bacterial IgA proteases
• antigenic/phase variation
• biofilms: general evasion strategy
• Ex. catheter have single species biofilms whereas dental plaques are multipe species
• attachment upregulates genes and growth rates
• biofilms more resistant to antibiotics

Question 11

Bacterial strategies for iron sequestration

Answer 11

1. specific surface receptors: grab host iron (chelators); Ex. Neisseria sp.
2. Secretion siderophores: complex with iron; Ex. E. coli, K. pneumoniae

Question 12

Infection: direct damage mechanisms

Answer 12

1. Degradative enzymes

• Hyaluronidase: breaks down hyaluronic acid of CT
• Streptokinase: breaks down fibrin clots
• Collagenase

2. Physical growth thru tissues: Aspergillosis unknown mechanism of damage
3. Toxic structure: LPS
4. Toxins

Question 13

Fungal toxins

Answer 13

• A. fumigatus: gliotoxin; inhibits macrophage phagocytosis, T-cell activation & induces apoptosis
• A. flavus: Aflatoxin; carcinogenic

Question 14

Bacterial toxins

Answer 14

Exotoxins

• protein
• secreted into extracell environment
• specificity varies
• very potent
• Gram +ve and -ve
• Toxicity: minute amounts
• Effects on body: T-cell activation
• Toxoid formation
• no fever
• secreted from live cells

Endotoxins

• only acts as toxin under certain circumstances
• LPS of Gram -ve
• toxicity: high doses
• systemic fever
• cell lysis for release

Question 15

Examples of Exotoxins

Answer 15

Excessive watery diarrhea

• V. cholera -> cholera toxin
• Enterotoxigenic E. coli -> LT/ST Enterotoxin

Flaccid Muscle paralysis: C. botulinum

Rigid muscle paralysis: C. tetani

Membrane disruption: C. perfringens -> cytotoxin

Shock: Staph aureus -> TSST-1

Pseudomembrane, systemic effects: Corynebacterium diphtheriae

Question 16

Classes of Exotoxins

Answer 16

• Class I: membrane-acting, Ex. TSST-1 & SPE (superantigens so divert/confuse host defenses) interacts directly w T-cells & APC
• II: membrane-damaging, Ex. phospholipases, lecithinase (C. perfringens), pore formation (Listeriolysin O)
• III: intracell, Ex. Diphtheria & cholera (ADP-ribosyltransferase), tetanus (GABA) & botulinum (ACh) (both Zinc metalloendoprotease)

Question 17

Most common toxin structures

Answer 17

• AB: single gene encodes for single peptide; post-transcriptionally modified to A&B which are covalently linked; Ex. diphtheria toxin
• A5B (5 rings): 2 genes encode A&B subunits, non-covalently associated in stable complex; Ex. cholera toxin, ETEC Enterotoxin

Question 18

Toxin-based vaccines

Answer 18

• DTaP
• tetanus
• inactivated by heat or chemicals

Question 19

Dissemination

Answer 19

• direct: Aspergillus (growth thru tissues)
• CSF: H. influenzae
• blood: B. anthracis (plasma), Listeria (mononuclear cells)
• lymphatics: Yersiniapestis

Question 20

Transmission

Answer 20

• Mycobacterium tuberculosis: highly transmissible b/c requires low effective dose