Pathogenesis Flashcards
Pathogenesis Concepts
Germ theory linked microbe and disease together
- Infectious disease: damage caused by the presence of microorganisms or their products
- Colonization: presence of microorganisms, not necessarily
result in diseases (ie. carrier state) - Virulence factors: Molecules that contribute to the ability of an organism to cause diseases, but not for growth.
Types of Pathogens
- Obligate pathogens: Only survive and replicate inside the host (e.g. Chlamydia trachomatis)
- Facultative pathogens: Capable of surviving outside the host. Cause disease when encounter the host (e.g. O157:H7 E. coli)
- Opportunistic pathogens: Normally benign, but can cause disease when the host is immunocompromised or
aged (Pseudomonas aeruginosa)
Koch’s Postulates
- The specific causative agent must associate with the disease.
- The disease organism must be isolated from the lesions of the infected case and grown in pure culture.
- The pure culture, inoculated into a susceptible animal, should reproduce the disease in the experimental host.
- The microbe must be re-isolated in pure culture from the experimentally infected animal.
Limitations of postulates
- The specific causative agent must associate with the disease. —> Assume a single etiological agent? Variation in host immunity? Dysbiosis of microbiota?
- The disease organism must be isolated from the lesions of the infected case and grown in pure culture. —> VBNC? Viruses?
- The pure culture, inoculated into a animal, should reproduce the disease in the experimental host. —> not susceptible?
- The microbe must be re-isolated in pure culture from the experimentally infected animal. —> How about treatments?
Prevent Colonisation
Control bacterial pathogen outgrow:
Lysozyme degrades cell wall peptidoglycan, low pH and dry skin, IgA, mucociliary clearance, sebum production, antimicrobial peptides, etc.
You produce 1.5L of mucus/day: Mucin -> ~50 to ~90% carbohydrates; water. Most pathogens never come close to the epithelial cells
Invading Host
- Penetration: internalize and cross the epithelial layer to obtain more nutrients
- Vector-borne infections: insects,
parasites - Fomites route: cuts, burn, surgeries…….
- Hijacking phagocytes and host epithelial cells
- Transcytosis of P. gingivalis
- Breaking tight junctions
Virulence factors affecting colonisation
- Pili (long) and fimbriae (short)
- Protein polymers that act as adhesins
- Gram negative bacteria—>anchor on OM
Gram positive bacteria—>anchor on peptidoglycan - Surface polysaccharides
- Capsular polysaccharides, exopolysaccharides, and others
- Other adhesins
- eg. M protein in Group A Streptococci (Streptococcus pyogenes) that adhere to CD46
Phagocytosis
innate immunity : phagocytosis
- Neutrophils
- Macrophages
- And others: e.g. Dendritic cells, Kupffer cells
Oxidative killing inside phagolysosomes ::
1. 2O2 + NADPH (NADPH oxidase)-> 2O2- + NADP +2H+(Superoxide dismutase) -> H2O2 -> HOCl + H2O(Myeloperoxidase,
H+ + Cl- (or some other anions))
-> OH.(Fe 3+ -> Fe 2+ : Fenton reaction)
Also contains nitric oxide, proteases, lipases, glycosidases, nucleases, lysozyme……….to name a few
Strategies to evade phagocytosis
- Evade detection by phagocytes
- Group A streptococci produce proteins that degrade cytokines: SpyCEP degrade IL-8 (neutrophil chemotactic factor)
- Chemotaxis inhibitory protein CHIP in Staphylococcus aureus binds to C5a receptor (chemoattractant for phagocytes)
- Block recognition and binding
- Capsular polysaccharides
- Kill phagocytes directly
- Toxins produced: pneumolysin, leukocidins, hemolysins
- Avoid targeting to the phagolysosomes
- Legionella pneumophila use Type IV secretion system to modulate host responses (e.g. stop fusion)
Host Detection
Host detection mechanisms: Toll-like
receptors (TLRs)
Complement System
Classical, lectin, and alternative pathways —> C3b deposition —> activation —> membrane attack complex (MAC) + inflammation
Opsonization
Opsonization (seasoning)
1. C3b binding on bacteria
2. C3b receptor on phagocytes
3. Phagocytosis
It can be difficult to “catch” the bacteria
strategies to evade complement
Strategies to evade complement
* Physically block binding
- Capsular polysaccharide and O-antigen
* Prevent activation
- M-protein targeting factor H in Streptococci
* Degradation of complement proteins
- Protease PaE degrade C3 in Pseudomonas aeruginosa
* Blocking MAC formation
- Borrelia burgdoferi: CD59-like protein that binds to C9
Acquired Immunity
Cytotoxic T cells kill cells infected by intracellular pathogens
T cells activation by professional antigen presenting cells
Antibody production : T helper cells “help” B-cells, stimulate antibodies production, recruit and activate phagocytes
Antibody Response Evasion
Strategies to evade antibody responses
* “Anti-antibodies”
* Protein A of S. aureus and protein G in S. pyogenes bind Fc region of antibodies but in a way that do not activate complement and opsonization
* Degradation of antibodies
* Haemophilus influenzae IgAse
* Switching surface antigens
* Capsule replacement and switching in Streptococcus pneumoniae
* Suppression of T cell response
* Super-antigens in S. aureus cause apoptosis of T cells by producing copious amount of toxic cytokines by binding directly to the MHCII complex and T-cell receptors
