Observed disease is the sum of:
- direct effect of growth of the pathogen
- the effect of factors produced by the pathogen
- the effect of the host response to the pathogen
- the pathogen counter measures to the host response
Study Pathogenesis
1) animal experiments using the human pathogen or close relative
2) learn from occasional human mutants
3) in vitro studies
4) study infected patients
Intracellular growth of bacteria
- entry into a cellular vesicle and subsequent fusion with a lysosome
- prevention of lysosome fusion
- lysis of the vesicle prior to lysosome fusion
- exit into the cytoplasm
Bacteria: virulence factors
Toxins- endotoxins in LPS
Invasions
Adhesion
Exotoxins
- secreted protein eg) diphtheria toxin - stops translation of mRNA
- variety of specific targets - enterotoxin (Vibrio cholerae), neurotoxin (Chlostridicem tetani), cytotoxin (Streptococcus haemolysin)
Endotoxins
- LPS in gram negative bacteria
- associated with endotoxic shock by stimulating the host TLR4 resulting in an inflammatory
- occasionally IS has a beneficial effect for bacteria
Secretion of active molecules by bacteria type 3 secretory systems
- Secretory system component comes close to cell
- secretory system and lock on and pierces cell
- effector molecules travels along and enters into cells
- links internal bacterium to cytoplasm of cell
- salmonella -pro inflammatory cytokine release
Immune response to viruses and countermeasures of viruses
1) innate immune mechanisms - available to every cell in our bodies - first line of defence
2) adaptive immune response- generation of antibodies
3) overshoot: immuno pathology - leads to damage and present as symptoms in disease
Intrinsic cellular defences: apoptosis
- active process of cellular self destruction - PCD
- highly organised orchestrated disassembly of critical molecular structures aimed at minimising disruption of surrounding tissues- progresses in a pathway to control and limit to one cell
- associated with well defined morphological changes
Apoptosis
1) membrane blebbing
2) phosphatidylserine flipage to the outer plasma membrane leaflet
3) loss of mitochondrial membrane potential - no longer make ATP
4) cytosol condensation
5) chromatin condensation
6) DNA fragmentation
7) organelle containing membrane bounded apoptotic bodies
8) engulfment of membranes structures and apoptotic cells by neighbouring cell or phagocytes
Non lethal persistent
Virus induces Bcl2 and suppresses apoptosis
Ebola virus ssRNA causes massive rapid intravascular apoptosis and necrosis
Triggers and effectors of apoptosis
- essential process vital in many areas of life
- controlled by monitoring cell cycle progression, growth regulation,
- following viral infection - biochemical alterations
Intrinsic pathway - abnormalities in DNA
- p53 Central regulator activates Bax and inhibits Bc12
- integrity of membrane lost > mitochondrial
- leakage > cyt c centre cell cytoplasm, which tells cell something wrong
- bind to Apal + Caspase 8 activated
- procaspase 3 > apoptosis
Extrinsic pathway
- Fas ligand bind and dig omers
- death domain binds FADD
- forms death signalling complex
- Caspase 3 - cell shrinkage and membrane blebbing - works on cytoskeleton and DNA degradation
