14: Pathogenesis Flashcards
What is pathogenesis?
The process and mechanism of disease development
- dependent on the accessibility, permissively, tissue tropism, virulence, immune defense
How do we study viral pathogenesis?
-Modulate the immune system: clonal T cell receptors, immune mediator deletion, cell deletion, and mediator overproduction
Transplant human cells or tissues into mice known as a xenograft.
Modulate the susceptibility or permissivity
Mice that receive the graft need to be immunodeficient to prevent rejecting the graft.
What is virulence? factors that influence it.
The disease producing power of a virus,
– it can be quantified by monitoring signals, pathological lesions and avg. time to death.
factors:
age, sex, species, immune defence, route of inoculation
How does pathogenesis occur via virulence gene?
Virulence genes are genes coding for proteins that can cause severe disease during viral infection
✓ It affects the hosts ability to reproduce
✓Directly toxic
✓Modifies the hosts defence mechanism
✓Facilitates virus spread in and among hosts
How do virulence genes alter the viruses reproduction and disease development?
- Wildtype viruses reproduce well and can cause central nervous system disease (neurovirulent)
- Mutations can lead to general replication defects (not grow well in mouse or culture)
- Mutations leading to a defect in a gene needed for virulence ( grow only in culture)
How do virulence genes modify host defences?
Immune modulators:
-Inhibiting apoptosis and autophagy
- Viroreceptors (viral homologs of cytokine receptors)
- Modification of MHC1 or 2 pathways
Which virus has toxic viral proteins?
Rotavirus has non-structural protein 4 (NSP4).
NSP4 inhibits sodium glucose transporter (SGLT) and activates phospholipase (PLC) which disrupts gut permeability + diarrhea
How is cellular/tissue damage mediated during viral infections?
- Via viruses themselves
- Via host immune response (immunopathology)
What are the mechanisms of cell injury by viruses?
Cytolytic viruses: cause CPE (apoptosis, necrosis and pyroptosis)
Viroporins: viral hydrophobic proteins induce cell permeability which causes virus particles to leave cell
Viral inhibition of host protein translation machinery: results in the lost of membrane integration and cytoplasmic degradation
What is Immunopathology?
Immunopathology is the damage (fever/ache/chills) caused by viral disease that results from host immune response.
Primary basis of disease for noncytolytic viruses such as hepatitis B virus.
It is caused by activated T cells but antibodies produced by B cells can be the source of the disease.
What are the patterns of viral infection?
Acute
Latent
Persistent (asymptomatic)
Persistent (chronic)
What is acute infection?
Influenza virus.
There is a start of infection and there are innate defences. When the virus reaches a certain threshold then there is adaptive immunity. Memory B cells are produced which provide lasting protection
What is latent infection?
HSV1 or HSV2
There is an initial acute infection with quiescent phases (no viral reproduction) followed by rounds of reactivation (symptoms or no) but it does produce infectious viral particles
Viral reproduction occurs at mucosal epithelium and it spreads between epithelial cells and deeper to engage nerve axon terminals. Viral genome is transported within the axon to neuronal cell body.
Infection is 7-14 days but viral genome remains dormant in the neuronal nucleus.
Reactivation of viral genome replication can be caused by a latent infection (cold sores)
Persistant chronic infection
- Hepatitis C Virus, 20% people will resolve the infection, 80% will develop chronic infection that can persist for decades.
- Out of 80% approx. 30% will develop liver scarring & hardening (cirrhosis) and & 7% can develop hepatocellular carcinoma
Modulation of immune defences can convert an acute infection to a persistent infection by?
Persistent infections occur when he acute infection is not cleared and continuously producing virus particles, proteins, and genomes.
ex. Viral proteins can block cell surface MHC class 1 antigen presentation at any step antigen processing & MHC assembly
