Flashcards in L10. Pathogenesis of Viruses 2 Deck (19)
Briefly describe the innate response to viral infection.
DCs and Macrophages uptake the viral particles or with the virus infected cells. These lead to the activation of NK cells which eventually lead to the lysis of virus-infected cells (and or activation of adaptive responses)
What are the interferons?
Interferons are a soluble factor released by virus infected cells that inhibit viral replication in neighbouring cells (make an antiviral environment) mainly by interferon signalling.
What are the type 1 interferons and their actions? – What are they released by?
IFN-alpha and IFN-beta released by macrophages and by DCs
Actions: inhibits viral replication, activate NK cells, increase expression of MHCI peptides
What are the type 2 interferons and their actions? – What are they released by?
IFN-y released by NK cells
Actions: inhibits viral replication, activates and upregulates macrophages, Enhances expression of both MHCI and MHCII
How have viruses evolved to evade the immune response?
By either developing ways of not being recognised by the immune system or by directly interfering with the function of the immune system and its mechanisms.
What are the 9 viral evasion strategies?
By interfering, modulating and/or evading…
1. Antibody and T cell evasion
2. Antibody recognition/action
3. T cell priming by the DC
4. T cell recognition
5. NK cells
8. Apoptosis inhibition
Describe antigenic variation. Give 2 examples
Viral antigens have several epitopes and due to random mutations and selection, some viruses are able to change their antigenic structure, thereby become unrecognizable to the immune system and any preformed antibodies against it.
Eg. HIV (variation within a patient) and Influenza (variation population wide)
How is inhibition of T cell priming by the DCs done and how does it benefit the virus? Describe the 4 main methods.
Normally DCs interact with T cells through presentation via MHC molecules and cytokine signalling processes. Viruses have developed means to evade these:
1. Homologues for TLR cytoplasmic tails which renders the TLRs non-functional
2. Inhibition of the intracellular signalling processes from the TLR to the DCs
3. Inhibition of cytokine production within the DC cell that enables its maturation
4. Inhibition of the interaction process between DC cells and T cells)
Describe the APC to CD8 interaction
Mature APCs have processed the antigens in proteasomes and proteins enter the ER by the transport antigenic peptides where they interact with MHC I molecules. MHCI and protein antigen complexes leave the ER in vesicles towards the surface for expression. Expression enables interaction with T cells for CD8 maturation.
What are the 6 different mechanisms of evading CD8 T cells?
1. CD8 peptide antigenic variation (antigen is not longer recognised by the T cell that was raised against the original antigen)
2. Induction of the endocytosis pathway: endocytosis of the MHC and antigen complex
3. Proteosome complex inhibition, meaning the protein antigen cannot be processed
4. TAP inhibition (both cytosolic and ER sided inhibitions) preventing antigen peptides from entering and interacting with MHC I
5. Binding of the MHC protein in the ER preventing its exit to the surface.
6. Down regulation of the MHCI gene expression (transcription
What is a negative consequence (to the virus) of the CD8 T cell evasion method of down-regulating MHCI?
Down-regulation of MHCI means there is a loss of the inhibition signal for NK cells. Thus the infected cell (and the virus) is susceptible to innate NK attack
How are NK cells activated and inactivated?
NK cells are innate immunity mediators that have a signalling and recognition based activation and inactivation.
Activation Signal = NK activating ligand binds to viral proteins leading to NK cell killing
Inhibition Signal = NK inhibiting ligand binds to MHC I and this prevents any killing (overrides and activation signals) – prevents host degradation.
How do viruses evade NK mediated immune responses?
1. By down regulating or preventing the expression of MHCI on the infected cell surface
2. By expressing an MHCI-like molecule on the surface: it looks like MHCI but doesn’t act like it
How do interferons regulate transcription and translation of proteins
Interferons up-regulate transcription of various cytokines that are important in mediating the anti-viral environment.
Describe the PKR pathway
The pathway INHIBITS viral protein expression:
PKR (protein Kinase RNA-derived) is generated by interferons in the inactive form in all cells.
dsRNA (viral specific) catalyses the auto-activation of the kinase.
The kinase is able to phosphorylate (inactivate) the transcription factor eIFalpha2, which is important for viral transcription.
How do viruses evade interferons and the PKR pathway [3 mechanisms]
1. Some viruses have segmented genomes of very short stretches of dsRNA which are not long enough for the adjacent looping of the PKR
2. Release of proteins that are able to coat the dsRNA meaning PKR cannot bind and auto-activate
3. eIFalpha2 homologues which bind to activated PKR preventing inactivation of the actual eIFalpha2
What are some genetic factors in host susceptibility and resistance?
- Inherited defects (eg. absence of Ig Classes)
- Polymorphisms of genetic elements (eg. MHC haplotypes give diversity in the susceptibility to some viruses)
- Interferon-inducible genes (MxA and MxB) – important to influenza
- Receptor Genes: the expression of different receptors for viral binding (eg. CCR5 deficiency confers HIV resistance)
What are some non-genetic factors in host susceptibility to infection and resistance?
- Age (newborns and elderly)
- Hormones (pregnancy and males are particularly susceptible)
- Dual infections