L10. Pathogenesis of Viruses 2 Flashcards Preview

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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
6. Interferons
7. Cytokines
8. Apoptosis inhibition
9. Complement


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)
- Malnutrition
- Hormones (pregnancy and males are particularly susceptible)
- Dual infections


What are the 4 major outcomes of viral infection?

1.. Fatality: normally caused by viruses that haven’t evolved parallel to man, it is not in the viruses interest to kill its host
2. Recovery: successful clearance of the infection by the immune response. Eg. influenza
3. Permanent damage: often successful clearance of the infection but not without damage caused by the infection. Eg. paralysis by poliomyelitis or cancer caused by viruses that cause metastatic changes.
4. Persistent (latent) infection: caused by viruses able to survive in cells.