Viral Pathogenesis 2 Flashcards
What happens in the innate immune system when a virus infects a cell?
The virus infected cell will produce IFN-alpha/beta. The virus will also interact with macrophages and dendritic cells. The macrophages and dendritic cells will produce IFN-alpha/beta, IL-12 and pro-inflammatory cytokines (IL-1, IL-6, TNFalpha) and chemokines. The IFN-alpha/beta and the IL-12 activate NK cells. The NK cells will produce IFN-gamma and also kill infected cells. Dendritic cells will present the antigen to T cells.
What are the roles of the type 1 interferons (IFN-alpha/beta)?
Inhibit viral replication, activate NK cells, enhance MHC class I expression
What are the roles of type 2 interferons (IFN-gamma)
Inhibit viral replication, activates macrophages, enhances MHC class I and class II expression
What are the two ways that viruses can combat the immune system?
Either by not being recognised by the immune system or by interfering with the function of a particular part of the immune system
What is antigenic drift?
Change in the antigenic structure of a virus
What viruses undergo antigenic drift?
HIV and influenza
How does vaccinia virus inhibit T cell priming by DC?
By encoding a homologue of the cytoplasmic tail of TLR4 - this means that the signalling molecules will bind to the homologue rather than the actual cytoplasmic tail of TLR4 and signalling will be inhibited.
How does the HSV virus inhibit T cell priming by DC?
By blocking the signal transduction from the TLR
How do vaccinia and HCV viruses inhibit T cell priming by DC?
By inhibiting the maturation of DCs by blocking the cytokines released by immature DCs to signal to other DCs to mature
How do measles and CMV viruses inhibit T cell priming by DC?
By interfering with the costimulatory molecules of DCs required for T cell priming
How does HIV evade CD8 T cell recognition?
By mutating the epitope so can’t associate with MHC class I and so the TCR won’t recognise them. Also by encoding a protein which induces endocytosis of MHC class I
How does HSV evade CD8 T cell recognition?
By encoding a peptide that blocks the TAP transporter from the cytosolic side
How does CMV evade CD8 T cell recognition?
By encoding a peptide that blocks the TAP transporter from the luminal side
How does adenovirus evade CD8 T cell recognition?
By encoding a protein that binds to MHC in the ER and won’t let it get out into the vesicle
How does EBV evade CD8 T cell recognition?
By inhibiting the proteosome complex which degrades the viral proteins into epitopes
Which viruses decrease production of MHC class I genes?
HIV, RSV, adenovirus
What viruses are humans with an NK cell defiency highly susceptible to?
varicella and cytomegalyvirus
What two kinds of receptors do NK cells have?
Activation receptors which recognise things on the infected cell surface which are there as a result of viral infections, and inhibitory receptors which recognise MHC class I molecules.
When will the NK cell be able to kill the target cell?
If the activation receptor is activated and if MHC class I is aberrantly expressed or not expressed at all so the inhibitory receptor is not activated
What is the purpose of this?
So that if the virus makes the cell stop expressing MHC class I to evade CD8 T cells then NK cells can kill them
How does human CMV evade NK cell killing?
By encoding an MHC class I like molecule that is expressed on the cell surface that delivers a negative signal to NK cells but cannot present proteins to CD8 T cells
What is the role of interferons?
Helps neighbouring cells not to get infected by the virus - binding of interferons to receptors stimulates a signalling pathway that leads to up regulation of proteins such as MHC class I and class II and PKR
What happens in the PKR pathway?
Interferon binds, synthesis of PKR in an inactive form, PKR is autophosprylated in the presence of dsRNA as a cofactor, active PKR phoshprylates eIF2alpha to its inactive form to prevent translation of proteins from the ribosome
How does dsRNA act as a cofactor?
PKR hooks over the dsRNA to bring the two domains in close proximity so they can autophosphorylate
How does EBV and adenovirus evade the PKR pathway?
Their RNA is only in short stretches - not long enough for the PKR to bind
How do vaccinia and reovirus evade the PKR pathway?
By encoding proteins which bind to their dsRNA to protect it
How else does vaccinia evade the PKR pathway?
By encoding a homologue of eIF2 so that if PKR is activated it will phosphorylate the homologue rather than the real eIF2
What are some genetic factors that influence susceptibility to viral infection?
Inherited defects e.g. lack of Ig class, polymorphisms e.g. in the MHC genes, defects in interferon inducible genes, defects in expressing receptors
What deficiency may be beneficial in avoiding HIV?
Lack of CCR5 gene
What are some non genetic factors that influence susceptibility to viral infection?
Age (newborns and the elderly), malnutrition, hormones, pregnancy, dual infections
What are the outcomes of viral infection?
Fatal, full recovery, permanent damage, persistence
