Investigating the effect of the KSHV vIRF2 and vIRF4 proteins on the interferon response

Hindle, Laura Nambikai (2013). Investigating the effect of the KSHV vIRF2 and vIRF4 proteins on the interferon response. University of Birmingham. Ph.D.

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Abstract

The type I IFN response forms part of the innate immune system, which is the first line of defence against invading viruses. Kaposi’s sarcoma-associated herpesvirus, a gamma herpesvirus, encodes a number of genes that down regulate the type I IFN response. These include four viral interferon regulatory factors (vIRFs). vIRFs 1, 2 and 3 have been shown to inhibit type I IFN signalling previously, whereas vIRF4 was, until now, not thought to inhibit this pathway. The aim of this study was to determine the mechanism by which vIRF2 inhibits type I IFN signalling and to characterise the effects of the vIRF4 protein on this system. Cell lines were engineered to express inducible vIRF2 or vIRF4 proteins that both demonstrated significant inhibition of JAK-STAT signalling via ISRE-luc reporter assays. Electrophoretic mobility shift assays showed that vIRF2 and vIRF4 could significantly reduce ISGF3:ISRE complex formation. Stable isotope labelling of amino acids in cell culture coupled to LC-MS/MS was employed to facilitate the identification of the vIRF2 and vIRF4 interactomes. USP7 and CBP were identified as binding partners for both viral proteins and their contribution to inhibition of JAK-STAT signalling was explored.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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