James, Claire Deborah (2011)
M.Res. thesis, University of Birmingham.
Approximately 15-20% of human cancers are associated with viral agents (Parkin, 2006). The human tumour virus Kaposi’s sarcoma associated herpesvirus (KSHV) is one such virus. It is the aetiological agent of the AIDS-defining malignancy Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL), and is linked to the development of multi-centric Castleman’s disease (MCD). As a herpesvirus, KSHV resides in a latent state within infected host cells, evading various innate and adaptive immune mechanisms. The widely expressed and highly conserved toll-like receptor (TLR) family plays a major role in binding of pathogen-associated molecular patterns (PAMPs), thus identifying pathogens and leading to the stimulation of relevant host immune responses. Members of the Herpesviridae family are known to act upon, interact with and/or be detected by certain TLRs. Based on this precedence, we have investigated the interaction of KSHV on human TLRs in the human epithelial kidney cell line, 293. We evaluated the initial effect of ectopic TLR expression on KSHV infection level and the effect of KSHV infection on ectopic TLR transcript levels. Using flow cytometry, we found that KSHV infection is sensitive to the expression of TLRs 2, 3, 4 and 5, presumably via KSHV PAMP recognition, and is not sensitive to the ectopic expression of TLRs 1, 6, 7, 8 and 9. Semi-quantitative PCR revealed that TLR 7 mRNA levels are decreased by KSHV infection. We suggest that this result indicates that KSHV utilises some mechanism to decrease mRNA levels in order to evade potential antiviral responses triggered by the receptor.
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