HPV high-risk types suppress the transcriptional activity of TLR9 in human primary epithelial cells: a new mechanism for viruses to escape innate immune recognition?

Every year approximately 500,000 women die due to Human papillomavirus (HPV)-induced cervical cancer (mucosal, HPV types 16 and 18). Innate immunity plays a role in controlling neoplastic development, however this family of dsDNA viruses can deregulate immune surveillance leading to viral persistence and then cancer. Two viral HPV proteins, E6 and E7, play a key role in the cellular transformation of keratinocytes, the cellular host of HPV, however, the routes in deregulating the innate immune response have not been well characterised. We analysed the expression and regulation of the entire panel of TLRs in human basal keratinocytes following HPV16 E6 and E7 infection in vitro. In non-infected cells, poly I:C, flagellin and CpG responses were observed, inducing IL-8 and MIP3a secretion. In HPV16 E6 and E7 infected cells, TLR3 and 5 responses were enhanced, uridine (a TLR8 ligand) induced cytokine secretion, but CpG responses were lost and the proteasome degradation pathway did not mediate the down regulation of TLR9. Analysis of mRNA revealed that all TLRs, with the exception of TLR1, were expressed in primary cells, however, following infection with HPV16E6 and E7, an upregulation of TLR3, 5 and 8 and repression of TLR9 was observed. Using a synthetic TLR9 promoter linked to luciferase we have shown that oncoproteins HPV16 E6 and/or E7 suppressed the transcriptional activity of this promoter.Remarkably, neither E6 nor E7 from HPV6 (a non-oncogenenic mucosal type) interferes with TLR9 transcription. We will elucidate the mechanisms involved in TLR9 deregulation by HPV high-risk types. In addition we shall discuss the expression profile of TLR9 and other TLRs in human cervical tumour specimens. Therefore HPV may escape TLR9 innate immune recognition, which may be a probable pre-requisite for HPV16 induced carcinogenesis