TLR9 expression and function is abolished by the cervical cancer-associated human papillomavirus type 16.
Cervical cancer development is linked to the persistent infection by high-risk mucosal human papillomaviruses (HPVs) types. The E6 and E7 major oncoproteins from this dsDNA virus play a key role in the deregulation of the cell cycle, apoptosis, and adaptive immune surveillance. In this study, we show for the first time that HPV type 16 (HPV16), the most carcinogenic type among the high-risk subgroup, interferes with innate immunity by affecting the expression of TLRs. Infection of human primary keratinocytes with HPV16 E6 and E7 recombinant retroviruses inhibits TLR9 transcription and hence functional loss of TLR9-regulated pathways. Similar findings were achieved in HPV16-positive cancer-derived cell lines and primary cervical cancers, demonstrating that this event occurs also in an in vivo context. Interestingly, E6 and E7 from the low-risk HPV type 6 are unable to down-regulate the TLR9 promoter. In addition, E6 and E7 from the high-risk HPV type 18, which are known to persist less competently in the host than HPV16, have reduced efficiency compared with HPV16 in inhibiting TLR9 transcription. Furthermore, a CpG motif derived from the HPV16 E6 DNA sequence activated TLR9, indicating this virus is able to initiate innate responses via the receptor it later down-regulates. This study reveals a novel mechanism used by HPV16 to suppress the host immune response by deregulating the TLR9 transcript, providing evidence that abolishing innate responses may be a crucial step involved in the carcinogenic events mediated by HPVs.
Hasan
Uzma A
UA
International Agency for Research on Cancer-World Health Organization, 150 Cours Albert-Thomas, 69372 Lyon Cedex 08, France. hasan@iarc.fr
Bates
Elizabeth
E
Takeshita
Fumihiko
F
Biliato
Alexandra
A
Accardi
Rosita
R
Bouvard
Veronique
V
Mansour
Mariam
M
Vincent
Isabelle
I
Gissmann
Lutz
L
Iftner
Thomas
T
Sideri
Mario
M
Stubenrauch
Frank
F
Tommasino
Massimo
M
D002471:Cell Transformation, Neoplastic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000276:immunology* / Q000378:metabolism; D052161:Human papillomavirus 18 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D009856:Oncogene Proteins, Viral / Q000276:immunology* / Q000378:metabolism; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012097:Repressor Proteins / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000096:biosynthesis / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; C059731:oncogene protein E7, Human papillomavirus type 16