TLR2 - TLR9 Expression and Function Is Abolished by the...

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Unformatted text preview: TLR9 Expression and Function Is Abolished by the Cervical Cancer-Associated Human Papillomavirus Type 16 1 Uzma A. Hasan, 2 * Elizabeth Bates, † Fumihiko Takeshita, ‡ Alexandra Biliato,* Rosita Accardi,* Veronique Bouvard,* Mariam Mansour,* Isabelle Vincent, § Lutz Gissmann, ¶ Thomas Iftner, i Mario Sideri, # Frank Stubenrauch, i and Massimo Tommasino* 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 keratino- cytes 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 deregu- lating the TLR9 transcript, providing evidence that abolishing innate responses may be a crucial step involved in the carcinogenic events mediated by HPVs. The Journal of Immunology, 2007, 178: 3186–3197. H uman papillomaviruses (HPVs) 3 are double-stranded circular DNA viruses, of which over 90 different types have been fully characterized so far. They can be clas- sified in general and divided into mucosal and cutaneous types based on their tissue tropism (1). The mucosal HPV types are well characterized and are classified into two groups: low-risk (LR) HPVs (e.g., types 6 and 11) that are mainly associated with benign genital warts, and high-risk (HR) HPVs (e.g., types 16 and 18) that are the etiological agents of cervical cancer (2), affecting ; 500,000 women worldwide (3). Among the HR types, HPV16 is the most prevalent type in premalignant and malignant cervical lesions (4, 5). The product of two early genes, E6 and E7 , are mainly responsible for the carcinogenic activity of the virus (6)....
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TLR2 - TLR9 Expression and Function Is Abolished by the...

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