The human papillomavirus (HPV) E7 protein antagonises an Imiquimod-induced inflammatory pathway in primary human keratinocytes.
High-risk human papillomaviruses (HPV) are the etiological pathogen of cervical and a number of ano-genital cancers. How HPVs overcome the significant barriers of the skin immune system has been the topic of intensive research. The E6 and E7 oncoproteins have emerged as key players in the deregulation of host innate immune pathways that are required for the recruitment of effector cells of the immune response. Here we demonstrate that E7, and to a lesser extend E6, strongly reduce NFκB activation in response to the inflammatory mediator imiquimod. Moreover, we establish that undifferentiated keratinocytes do not express the putative receptor for imiquimod, TLR7, and as such are stimulated by imiquimod through a novel pathway. Inhibition of imiquimod induced cytokine production required residues in the CR1 and CR3 regions of E7 and resulted in reduced nuclear translocation and acetylation of the p65 sub-unit of NFκB. The results provide further evidence for a TLR7-independent role of imiquimod in the epithelial immune response and reinforce the ability of the HPV oncoproteins to disrupt the innate immune response, which may have important consequences for establishment of a chronic infection.
School of Molecular and Cellular Biology, Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom.
Kathryn H
KH
Richards
School of Molecular and Cellular Biology, Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom.
Christopher W
CW
Wasson
School of Molecular and Cellular Biology, Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom.
Oliver
O
Watherston
School of Molecular and Cellular Biology, Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom.
Rosella
R
Doble
School of Molecular and Cellular Biology, Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom.
G
G
Eric Blair
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom.|NIHR Leeds Musculoskeletal Biomedical Research Unit, Chapel Allerton Hospital Leeds, United Kingdom.|Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford, United Kingdom.
Miriam
M
Wittmann
School of Molecular and Cellular Biology, Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom.
Andrew
A
Macdonald
D000634:Aminoquinolines / Q000633:toxicity; D015967:Gene Expression Regulation, Viral; D006801:Humans; D000077271:Imiquimod; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000821:virology; D015603:Keratinocytes / Q000821:virology; D016328:NF-kappa B / Q000235:genetics; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis* / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics / Q000472:pathogenicity; D050725:Papillomavirus E7 Proteins / Q000096:biosynthesis* / Q000235:genetics; D030361:Papillomavirus Infections / Q000235:genetics* / Q000821:virology; D061251:Primary Cell Culture; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D051199:Toll-Like Receptor 7 / Q000235:genetics
D000634:Aminoquinolines; C068651:E6 protein, Human papillomavirus type 16; C466080:E6 protein, human papillomavirus type 1; D016328:NF-kappa B; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D000077271:Imiquimod