The human papillomavirus (HPV) E7 protein antagonises an Imiquimod-induced inflammatory pathway in primary human keratinocytes

Sci Rep. 2015 Aug 13:5:12922. doi: 10.1038/srep12922.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / toxicity
  • Gene Expression Regulation, Viral
  • Humans
  • Imiquimod
  • Immunity, Innate / genetics*
  • Inflammation / chemically induced
  • Inflammation / genetics*
  • Inflammation / virology
  • Keratinocytes / virology
  • NF-kappa B / genetics
  • Oncogene Proteins, Viral / biosynthesis*
  • Oncogene Proteins, Viral / genetics
  • Papillomaviridae / genetics
  • Papillomaviridae / pathogenicity
  • Papillomavirus E7 Proteins / biosynthesis*
  • Papillomavirus E7 Proteins / genetics
  • Papillomavirus Infections / genetics*
  • Papillomavirus Infections / virology
  • Primary Cell Culture
  • Repressor Proteins / biosynthesis*
  • Repressor Proteins / genetics
  • Toll-Like Receptor 7 / genetics

Substances

  • Aminoquinolines
  • E6 protein, Human papillomavirus type 16
  • E6 protein, human papillomavirus type 1
  • NF-kappa B
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Repressor Proteins
  • TLR7 protein, human
  • Toll-Like Receptor 7
  • Imiquimod