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Use of Interferon-γ Enzyme-linked Immunospot Assay to Characterize Novel T-cell Epitopes of Human Papillomavirus
Published on: March 8, 2012
The human papillomavirus (HPV) E7 protein antagonises an Imiquimod-induced inflammatory pathway in primary human
Kathryn H Richards1, Christopher W Wasson1, Oliver Watherston1
1School of Molecular and Cellular Biology, Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom.
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.
Insights
High-risk human papillomaviruses (HPV) oncoproteins E6 and E7 disrupt the innate immune response. They inhibit NF-kappaB activation, potentially aiding chronic HPV infection establishment.
Area of Science:
- Immunology
- Virology
- Oncology
Background:
- High-risk human papillomaviruses (HPV) cause cervical and ano-genital cancers.
- HPV's ability to overcome the skin's immune defenses is crucial for infection.
- HPV oncoproteins E6 and E7 are implicated in disrupting innate immune pathways.
Purpose of the Study:
- To investigate the role of HPV oncoproteins E6 and E7 in modulating the innate immune response to imiquimod.
- To elucidate the mechanism by which HPV oncoproteins interfere with immune signaling pathways.
Main Methods:
- Assessing NF-kappaB activation in response to imiquimod in the presence of HPV oncoproteins.
- Investigating imiquimod stimulation pathways in undifferentiated keratinocytes lacking TLR7.
- Analyzing the impact of E7 mutations on imiquimod-induced cytokine production and NF-kappaB p65 subunit activity.
Main Results:
- HPV E7 and E6 significantly reduce NF-kappaB activation by imiquimod.
- Undifferentiated keratinocytes respond to imiquimod via a TLR7-independent pathway.
- Specific regions (CR1, CR3) of E7 are essential for inhibiting imiquimod-induced cytokine production.
- HPV oncoproteins reduce nuclear translocation and acetylation of the NF-kappaB p65 subunit.
Conclusions:
- HPV oncoproteins E6 and E7 actively suppress innate immune responses, specifically NF-kappaB activation.
- A novel TLR7-independent pathway mediates imiquimod's effect in epithelial cells.
- The disruption of innate immunity by HPV oncoproteins may facilitate chronic infection.
