Human Beta Papillomavirus Type 8 E1 and E2 Proteins Suppress the Activation of the RIG-I-Like Receptor MDA5

Stephanie Rattay; Martin Hufbauer; Christian Hagen; Bastian Putschli; Christoph Coch; Baki Akgül; Gunther Hartmann

doi:10.3390/v14071361

Viruses (Jun 2022)

Human Beta Papillomavirus Type 8 E1 and E2 Proteins Suppress the Activation of the RIG-I-Like Receptor MDA5

Stephanie Rattay,
Martin Hufbauer,
Christian Hagen,
Bastian Putschli,
Christoph Coch,
Baki Akgül,
Gunther Hartmann

Affiliations

Stephanie Rattay: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Gebäude 12, Venusberg-Campus 1, 53127 Bonn, Germany
Martin Hufbauer: Institute of Virology, Medical Faculty and University Hospital Cologne, University of Cologne, Fürst-Pückler-Str. 56., 50935 Cologne, Germany
Christian Hagen: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Gebäude 12, Venusberg-Campus 1, 53127 Bonn, Germany
Bastian Putschli: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Gebäude 12, Venusberg-Campus 1, 53127 Bonn, Germany
Christoph Coch: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Gebäude 12, Venusberg-Campus 1, 53127 Bonn, Germany
Baki Akgül: Institute of Virology, Medical Faculty and University Hospital Cologne, University of Cologne, Fürst-Pückler-Str. 56., 50935 Cologne, Germany
Gunther Hartmann: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Gebäude 12, Venusberg-Campus 1, 53127 Bonn, Germany

DOI: https://doi.org/10.3390/v14071361
Journal volume & issue: Vol. 14, no. 7
p. 1361

Abstract

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Persistent infections of the skin with the human papillomavirus of genus beta (β-HPV) in immunocompetent individuals are asymptomatic, but in immunosuppressed patients, β-HPV infections exhibit much higher viral loads on the skin and are associated with an increased risk of skin cancer. Unlike with HPV16, a high-risk α-HPV, the impact of β-HPV early genes on the innate immune sensing of viral nucleic acids has not been studied. Here, we used primary skin keratinocytes and U2OS cells expressing HPV8 or distinct HPV8 early genes and well-defined ligands of the nucleic-acid-sensing receptors RIG-I, MDA5, TLR3, and STING to analyze a potential functional interaction. We found that primary skin keratinocytes and U2OS cells expressed RIG-I, MDA5, TLR3, and STING, but not TLR7, TLR8, or TLR9. While HPV16-E6 downregulated the expression of RIG-I, MDA5, TLR3, and STING and, in conjunction with HPV16-E7, effectively suppressed type I IFN in response to MDA5 activation, the presence of HPV8 early genes showed little effect on the expression of these immune receptors, except for HPV8-E2, which was associated with an elevated expression of TLR3. Nevertheless, whole HPV8 genome expression, as well as the selective expression of HPV8-E1 or HPV8-E2, was found to suppress MDA5-induced type I IFN and the proinflammatory cytokine IL-6. Furthermore, RNA isolated from HPV8-E2 expressing primary human keratinocytes, but not control cells, stimulated a type I IFN response in peripheral blood mononuclear cells, indicating that the expression of HPV8-E2 in keratinocytes leads to the formation of stimulatory RNA ligands that require the active suppression of immune recognition. These results identify HPV8-E1 and HPV8-E2 as viral proteins that are responsible for the immune escape of β-HPV from the innate recognition of viral nucleic acids, a mechanism that may be necessary for establishing persistent β-HPV infections.

Published in Viruses

ISSN: 1999-4915 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Microbiology
Website: http://www.mdpi.com/journal/viruses

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