Human papillomavirus targets crossroads in immune signaling

Tummers, Bart (2016)

Doctoral Thesis

Persistent infections with high-risk type human papillomaviruses (hrHPVs) can progress to cancer. HrHPVs infect keratinocytes (KCs) and successfully suppress host immunity for up to two years despite the fact that KCs are well equipped to detect and initiate immune responses to invading pathogens. HrHPV interferes with the innate immune response by affecting several signaling pathways that otherwise would prompt anti-viral mechanisms in the host cell. Furthermore, hrHPV interferes with the production of cytokines that are involved in the attraction of immune cells to the infected epithelium. In addition, hrHPV hides itself from the immune system by suppressing the antigen presentation machinery and employs means to hamper the response of KC__s to signals from adaptive immune cells. In this thesis we show that hrHPV attenuates innate immune signaling (Chapter 2) and CD40-mediated (Chapter 3) and IFN_ and/or TNF_-induced (Chapter 4) adaptive immune signaling. HrHPV exploits the cellular proteins UCHL1 (Chapter 2) and IFRD1 (Chapter 4) that act on multiple points in the IRF and NF_B signaling pathways. Moreover, hrHPV downregulates cellular IFITM1 to resist the growth inhibitory effects of IFN_ and/or TNF_ (Chapter 5). Our data provide important new insights on how hrHPV can persist in the face of host immunity.

• NFkB
• Immune evasion
• Adaptive immunity
• Innate immunity
• Keratinocyte
• HPV

• All authors: Tummers, Bart
• Supervisor: Burg, S.H. van der
• Co-supervisor: Boer, J.M.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2016-01-21
• ISBN (print): 9789462331938