Abstract : Human papillomavirus (HPV) is part of our virome and infects skin and mucous sites. Most infections are asymptomatic or cause only benign lesions that are controlled by the host’s defense mechanisms, occurring in both the epithelial and the immune system. However, persistent infections with certain types of mucosal HPV at high risk of developing cancer cause virtually all cases of cervical cancer, most anogenital cancers, and an increasing proportion of oropharyngeal cancers. Prophylactic vaccines are effective in preventing lesions associated with mucosal HPV types, but there is currently no antiviral treatment for an established HPV infection. In this PhD thesis, we aimed to study host factors involved in the HPV life cycle and carcinogenesis at two levels: the infected keratinocyte and the immune system. Studies in the context of some immunodeficient patients (WHIM syndrome, WS) with selective susceptibility to HPV pathogenesis have identified the chemokine CXCL12 and its receptor CXCR4 coupled to the classic G protein (whose mutations cause WS) as susceptibility factors host who act as guardians of the HPV life cycle. CXCL12 / CXCR4 together with ACKR3, the second receptor of CXCL12 with atypical bait activity, can modulate both epithelial and immune antiviral responses. Therefore, we first investigated the intrinsic contribution of ACKR3 to the HPV life cycle in cultured human 3D epithelial cells (3D-EpC), the only model that allows for HPV replication. Our results indicate that increased ACKR3 activity shows pro-oncogenic potential as it shifts the productive life cycle of HPV towards oncogenesis and that blocking ACKR3 could be an attractive therapeutic approach to promote HPV replication. Furthermore, we studied the functional consequences of the HPV productive life cycle in cell-cell communication, being pioneers in setting up the FLIP technique in 3D-EpC. Finally, we investigated the impact of the WS CXCR4 mutation at the level of skin immune cells in the context of HPV-induced carcinogenesis. We therefore gained insight into the role of CXCR4 in the distribution, phenotype and migration of dendritic cells and Langerhans cells and how their deregulation in the context of WS could explain the selective susceptibility of WS patients to HPV pathogenesis. In conclusion, this work provides new insights into HPV-host interactions at the level of epithelial and immune cells. We unraveled the central role of ACKR3 in the intrinsic response of keratinocytes against HPV and deepened our knowledge on the role of CXCL12 / CXCR4 in skin immunity in health and in HPV carcinogenesis.
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Take up again : The epitheliotropic members of our virome, human papillomaviruses (HPVs) mainly cause asymptomatic or benign infections, controlled by host defense mechanisms at the epithelial and immune levels. However, persistent infection with some high-risk carcinogenic HPVs (hrHPVs) can lead to the development of tumors. Thus, tropic mucosal hrHPVs cause 98% of cervical cancers and are implicated in an increasing number of anogenital and oropharyngeal cancers. Prophylactic vaccines are effective in preventing tropic hrHPV-associated lesions of the mucosa, but there is currently no antiviral treatment for established infection. In this doctoral thesis, we tried to study the host factors involved in the life cycle of HPV and its carcinogenesis at two levels: those of the infected keratinocyte and of the immune system. Studies in some immunocompromised patients (WHIM syndrome, WS) with selective susceptibility to HPV pathogenesis have identified the chemokine CXCL12 and CXCR4, its G protein-coupled receptor (whose mutations cause WS) as factors that control the life cycle of these viruses. CXCL12 / CXCR4 as well as ACKR3, the decoy receptor of CXCL12, can modulate both epithelial and immune antiviral responses. We first investigated the contribution of ACKR3 to the HPV life cycle in 3D cultures of human epithelial cells (3D-EpC), the only model that allows HPV replication. Our results indicate that increased ACKR3 activity has pro-oncogenic potential as it shifts the productive life cycle of HPV towards oncogenesis and that blocking ACKR3 could be an attractive therapeutic approach to promote cell replication. ‘HPV. Subsequently, we studied the functional consequences of the HPV productive life cycle in intercellular communication, implementing the FLIP technique in 3D-EpC. Finally, we investigated the impact of a WS-associated CXCR4 mutation on skin immune cells in the context of HPV-induced carcinogenesis. We thus demonstrated the role of CXCR4 in the distribution, activation and migration of dendritic cells of the dermis and Langerhans cells; their possible dysregulation in the context of WS may contribute to the selective susceptibility of patients to HPV pathogenesis. In conclusion, this work provides mechanistic keys on HPV-host interactions at the epithelial and immune levels. It reveals the central role of ACKR3 in the intrinsic response of keratinocytes to HPV and deepens our knowledge of the role of the CXCL12 / CXCR4 axis in skin immunity to HPV homeostasis and carcinogenesis.
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