CONTRIBUTION DES PAPILLOMAVIRUS HUMAINS A L'HOMEOSTASIE CUTANEE

par Marta Lagana

Projet de thèse en Immunologie

Sous la direction de Françoise Bachelerie et de Géraldine Schlecht-louf.

Thèses en préparation à université Paris-Saclay , dans le cadre de École doctorale Innovation thérapeutique : du fondamental à l'appliqué , en partenariat avec Inflammation, Microbiome, Immunosurveillance (laboratoire) et de Faculté de pharmacie (référent) depuis le 01-10-2019 .


  • Résumé

    Les papillomavirus humains (HPV), plus de 200 types différents identifiés à ce jour, sont des virus épithéliotropes acquis tôt dans la vie qui constituent une partie importante du microbiote cutané et muqueux humain commensal, avec une prévalence de 69 % dans la peau humaine[1], ce qui suggère que HPV pourrait jouer un rôle encore mal connu dans l'homéostasie épithéliale. Leur oncogénicité peut toutefois apparaître dans le contexte d'une infection persistante par des HPV muqueux à haut risque (hr HPV) responsables de 5 % des cancers humains dans le monde, dont la plupart des cas de cancer du col de l'utérus sont dus au HPV16[2]. La pathogenèse associée au hrHPV va des lésions bénignes aux cancers du col de l'utérus, des organes génitaux et de l'oropharynx et dépend du type de virus, de l'état de l'hôte (ex. immunitaire ou génétique[3, 4]) et des interactions avec les autres parties du microbiome (bactéries, champignons, parasites, etc.). De plus, la persistance des hrHPVs cutanés a un rôle pathogène sous estimé dans le cancer de la peau non mélanome chez les patients immunodéprimés et, en synergie avec les UV, chez les individus immunocompétents.

  • Titre traduit

    HUMAN PAPILLOMAVIRUS CONTRIBUTION TO SKIN HOMEOSTASIS AND IMMUNE FITNESS


  • Résumé

    Human papillomaviruses (HPV), more than 200 different types identified so far, are epitheliotropic viruses acquired early in life that constitute an important part of the commensal human mucosal and cutaneous microbiota, with a prevalence of 69% in human skin [1].This suggests that HPV might play an underappreciated role in epithelium homeostasis. Their oncogenicity, however, can appear in the context of persistent infection with high-risk mucosal HPVs (hrHPVs) that are responsible for 5% of human cancers worldwide, of which most cases of cervical carcinoma are due to HPV16 [2]. hrHPV-associated pathogenesis ranges from benign lesions to cervical, genital and oro-pharyngeal cancers and is dependent upon the type of virus, the status of the host (e.g. immune/genetic [3, 4]) and interactions with other parts of the microbiome (i.e. bacterial, fungi, parasites). Moreover, persistency of cutaneous hrHPVs has an underappreciated pathogenic role in non-melanoma skin cancer in immunosuppressed patients and in synergy with UV, in immune-competent individuals. The mechanisms allowing for HPV asymptomatic persistent infections containment by the host at the infected cell and immune levels, as well as the host, environmental, and viral factors unveiling HPV pathogenic potential are still poorly understood. So far, host-HPV interactions have been exclusively studied for hrHPVs, their persistence being associated with deregulated expression of the E6/E7 viral oncoproteins and achieved by hindering host defenses or exploiting host-susceptibility factors both at the infected (i.e. keratinocytes) and immune cell levels [5, 6]. Along this line, type I IFN (e.g. cGAS or TLR9 [7, 8]) and IL-1β responses [9, 10] induction upon hrHPV16 infection of target cells can be inhibited by viral oncogenes either directly or indirectly, notably through the hijacking of adapters and/or transcription factors (e.g. STING/TMEM173 and Interferon Regulatory Factor). By hindering intrinsic keratinocytes responses, hrHPV have the potential, through deregulated expression of their oncogenes, to limit anti-viral innate immunity, including activation of Langerhans Cells (LC) that directly interact with keratinocytes (KCs) and survey epithelia. However, due to the technical challenges faced in the study of HPVs, which complete their life cycle upon epithelial cell differentiation and thus require tridimensional cultures, and the lack of adequate animal model, the interactions between HPV-infected KCs and LC and their possible contribution to skin homeostasis and immune fitness (including innate immunity “training” [11] in case of HPV persistence) remain completely unexplored. In particular, the responses induced in the context of cutaneous hrHPV replication and persistence, which are expected to be different than those elicited by mucosal hrHPV due notably to E5 oncoprotein absence as well as differences in E6/E7 oncoproteins, remain unknown.