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Genre/Form: | Thèses et écrits académiques |
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Material Type: | Document, Thesis/dissertation |
Document Type: | Computer File |
All Authors / Contributors: |
Floriane Meuris; Françoise Bachelerie; Jean-Luc Galzi; Muriel Masson; Jean-Luc Prétet; Jean Donadieu, docteur en meÌdecine).; Michael Herfs; Johannes Schweizer; Université Paris-Sud (1970-2019).; Ecole doctorale Innovation Thérapeutique : du Fondamental à l'Appliqué (Châtenay-Malabry, Haut-de-Seine / 2000-2015).; Inflammation, microbiome, immunosurveillance (Châtenay-Malabry, Hauts-de-Seine / 2010-....). |
OCLC Number: | 924124984 |
Notes: | Titre provenant de l'écran-titre. |
Description: | 1 online resource |
Responsibility: | Floriane Meuris ; sous la direction de Françoise Bachelerie. |
Abstract:
Human papillomaviruses (HPVs), which encompass almost 300 different types identified so far, specifically infect epitheliums. Most of the time, HPVs are associated with asymptomatic infections suggesting an efficient control by the host immune system. However, when these infections persist, HPVs can cause cutaneous warts but also mucosal lesions that can progress to dysplasia and cancer (e.g. cervical cancers). The host factors involved in HPV persistence and derived-pathogenesis remain quite obscure. The first evidence for a role of the CXCL12/CXCR4 signaling axis in HPV pathogenesis came from observations made in the context of a rare immunodeficiency disorder, the WHIM syndrome. This syndrome is caused by dysfunctions of the axis formed by the chemokine CXCL12 and its receptor CXCR4 - caused by inherited heterozygous mutations in CXCR4 leading to a gain-of-function of the CXCL12/CXCR4 axis - and featured by a high susceptibility to severe, persistent and sometimes malignant HPV infections. In light of this susceptibility, the aim of my thesis was to characterise the molecular mechanisms involved and to find out whether it extend to a more general interplay between the CXCL12/CXCR4 axis and HPV biological cycle and pathogenesis.In the first part of my work, I investigated the consequences of CXCL12/CXCR4 dysfunctions - through the CXCR4 gain-of-function - on the HPV18 life cycle in three-dimensional organotypic epithelial cultures. We found that CXCR4 dysfunctions limited the viral replication at the benefit of cell transformation. The mechanisms included an increased in cell proliferation and a change in viral protein expression profile in favour of oncoproteins and at the expense of proteins involved in viral replication.In the second part of my work, I determined the impact of the CXCL12/CXCR4 blockade on a murin model of HPV16-induced neoplasia (K14-HPV16 mice). Treatment of these mice by AMD3100, a selective antagonist of CXCR4, results in a normalisation of HPV-induced lesions manifested by a significant decrease of skin hyperplasia. This effect is associated with a reduction in keratinocyte hyperproliferation and immune cell infiltration in dermis.To conclude, this thesis work identifies the CXCL12/CXCR4 axis as a new host factor involved in human papillomavirus-induced carcinogenesis, and reveals the benefit of therapeutic strategies based on the blockade of this axis.
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