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RODRIGUES-Crimean-congo hemoohagic fever : contribution to the pathogenesis undestanding

Soutenance de thèse

Mercredi 11 jan 2012



Description générale
Crimean-Congo hemorrhagic fever virus (CCHFV) is a widely distributed tick-borne member of the Nairovirus genus (Bunyaviridae) with an average mortality rate of 30% in humans. The mononuclear phagocytes, the hepatocytes and the endothelial cells were described to be the main target cells in both human clinical studies and animal model in vivo studies. CCHFV induces a severe hemorrhagic disease in infected patients that includes, among other symptoms, acute inflammation and liver lesions. We analyzed the in vitro cellular response of host antigen presenting cells (APC) and hepatocytes. Then, to better elucidate the pathogenesis of CCHFV, we compared the response of these cells after infection with Dugbe virus (DUGV), a mild pathogenic virus genetically close to CCHFV. In order to improve DUGV detection we also developed a molecular real-time quantitative tool to detect and quantify DUGV. We found that CCHFV induced an inflammatory response in both APCs tested; however DUGV induced a higher cytokine/chemokine response. Our results suggest that CCHFV was able to selectively inhibit the activation of the inflammatory mediators in the in vitro infection and that these differences could be relevant in pathogenesis. On the other hand, when we in vitro infected hepatocytes with CCHFV, we observed that it was able to induce ER-stress, activate inflammatory mediators and modulate both mitochondrial and death receptor pathways of apoptosis. When we compared this cellular response with that induced by DUGV, we found that the most striking difference was the absence of apoptosis. These differences could, in part, explain the role of the liver in the pathogenesis of CCHFV. Overall, these results give new insights into the pathogenesis of CCHFV.

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