The impact of IFN-y-mediated endothelial cell activation for the progression of the mycobacterial granuloma

Ribeiro, Nuno Miguel Pimenta

http://hdl.handle.net/10400.22/29537

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Authors

Ribeiro, Nuno Miguel Pimenta

Advisor(s)

Resende, Mariana

Nova, Manuel Vila

Ferraz, Ricardo

Abstract(s)

Mycobacterial infections, specifically those caused by Mycobacterium tuberculosis and Mycobacterium avium, continue to pose a challenge to public health. Understanding the genesis of granulomas brings u sone step further in understanding how to modulate the imune response to achive better disease outcomes. IFN-ɤ-mediated endotelial cell activation has been linked with increased permeability of the endothelium, enhancing leukocyte extravasation into the affected tissues. In this work we aimed to establish the role of IFN-ɤ signaling on endotelial cells (ECs) in promoting celular recruitment and in driving not only granuloma formation, but also central necrosis (a direct consequence of sever inflammation during mycobacterial infections). For that we used na inducible endotelial-specific IFN-ɤR1-KO mouse model (VE-Cadherin-CreERT2xifngR1fl/fl), intravenouslu infected with a low dose of Mycobacterium avium 25291, a strain known to induce prominente pathology with granulomas developing central necrosis. Ablation of IFNgR1 on ECs majorly impacted the histology of the livers and spleens, at 120 days post infection, displaying a significant reduction in inflammation. Compared to control mice, animals with impaired IFN-ɤ signaling on ECs exhibited reduced granuloma formation and a substantial decrease in necrotic lesions in the liver, along with complete abrogation of necrotic features and lower bacterial burdens in the spleen. These results suggest that IFN-ɤ signaling on ECs is an important mechanism to control inflammation on M. avium infected animals. Modulation of IFN-ɤ signaling on ECs might open up new avenues to manipulate inflammation and devise new therapies to control pathology by promoting disease tolerance.