Metformin reduces intracellular M. tuberculosis replication and inflammation in vitro: A potential host-directed therapy for ocular tuberculosis?

Résumé fourni par la source

Ocular tuberculosis (TB) remains a leading cause of infectious uveitis in TB-endemic settings. Antitubercular therapy, with or without adjunctive corticosteroids or immunosuppressive agents, is the mainstay of treatment; however, more rapid resolution of intraocular inflammation is desirable to reduce visual morbidity. This preliminary study investigates metformin as a potential host-directed therapy (HDT) for ocular TB through in silico prediction and validation using in vitro disease models. In silico drug discovery was conducted using a bioinformatics platform. In vitro assays were performed using retinal pigment epithelial (RPE) cells and human retinal endothelial cells (RECs) infected with both the H37Rv and a hypervirulent clinical (Beijing) Mycobacterium tuberculosis ( Mtb) strains, with and without metformin treatment. Colony-forming unit (CFU) assays and cytokine expression levels in culture supernatants were measured. Through in silico prediction, metformin was identified as a potential HDT for ocular TB. It exhibited significant “anti-match” characteristics when compared to inflammatory pathways derived from the transcriptomic profiles of Mtb -infected RPE cells. A reduction in intracellular Mtb replication (t= 48 hours) was observed in Mtb -infected RPE cells treated with 4 mM metformin (median CFU: 2.4 × 10 5 CFU/mL vs. 3.9 × 10 5 CFU/mL in untreated cells; p = 0.019). Metformin treatment decreased the production of CCL2/MCP-1 and IL-6 in both Mtb -infected RPE cells and RECs. Additionally, in RECs, a significant reduction in the production of CXCL10/IP-10, CCL5/RANTES, and IL-8 was observed. Altogether, our data suggests that metformin demonstrates potential as a HDT for ocular TB by inhibiting intracellular Mtb replication and reducing inflammation in in vitro ocular TB models.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.