Biology subjects

Makota, F. V.

Publications and source records attributed to Makota, F. V..

2 recordsLinked to original sources

bioRxiv2024

IL-2 enhances effector function but suppresses follicular localization of CD8+ T cells in chronic infection

Cytotoxic CD8+ T cells, essential in combating viral infections and cancer, become dysfunctional from prolonged antigen exposure. Precursors of exhausted T (TPEX) cells are pivotal in sustaining immune responses in chronic diseases and mediating immunotherapy efficacy. They also control viral infection within B-cell follicles, facilitated by CXCR5 expression. How cytokines regulate TPEX cell fate and follicular entry is not well understood. We reveal that IL-2 treatment enhances CD8+ T cell effector functions in chronic LCMV infection but hinders CXCR5+ TPEX cell formation and infection control within B-cell follicles. Mechanistically, IL-2 suppresses TPEX cell differentiation in a STAT5 and BLIMP1-dependent manner. Using an IL-2 fusion protein targeting CD122, we shifted the differentiation towards CX3CR1+ T cells with increased effector function. Clinical observations with low-dose IL-2 in autoimmune disease confirmed IL-2s inhibitory effect on CXCR5+ TPEX cells, underscoring IL-2s crucial regulatory role and therapeutic potential in modulating TPEX and effector T cell generation.

immunology↗

bioRxiv2022

A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites

With the advent of resistance to existing treatments, new drugs are needed to combat apicomplexan parasites such as the causative agents of malaria (Plasmodium species) and toxoplasmosis (Toxoplasma gondii). To identify new inhibitors of the mitochondrial electron transport chain (ETC) in these parasites, we developed a Seahorse XFe96 flux analyzer approach to screen compounds from the Medicines for Malaria Venture Pathogen Box for ETC inhibition. We identified six chemically diverse, on-target inhibitors of the ETC of T. gondii, five of which also target the ETC of Plasmodium falciparum. Two of the identified compounds (MMV024937 and MMV688853) represent novel ETC inhibitor chemotypes. We pinpoint the molecular targets of these inhibitors, demonstrating that all target ETC Complex III, with MMV688853 additionally targeting a kinase with a key role in parasite invasion of host cells. Most of the compounds remain effective inhibitors of parasites that are resistant to the clinically used Complex III inhibitor atovaquone. In sum, we have developed a versatile screening approach to identify and characterize new inhibitors of the ETC in apicomplexan parasites.

microbiology↗