The Bhagirath Singh Early Career Award in Infection and Immunity 2025 Recipient
Francesca Di Cara
Chronic inflammatory diseases are the greatest threat to human health worldwide. Acute inflammation is part of the body's defense mechanism. Chronic inflammation has the same symptoms as acute inflammation, but they cannot resolve, leading to diseases. The hallmarks of chronic inflammation are the infiltration of immune cells, such as macrophages and lymphocytes, into the tissue site, producing signaling molecules called inflammatory cytokines such as TNF-a that sustain immune responses. To date, therapies blocking TNF-a are the most effective in inflammatory diseases as they prevent the activation of immune and inflammatory cascades such as TNF pathway. However, not every patient responds. We need to develop novel therapies, and to do it, we must better understand how inflammatory cascades, such as the TNF pathway, work. We used the fruit fly model system, as their genes can be easily manipulated and have basic cellular processes, including aspects of the immune defense, similar to those in humans, to quickly explore new mechanisms that control the TNF pathway. We discovered that peroxisomes, structures within every cell, regulate TNF signaling. Peroxisomes are important to turn the immune system on and off. We found that peroxisomes in the immune cells are required to "build" the TNF signal by organizing its key signaling protein into scaffolds. We confirmed this result in humans. Our research program aims to define 1) what step of the TNF signaling is controlled by peroxisomes under sterile and immune stimuli; 2) how peroxisomes orchestrate the signaling "scaffolds" in the TNF pathway; 3) Are these signaling found altered in immune cells of patients affected by autoinflammatory diseases or by peroxisomal dysfunctions known as PBDs and could they be harnessed to develop novel treatments; Results from this study will identify new mechanisms that regulate TNF pathways-mediated inflammation and will direct the development of new therapies.
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