EMD Seminar Series Monell Lecture: Shaden Kamhawi - "Noncanonical processing of GSDMD contributes to a distinct vector-specific inflammatory response following Leishmania mexicana transmission via sand fly bites"

Cutaneous leishmaniasis (CL) manifests in different forms ranging from uncomplicated, self-healing skin lesions to chronic diffuse non-healing lesions, such as those caused by L. major and L. mexicana, respectively. The drivers of these distinct pathologies are not well understood. Previously, we demonstrated that bites from a Leishmania-infected sand fly initiates a vector-specific acute and intense host immune response driven by inflammasome-dependent IL1b production. We also established that prolonged bleeding during feeding of the vector sand fly controls this inflammation through induction of the cytoprotective enzyme, hemeoxygenase-1. Both events contribute to parasite survival and establishment in the host, and account, in part, for the enhanced virulence of vector-transmitted parasites. We now show the differential production of a noncanonical p40 NT-GSDMD fragment in response to L. mexicana-infected bites that was less pronounced after vector-transmission of L. major. This translated into a robust production of IL-33 after L. mexicana-infected bites that was not reproduced following needle injection of the parasites. We hypothesize that the association between IL-33 and type 2 immunity may allude to a new pathway that favors development of non-healing chronic CL. Investigating the interactions occurring at the site of Leishmania-infected vector bites continues to reveal key insights into the drivers of leishmaniasis pathology.

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