Gasdermin-D activation promotes NLRP3 activation and host resistance to Leishmania infection

Keyla S. G. de Sá, Luana A. Amaral, Tamara S. Rodrigues, Adriene Y. Ishimoto, Warrison A. C. Andrade, Leticia Almeida, Felipe Freitas-Castro, Sabrina S. Batah, Sergio C. Oliveira, Mônica T. Pastorello, Alexandre T. Fabro and Dario S. Zamboni ()
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Keyla S. G. de Sá: Universidade de São Paulo
Luana A. Amaral: Universidade de São Paulo
Tamara S. Rodrigues: Universidade de São Paulo
Adriene Y. Ishimoto: Universidade de São Paulo
Warrison A. C. Andrade: Universidade de São Paulo
Leticia Almeida: Universidade de São Paulo
Felipe Freitas-Castro: Universidade de São Paulo
Sabrina S. Batah: Universidade de São Paulo
Sergio C. Oliveira: Universidade Federal de Minas Gerais
Mônica T. Pastorello: Universidade de São Paulo
Alexandre T. Fabro: Universidade de São Paulo
Dario S. Zamboni: Universidade de São Paulo

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Intracellular parasites from the Leishmania genus cause Leishmaniasis, a disease affecting millions of people worldwide. NLRP3 inflammasome is key for disease outcome, but the molecular mechanisms upstream of the inflammasome activation are still unclear. Here, we demonstrate that despite the absence of pyroptosis, Gasdermin-D (GSDMD) is active at the early stages of Leishmania infection in macrophages, allowing transient cell permeabilization, potassium efflux, and NLRP3 inflammasome activation. Further, GSDMD is processed into a non-canonical 25 kDa fragment. Gsdmd–/– macrophages and mice exhibit less NLRP3 inflammasome activation and are highly susceptible to infection by several Leishmania species, confirming the role of GSDMD for inflammasome-mediated host resistance. Active NLRP3 inflammasome and GSDMD are present in skin biopsies of patients, demonstrating activation of this pathway in human leishmaniasis. Altogether, our findings reveal that Leishmania subverts the normal functions of GSDMD, an important molecule to promote inflammasome activation and immunity in Leishmaniasis.

Date: 2023
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DOI: 10.1038/s41467-023-36626-6

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