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

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de Sa, Keyla S. G. ; Amaral, Luana A. ; Rodrigues, Tamara S. ; Ishimoto, Adriene Y. ; de Andrade, Warrison A. C. ; de Almeida, Leticia ; Freitas-Castro, Felipe ; Batah, Sabrina S. ; Oliveira, Sergio C. ; Pastorello, Monica T. ; Fabro, Alexandre T. ; Zamboni, Dario S.

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 14, n. 1, p. 19-pg., 2023-02-24.

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. Here, de Sa et al. show that Gasdermin-D is transiently activated in Leishmania-infected macrophages and promotes NLRP3 inflammasome activation, but not cell death. Gasdermin-D is cleaved into a noncanonical fragment, indicating that Leishmania subverts Gasdermin-D-mediated host response to establish leishmaniasis. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 18/14398-0 - UK:Brazil Joint Centre Partnership in Leishmaniasis (JCPiL)
• Grantee: Angela Kaysel Cruz
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/11342-6 - Mechanisms and consequences of the activation of cytoplasmic receptors by intracellular pathogens
• Grantee: Dario Simões Zamboni
• Support Opportunities: Research Projects - Thematic Grants