Inflammasome activation: the importance in leishmaniasis, influenza and COVID-19

Leishmania is an obligate intracellular parasite that causes Leishmaniasis, a disease that affects millions of people worldwide. Leishmania evades immune response by inhibiting specific processes on parasite-containing immune cells, yet the NLRP3 inflammasome activation is key for disease outcome. The molecular mechanisms upstream of the inflammasome activation are still unclear and there is no evident host cell death in Leishmania-infected cells. Here, we investigated the participation of Gasdermin-D (GSDMD, a pore-forming effector protein associated with pyroptosis) during Leishmania infection in macrophages and in vivo. We demonstrated that despite the absence of pyroptosis, GSDMD is active at the early stages of L. amazonensis infection in macrophages, allowing a transient cell permeabilization and potassium efflux, promoting NLRP3 inflammasome activation. However, soon after the infection, GSDMD is processed in to a non-canonical 25 kDa fragment in Leishmania-infected cells. Non-canonical processing of GSDMD does not require caspase activation and may represent a subversion strategy used by Leishmania to inhibit cell death. Gsdmd-/- macrophages exhibit less ASC puncta formation and IL-1β production in response to infection, suggesting that the transient GSDMD-mediated permeabilization contributes for NLRP3 inflammasome activation. Mouse and macrophages deficient in GSDMD were highly susceptible to infection by several Leishmania species, including L. amazonensis, L. major, L. braziliensis and L. mexicana, confirming a key role of Gasdermin-D for inflammasome mediated host resistance to infection. Finally, ASC/NLRP3 puncta and cleaved Gasdermin-D were present in skin biopsies of leishmaniasis patients, supporting the role of these molecules during active disease in humans. Altogether, our findings reveal that Leishmania subvert the normal functions of GSDMD, a molecule that is key to promote inflammasome activation and immunity in Leishmaniasis. (AU)