![]() ![]() We demonstrate that GSDMD is critical in the immunity to Leishmaniasis. In this study, we evaluate the role of the GSDMD in Leishmania infection. In this context, the requirement of K + efflux for NLRP3 activation in Leishmania-infected cells is paradoxical because Leishmania parasites actively prevent plasma membrane damage to avoid host cell death, as extensively reported 27, 28, 29, 30. In addition, the efflux of K +, which is well reported to be essential for NLRP3 activation in response to many stimuli, is indeed required for inflammasome activation in response to Leishmania in mouse and human cells 15, 17, 26. It was previously shown that host signaling pathways such as Dectin-1/Syk Kinase and ROS production generated during parasite phagocytosis account for NLRP3 activation 18. Such characteristics make GSDMD of pivotal importance in the induction of protective immune responses against intracellular pathogens 24.Īlthough many studies performed by different groups have demonstrated the critical role of the inflammasomes in the host response to Leishmania, the precise molecular mechanisms that lead to inflammasome activation remain unclear. In addition, the pores formed by GSDMD work as channels for releasing IL-1β, which can occur even in viable cells 25. The N-terminal portion of the protein oligomerizes in the plasma membrane, forming ring-shaped pores that cause cell death due to the release of intracellular content and osmotic imbalance (reviewed in ref. Upon inflammasome activation, caspase-1 and/or caspase-11 cleave GSDMD, releasing the N-terminal fragment that is the effector domain. GSDMD is composed of an effector N-terminal region and a C-terminal region with inhibitory functions. Mechanistically, pyroptotic cell death occurs upon cleavage of Gasdermin-D (GSDMD), a pore-forming effector protein that is cleaved by caspase-1 and caspase-4/11 21, 22, 23. 19).Īctivation of inflammatory caspases through the inflammasome can lead to inflammatory cell death, known as pyroptosis, a process that is important for the elimination of intracellular pathogens (reviewed in ref. ![]() The inflammasome is a protein complex composed of a sensor protein (such as NLRP3), an adapter protein (such as ASC protein), and an inflammatory caspase, such as caspase-1 and caspase-4 (human) and caspase-11 (mice) (reviewed in ref. Members of the endosomal Toll-like receptors (TLR3, 7, and 9) and the inflammasomes are among the innate immune receptors activated during Leishmania infection 12, 13, 14, 15, 16, 17, 18. ![]() Regardless of cell death, activation of innate immune receptors is a critical mechanism for the restriction of Leishmania infection (reviewed in ref. Thus, early after infection, the parasite manipulates the cell death machinery to prevent host cell death and secure the formation of the parasitophorous vacuoles that support parasite replication. Accordingly, inhibition of apoptosis in Leishmania infection has been reported in a broad range of species and in many cell types 5, 6, 7, 8, 9, 10. Once in the mammalian hosts, Leishmania replicates in professional phagocytes, and it is well accepted that cell death of the host cells is an effective mechanism to impair Leishmania replication. It is estimated that about 2 million new cases appear yearly, and 12 million patients have active disease 1, 2. This disease’s clinical manifestations may be visceral or cutaneous, ranging from single and painless lesions to diffuse or mucocutaneous forms 1, 3, 4. More than 20 species can cause Leishmaniasis in humans. Leishmaniasis is a neglected tropical disease that mainly affects less privileged populations in tropical and subtropical countries in Africa, Asia, and Latin America 1, 2. Altogether, our findings reveal that Leishmania subverts the normal functions of GSDMD, an important molecule to promote inflammasome activation and immunity in Leishmaniasis. Active NLRP3 inflammasome and GSDMD are present in skin biopsies of patients, demonstrating activation of this pathway in human leishmaniasis. 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. Further, GSDMD is processed into a non-canonical 25 kDa fragment. 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. NLRP3 inflammasome is key for disease outcome, but the molecular mechanisms upstream of the inflammasome activation are still unclear. Intracellular parasites from the Leishmania genus cause Leishmaniasis, a disease affecting millions of people worldwide. ![]()
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