Dataset Information

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

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.

SUBMITTER: de Sa KSG

PROVIDER: S-EPMC9958042 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

de Sá Keyla S G KSG Amaral Luana A LA Rodrigues Tamara S TS Ishimoto Adriene Y AY de Andrade Warrison A C WAC de Almeida Leticia L Freitas-Castro Felipe F Batah Sabrina S SS Oliveira Sergio C SC Pastorello Mônica T MT Fabro Alexandre T AT Zamboni Dario S DS

Nature communications 20230224 1

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 ...[more]

PMID: 36828815

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Project description:For more than 3 decades, mounting evidence has associated porcine reproductive and respiratory syndrome virus (PRRSV) infection with late-term abortions and stillbirths in sows and respiratory disease in piglets, causing enormous economic losses to the global swine industry. However, to date, the underlying mechanisms of PRRSV-triggered cell death have not been well clarified, especially in the pulmonary inflammatory injury characterized by the massive release of pro-inflammatory factors. Here, we demonstrated that PRRSV infection triggered gasdermin D-mediated host pyroptosis in vitro and in vivo. Mechanistically, PRRSV infection triggered disassembly of the trans-Golgi network (TGN); the dispersed TGN then acted as a scaffold for NLRP3 activation through phosphatidylinositol-4-phosphate. In addition, PRRSV replication-transcription complex (RTC) formation stimulated TGN dispersion and pyroptotic cell death. Furthermore, our results indicated that TMEM41B, an endoplasmic reticulum (ER)-resident host protein, functioned as a crucial host factor in the formation of PRRSV RTC, which is surrounded by the intermediate filament network. Collectively, these findings uncover new insights into clinical features as previously unrecognized mechanisms for PRRSV-induced pathological effects, which may be conducive to providing treatment options for PRRSV-associated diseases and may be conserved during infection by other highly pathogenic viruses. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the pathogens responsible for major economic losses in the global swine industry. Characterizing the detailed process by which PRRSV induces cell death pathways will help us better understand viral pathogenesis and provide implications for therapeutic intervention against PRRSV. Here, we showed that PRRSV infection induces GSDMD-driven host pyroptosis and IL-1β secretion through NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in vitro and in vivo. Furthermore, the molecular mechanisms of PRRSV-induced NLRP3 inflammasome activation and pyroptosis are elucidated here. The dispersed trans-Golgi network (TGN) induced by PRRSV serves as a scaffold for NLRP3 aggregation into multiple puncta via phosphatidylinositol 4-phosphate (PtdIns4P). Moreover, the formation of PRRSV replication-transcription complex is essential for TGN dispersion and host pyroptosis. This research advances our understanding of the PRRSV-mediated inflammatory response and cell death pathways, paving the way for the development of effective treatments for PRRSV diseases.

Project description:Parasites of the Leishmania genus infect and survive within macrophages by inhibiting several microbicidal molecules, such as nitric oxide and pro-inflammatory cytokines. In this context, various species of Leishmania have been reported to inhibit or reduce the production of IL-1β both in vitro and in vivo. However, the mechanism whereby Leishmania parasites are able to affect IL-1β production and secretion by macrophages is still not fully understood. Dependent on the stimulus at hand, the maturation of IL-1β is facilitated by different inflammasome complexes. The NLRP3 inflammasome has been shown to be of pivotal importance in the detection of danger molecules such as inorganic crystals like asbestos, silica and malarial hemozoin, (HZ) as well as infectious agents. In the present work, we investigated whether Leishmania parasites modulate NLRP3 inflammasome activation. Using PMA-differentiated THP-1 cells, we demonstrate that Leishmania infection effectively inhibits macrophage IL-1β production upon stimulation. In this context, the expression and activity of the metalloprotease GP63 - a critical virulence factor expressed by all infectious Leishmania species - is a prerequisite for a Leishmania-mediated reduction of IL-1β secretion. Accordingly, L. mexicana, purified GP63 and GP63-containing exosomes, caused the inhibition of macrophage IL-1β production. Leishmania-dependent suppression of IL-1β secretion is accompanied by an inhibition of reactive oxygen species (ROS) production that has previously been shown to be associated with NLRP3 inflammasome activation. The observed loss of ROS production was due to an impaired PKC-mediated protein phosphorylation. Furthermore, ROS-independent inflammasome activation was inhibited, possibly due to an observed GP63-dependent cleavage of inflammasome and inflammasome-related proteins. Collectively for the first time, we herein provide evidence that the protozoan parasite Leishmania, through its surface metalloprotease GP63, can significantly inhibit NLRP3 inflammasome function and IL-1β production.

Dataset Information

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

Publications

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

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