We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
NLRP1-dependent activation of Gasdermin D in neutrophils controls cutaneous leishmaniasis.
- Authors
Goris, Michiel; Passelli, Katiuska; Peyvandi, Sanam; Díaz-Varela, Miriam; Billion, Oaklyne; Prat-Luri, Borja; Demarco, Benjamin; Desponds, Chantal; Termote, Manon; Iniguez, Eva; Dey, Somaditya; Malissen, Bernard; Kamhawi, Shaden; Hurrell, Benjamin P.; Broz, Petr; Tacchini-Cottier, Fabienne
- Abstract
Intracellular pathogens that replicate in host myeloid cells have devised ways to inhibit the cell's killing machinery. Pyroptosis is one of the host strategies used to reduce the pathogen replicating niche and thereby control its expansion. The intracellular Leishmania parasites can survive and use neutrophils as a silent entry niche, favoring subsequent parasite dissemination into the host. Here, we show that Leishmania mexicana induces NLRP1- and caspase-1-dependent Gasdermin D (GSDMD)-mediated pyroptosis in neutrophils, a process critical to control the parasite-induced pathology. In the absence of GSDMD, we observe an increased number of infected dermal neutrophils two days post-infection. Using adoptive neutrophil transfer in neutropenic mice, we show that pyroptosis contributes to the regulation of the neutrophil niche early after infection. The critical role of neutrophil pyroptosis and its positive influence on the regulation of the disease outcome was further demonstrated following infection of mice with neutrophil-specific deletion of GSDMD. Thus, our study establishes neutrophil pyroptosis as a critical regulator of leishmaniasis pathology. Author summary: Leishmaniases are neglected infectious diseases with around 1 million new cases reported per year. Neutrophils are rapidly and massively recruited to the site of infection. Several Leishmania species including Leishmania mexicana, inhibit the host neutrophil antimicrobial response, using these cells as an entry shelter. Here, we discover a novel host defense mechanism against Leishmania mexicana that controls neutrophil presence at the onset of infection. The inflammasomes are multiprotein signaling complexes that detect infection and induce pyroptotic cell death. We show that the NLRP1 inflammasome is important in the control of lesion development and parasite burden. We identify NLRP1-driven GSDMD pyroptosis in neutrophils as critical in the control of the early neutrophil pool, impacting the outcome of infection. Taken together, we show that neutrophil pyroptosis is an essential player in cutaneous leishmaniasis.
- Subjects
MYELOID cells; CUTANEOUS leishmaniasis; CELL death; LEISHMANIA mexicana; PYROPTOSIS
- Publication
PLoS Pathogens, 2024, Vol 20, Issue 9, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1012527