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Gray Postdoctoral Fellowship"],"award-info":[{"award-number":["Howard Hughes Medical Institute Hanna H. Gray Postdoctoral Fellowship"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    <jats:italic>Salmonella enterica<\/jats:italic>\n                    serovar Typhimurium is a Gram-negative pathogen that uses two distinct type III secretion systems (T3SSs), termed\n                    <jats:italic>Salmonella<\/jats:italic>\n                    pathogenicity island (SPI)-1 and SPI-2, to deliver virulence factors into the host cell. The SPI-1 T3SS enables\n                    <jats:italic>Salmonella<\/jats:italic>\n                    to invade host cells, while the SPI-2 T3SS facilitates\n                    <jats:italic>Salmonella<\/jats:italic>\n                    \u2019s intracellular survival. In mice, a family of cytosolic immune sensors, including NAIP1, NAIP2, and NAIP5\/6, recognizes the SPI-1 T3SS needle, inner rod, and flagellin proteins, respectively. Ligand recognition triggers assembly of the NAIP\/NLRC4 inflammasome, which mediates caspase-1 activation, IL-1 family cytokine secretion, and pyroptosis of infected cells. In contrast to mice, humans encode a single NAIP that broadly recognizes all three ligands. The role of NAIP\/NLRC4 or other inflammasomes during\n                    <jats:italic>Salmonella<\/jats:italic>\n                    infection of human macrophages is unclear. We find that although the NAIP\/NLRC4 inflammasome is essential for detecting T3SS ligands in human macrophages, it is partially required for responses to infection, as\n                    <jats:italic>Salmonella<\/jats:italic>\n                    also activated the NLRP3 and CASP4\/5 inflammasomes. Importantly, we demonstrate that combinatorial NAIP\/NLRC4 and NLRP3 inflammasome activation restricts\n                    <jats:italic>Salmonella<\/jats:italic>\n                    replication in human macrophages. In contrast to SPI-1, the SPI-2 T3SS inner rod is not sensed by human or murine NAIPs, which is thought to allow\n                    <jats:italic>Salmonella<\/jats:italic>\n                    to evade host recognition and replicate intracellularly. Intriguingly, we find that human NAIP detects the SPI-2 T3SS needle protein. Critically, in the absence of both flagellin and the SPI-1 T3SS, the NAIP\/NLRC4 inflammasome still controlled intracellular\n                    <jats:italic>Salmonella<\/jats:italic>\n                    burden. These findings reveal that recognition of\n                    <jats:italic>Salmonella<\/jats:italic>\n                    SPI-1 and SPI-2 T3SSs and engagement of both the NAIP\/NLRC4 and NLRP3 inflammasomes control\n                    <jats:italic>Salmonella<\/jats:italic>\n                    infection in human macrophages.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009718","type":"journal-article","created":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T13:39:07Z","timestamp":1643031547000},"page":"e1009718","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":81,"title":["Human NAIP\/NLRC4 and NLRP3 inflammasomes detect Salmonella type III secretion system activities to restrict intracellular bacterial replication"],"prefix":"10.1371","volume":"18","author":[{"given":"Nawar","family":"Naseer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa S.","family":"Egan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4824-9898","authenticated-orcid":true,"given":"Valeria M.","family":"Reyes Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William P.","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma N.","family":"Hunter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tabitha","family":"Demissie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Rauch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor E.","family":"Brodsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5214-9577","authenticated-orcid":true,"given":"Sunny","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,1,24]]},"reference":[{"key":"ppat.1009718.ref001","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/978-3-319-41171-2_3","article-title":"Salmonella and the inflammasome: battle for intracellular dominance","author":"SM 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