{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:46:34Z","timestamp":1791337594008,"version":"4.3.1"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T00:00:00Z","timestamp":1665705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p><jats:italic>Streptococcus equi subsp. zooepidemicus<\/jats:italic> (<jats:italic>S. zooepidemicus<\/jats:italic>, SEZ) is an essential zoonotic bacterial pathogen that can cause various inflammation, such as meningitis, endocarditis, and pneumonia. Gasdermin D (GSDMD) is involved in cytokine release and cell death, indicating an important role in controlling the microbial infection. This study investigated the protective role of GSDMD in mice infected with SEZ and examined the role of GSDMD in peritoneal macrophages in the infection. GSDMD-deficient mice were more susceptible to intraperitoneal infection with SEZ, and the white pulp structure of the spleen was seriously damaged in GSDMD-deficient mice. Although the increased proportion of macrophages did not depend on GSDMD in both spleen and peritoneal lavage fluid (PLF), deficiency of GSDMD caused the minor release of the pro-inflammatory cytokines interleukin-1\u03b2 (IL-1\u03b2) and interleukin-18 (IL-18) during the infection <jats:italic>in vivo<\/jats:italic>. <jats:italic>In vitro<\/jats:italic>, SEZ infection induced more release of IL-1\u03b2, IL-18, and lactate dehydrogenase (LDH) in wild-type macrophages than in GSDMD-deficient macrophages. Finally, we demonstrated that pore formation and pyroptosis of macrophages depended on GSDMD. Our findings highlight the host defense mechanisms of GSDMD against SEZ infection, providing a potential therapeutic target in SEZ infection.<\/jats:p>","DOI":"10.3389\/fimmu.2022.1005925","type":"journal-article","created":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T08:39:12Z","timestamp":1665736752000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Gasdermin D protects against Streptococcus equi subsp. zooepidemicus infection through macrophage pyroptosis"],"prefix":"10.3389","volume":"13","author":[{"given":"Guobin","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjin","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunliu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3201\/eid2501.181029","article-title":"Zoonotic endocarditis in a man, the Netherlands","volume":"25","author":"Sleutjens","year":"2019","journal-title":"Emerg Infect Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/tbed.14331","article-title":"Zoonotic infection and clonal dissemination of streptococcus equi subspecies zooepidemicus sequence type 194 isolated from humans in Thailand","volume":"69","author":"Kerdsin","year":"2021","journal-title":"Transbound Emerg Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/tbed.13645","article-title":"Genetic characterization of streptococcus equi subspecies zooepidemicus associated with high swine mortality in the united states","volume":"67","author":"Chen","year":"2020","journal-title":"Transbound Emerg Dis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3201\/eid2610.191485","article-title":"Streptococcus equi subspecies zooepidemicus and sudden deaths in swine, Canada","volume":"26","author":"Costa","year":"2020","journal-title":"Emerg Infect Dis"},{"key":"B5","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1128\/microbiolspec.GPP3-0016-2018","article-title":"Infections caused by group c and G streptococcus (Streptococcus dysgalactiae subsp. equisimilis and others): Epidemiological and clinical aspects","volume":"7","author":"Baracco","year":"2019","journal-title":"Microbiol Spectr"},{"key":"B6","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1021\/acs.jproteome.6b00571","article-title":"Virulent and vaccine strains of streptococcus equi ssp. zooepidemicus have different influences on phagocytosis and cytokine secretion of macrophages","volume":"16","author":"Jie","year":"2017","journal-title":"J Proteome Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00465","article-title":"Streptococcus equi subsp. zooepidemicus invades and survives in epithelial cells","volume":"7","author":"Skive","year":"2017","journal-title":"Front Cell Infect Microbiol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2021.109165","article-title":"Streptococcus equi-derived extracellular vesicles as a vaccine candidate against streptococcus equi infection","volume":"259","author":"Lee","year":"2021","journal-title":"Vet Microbiol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.rvsc.2019.04.021","article-title":"Identification of a surface protective antigen, map of streptococcus equi subspecies zooepidemicus","volume":"124","author":"Tang","year":"2019","journal-title":"Res Vet Sci"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100381","article-title":"Critical roles of asc inflammasomes in caspase-1 activation and host innate resistance to streptococcus pneumoniae infection","volume":"187","author":"Fang","year":"2011","journal-title":"J Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C114.548982","article-title":"Rna and beta-hemolysin of group b streptococcus induce interleukin-1beta (Il-1beta) by activating Nlrp3 inflammasomes in mouse macrophages","volume":"289","author":"Gupta","year":"2014","journal-title":"J Biol Chem"},{"key":"B12","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1038\/nrmicro2070","article-title":"Pyroptosis: Host cell death and inflammation","volume":"7","author":"Bergsbaken","year":"2009","journal-title":"Nat Rev Microbiol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/4510628","article-title":"High glucose induces the loss of retinal pericytes partly Via Nlrp3-Caspase-1-Gsdmd-Mediated pyroptosis","volume":"2020","author":"Gan","year":"2020","journal-title":"BioMed Res Int"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aax4917","article-title":"Irf2 transcriptionally induces gsdmd expression for pyroptosis","volume":"12","author":"Kayagaki","year":"2019","journal-title":"Sci Signal"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/nature18629","article-title":"Inflammasome-activated gasdermin d causes pyroptosis by forming membrane pores","volume":"535","author":"Liu","year":"2016","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"108375","DOI":"10.1016\/j.exer.2020.108375","article-title":"Gsdmd, an executor of pyroptosis, is involved in il-1beta secretion in aspergillus fumigatus keratitis","volume":"202","author":"Zhao","year":"2020","journal-title":"Exp Eye Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1607769113","article-title":"Gsdmd P30 elicited by caspase-11 during pyroptosis forms pores in membranes","volume":"113","author":"Aglietti","year":"2016","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nature18590","article-title":"Pore-forming activity and structural autoinhibition of the gasdermin family","volume":"535","author":"Ding","year":"2016","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-021-00755-6","article-title":"Gsdme-mediated pyroptosis promotes inflammation and fibrosis in obstructive nephropathy","volume":"28","author":"Li","year":"2021","journal-title":"Cell Death Differ"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2020.06.015","article-title":"Miltirone induces cell death in hepatocellular carcinoma cell through gsdme-dependent pyroptosis","volume":"10","author":"Zhang","year":"2020","journal-title":"Acta Pharm Sin B"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.07.027","article-title":"Interleukin-1beta maturation triggers its relocation to the plasma membrane for gasdermin-D-Dependent and -independent secretion","volume":"24","author":"Monteleone","year":"2018","journal-title":"Cell Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2022.109411","article-title":"Caspase-1 deficiency impairs neutrophils recruitment and bacterial clearance in streptococcus equi ssp. zooepidemicus infected mice","volume":"268","author":"Lin","year":"2022","journal-title":"Vet Microbiol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.730567","article-title":"Prevention of cyclophosphamide-induced immunosuppression in mice with traditional Chinese medicine xuanfei baidu decoction","volume":"12","author":"Yan","year":"2021","journal-title":"Front Pharmacol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcis.2017.10.104","article-title":"Differential effects of graphene oxide nanosheets on candida albicans phagocytosis by murine peritoneal macrophages","volume":"512","author":"Diez-Orejas","year":"2018","journal-title":"J Colloid Interface Sci"},{"key":"B25","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.rvsc.2017.01.027","article-title":"Cd44 deficiency enhanced streptococcus equi ssp. zooepidemicus dissemination and inflammation response in a mouse model","volume":"115","author":"Fu","year":"2017","journal-title":"Res Vet Sci"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.18632\/aging.101831","article-title":"Methane alleviates sepsis-induced injury by inhibiting pyroptosis and apoptosis: In vivo and in vitro experiments","volume":"11","author":"Li","year":"2019","journal-title":"Aging (Albany NY)"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1960","article-title":"Caspase-1-Induced pyroptosis is an innate immune effector mechanism against intracellular bacteria","volume":"11","author":"Miao","year":"2010","journal-title":"Nat Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2016.100","article-title":"Pyroptosis is driven by non-selective gasdermin-d pore and its morphology is different from mlkl channel-mediated necroptosis","volume":"26","author":"Chen","year":"2016","journal-title":"Cell Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1809548115","article-title":"Caspase-8 induces cleavage of gasdermin d to elicit pyroptosis during yersinia infection","volume":"115","author":"Sarhan","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00491","article-title":"Macrophage cytokines: Involvement in immunity and infectious diseases","volume":"5","author":"Arango Duque","year":"2014","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2021.107781","article-title":"Interleukin-17 induces pyroptosis in osteoblasts through the Nlrp3 inflammasome pathway in vitro","volume":"96","author":"Lei","year":"2021","journal-title":"Int Immunopharmacol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1038\/s41419-019-1761-4","article-title":"Propofol directly induces caspase-1-Dependent macrophage pyroptosis through the Nlrp3-asc inflammasome","volume":"10","author":"Sun","year":"2019","journal-title":"Cell Death Dis"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12941","article-title":"Acid-sensing ion channels regulate nucleus pulposus cell inflammation and pyroptosis Via the Nlrp3 inflammasome in intervertebral disc degeneration","volume":"54","author":"Zhao","year":"2021","journal-title":"Cell Prolif"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/tbed.13584","article-title":"Novel streptococcus equi strains causing strangles outbreaks in Arabian horses in Egypt","volume":"67","author":"Tartor","year":"2020","journal-title":"Transbound Emerg Dis"},{"key":"B35","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1186\/s12879-017-2262-7","article-title":"Zoonotic necrotizing myositis caused by streptococcus equi subsp. zooepidemicus in a farmer","volume":"17","author":"Kittang","year":"2017","journal-title":"BMC Infect Dis"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.tvjl.2010.04.028","article-title":"Streptococcus zooepidemicus: An emerging canine pathogen","volume":"188","author":"Priestnall","year":"2011","journal-title":"Vet J"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2017.06.020","article-title":"Diversity of streptococcus equi subsp. zooepidemicus strains isolated from the Spanish sheep and goat population and the identification, function and prevalence of a novel arbutin utilisation system","volume":"207","author":"Steward","year":"2017","journal-title":"Vet Microbiol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1637\/aviandiseases-D-19-00191","article-title":"An outbreak associated with streptococcus equi subsp. zooepidemicus in layers: Evidence of fecal transmission","volume":"64","author":"Garmyn","year":"2020","journal-title":"Avian Dis"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2015.09.003","article-title":"Streptococcus equi meningitis","volume":"22","author":"van Samkar","year":"2016","journal-title":"Clin Microbiol Infect"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fvets.2022.827082","article-title":"Bacterin vaccination provides insufficient protection against streptococcus equi subspecies zooepidemicus infection in pigs","volume":"9","author":"Hau","year":"2022","journal-title":"Front Vet Sci"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.2460\/javma.247.3.300","article-title":"Streptococcus equi subsp zooepidemicus pleuropneumonia and peritonitis in a dromedary camel (Camelus dromedarius) calf in north America","volume":"247","author":"Stoughton","year":"2015","journal-title":"J Am Vet Med Assoc"},{"key":"B42","article-title":"[Spontaneous peritonitis by streptococcus equi subsp. zooepidemicus]","volume":"30","author":"Escudero-Jimenez","year":"2017","journal-title":"Rev Esp Quimioter"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000001512","article-title":"Therapeutic effects of hyaluronic acid in peritonitis-induced sepsis in mice","volume":"54","author":"Lee","year":"2020","journal-title":"Shock"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1002300","article-title":"Early enhanced local neutrophil recruitment in peritonitis-induced sepsis improves bacterial clearance and survival","volume":"185","author":"Craciun","year":"2010","journal-title":"J Immunol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"14961","DOI":"10.1038\/s41598-018-33264-7","article-title":"Chromosome replication as a measure of bacterial growth rate during escherichia coli infection in the mouse peritonitis model","volume":"8","author":"Haugan","year":"2018","journal-title":"Sci Rep"},{"key":"B46","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.micpath.2016.08.019","article-title":"Immuno-pathophysiological responses of mouse model to experimental infection with brucella melitensis and its lipopolysaccharides Via intraperitoneal route","volume":"100","author":"Osman","year":"2016","journal-title":"Microb Pathog"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151613","article-title":"Pyroptosis triggers pore-induced intracellular traps (Pits) that capture bacteria and lead to their clearance by efferocytosis","volume":"213","author":"Jorgensen","year":"2016","journal-title":"J Exp Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800788","article-title":"Gasdermin d promotes Aim2 inflammasome activation and is required for host protection against francisella novicida","volume":"201","author":"Zhu","year":"2018","journal-title":"J Immunol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1038\/s41586-021-04384-4","article-title":"Streptococcal pyrogenic exotoxin b cleaves gsdma and triggers pyroptosis","volume":"602","author":"Deng","year":"2022","journal-title":"Nature"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.167409","article-title":"Gasdermin d and beyond - gasdermin-mediated pyroptosis in bacterial infections","volume":"434","author":"Booty","year":"2022","journal-title":"J Mol Biol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900045","article-title":"Gasdermin d protects from melioidosis through pyroptosis and direct killing of bacteria","volume":"202","author":"Wang","year":"2019","journal-title":"J Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.02468-16","article-title":"Extracellular nucleases of streptococcus equi subsp. zooepidemicus degrade neutrophil extracellular traps and impair macrophage activity of the host","volume":"83","author":"Ma","year":"2017","journal-title":"Appl Environ Microbiol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1186\/s40164-022-00254-5","article-title":"A pig-a conditional knock-out mice model mediated by vav-icre: Stable gpi-deficient and mild hemolysis","volume":"11","author":"Chen","year":"2022","journal-title":"Exp Hematol Oncol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1159\/000335216","article-title":"Innate immune functions of macrophage subpopulations in the spleen","volume":"4","author":"den Haan","year":"2012","journal-title":"J Innate Immun"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aah5520","article-title":"Cd169(+) macrophages orchestrate innate immune responses by regulating bacterial localization in the spleen","volume":"2","author":"Perez","year":"2017","journal-title":"Sci Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/nature12034","article-title":"Macrophage biology in development, homeostasis and disease","volume":"496","author":"Wynn","year":"2013","journal-title":"Nature"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00763","article-title":"Unique action of interleukin-18 on T cells and other immune cells","volume":"9","author":"Nakanishi","year":"2018","journal-title":"Front Immunol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"649","DOI":"10.3390\/ijms20030649","article-title":"Interleukin-18 in health and disease","volume":"20","author":"Yasuda","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00133-15","article-title":"A group a streptococcus adp-ribosyltransferase toxin stimulates a protective interleukin 1beta-dependent macrophage immune response","volume":"6","author":"Lin","year":"2015","journal-title":"mBio"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.13373","article-title":"Inflammasome activation and il-1beta signalling in group a streptococcus disease","volume":"23","author":"Richter","year":"2021","journal-title":"Cell Microbiol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aah3539","article-title":"Il-1beta is an innate immune sensor of microbial proteolysis","volume":"1","author":"LaRock","year":"2016","journal-title":"Sci Immunol"},{"key":"B62","doi-asserted-by":"publisher","first-page":"132","DOI":"10.3390\/pathogens10020132","article-title":"The relevance of il-1-Signaling in the protection against gram-positive bacteria","volume":"10","author":"Midiri","year":"2021","journal-title":"Pathogens"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.02.006","article-title":"Gasdermin d in pyroptosis","volume":"11","author":"Burdette","year":"2021","journal-title":"Acta Pharm Sin B"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2015.139","article-title":"Gasdermin d is an executor of pyroptosis and required for interleukin-1beta secretion","volume":"25","author":"He","year":"2015","journal-title":"Cell Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1005925\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T08:39:17Z","timestamp":1665736757000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1005925\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,14]]},"references-count":64,"alternative-id":["10.3389\/fimmu.2022.1005925"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1005925","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,14]]},"article-number":"1005925"}}