{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,13]],"date-time":"2025-09-13T16:37:58Z","timestamp":1757781478386,"version":"3.41.2"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T00:00:00Z","timestamp":1611705600000},"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","award":["31400764, 81772229"],"award-info":[{"award-number":["31400764, 81772229"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LY13H190007"],"award-info":[{"award-number":["LY13H190007"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007194","name":"Wenzhou Municipal Science and Technology Bureau","doi-asserted-by":"publisher","award":["Y20150113"],"award-info":[{"award-number":["Y20150113"]}],"id":[{"id":"10.13039\/501100007194","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p><jats:italic>Vibrio vulnificus<\/jats:italic> (<jats:italic>V. vulnificus<\/jats:italic>) is an estuarine bacterium that is capable of causing rapidly fatal infection in humans. Proper\u00a0polarization\u00a0and bactericidal activity of\u00a0macrophages\u00a0play essential roles in defending against invading pathogens. How macrophages limit <jats:italic>V. vulnificus<\/jats:italic> infection remains not well understood. Here we report that tuberous sclerosis complex 1 (TSC1) is crucial for the regulation of <jats:italic>V. vulnificus<\/jats:italic>-induced macrophage polarization, bacterial clearance, and cell death. Mice with myeloid-specific deletion of TSC1 exhibit a significant reduction of survival time after <jats:italic>V. vulnificus<\/jats:italic> infection. <jats:italic>V. vulnificus<\/jats:italic> infection induces both M1 and M2 polarization. However, TSC1 deficient macrophages show enhanced M1 response to <jats:italic>V. vulnificus<\/jats:italic> infection. Interestedly, the absence of TSC1 in myeloid cells results in impaired bacterial clearance both <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> after <jats:italic>V. vulnificus<\/jats:italic> infection. Inhibition of the mammalian target of rapamycin (mTOR) activity significantly reverses <jats:italic>V. vulnificus<\/jats:italic>-induced hypersensitive M1 response and resistant bactericidal activity both in wild-type and TSC1-deficient macrophages. Moreover, <jats:italic>V. vulnificus<\/jats:italic> infection causes cell death of macrophages, possibly contributes to defective of bacterial clearance, which also exhibits in a mTORC1-dependent manner. These findings highlight an essential role for the TSC1-mTOR signaling in the regulation of innate immunity against <jats:italic>V. vulnificus<\/jats:italic> infection.<\/jats:p>","DOI":"10.3389\/fcimb.2020.596609","type":"journal-article","created":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T07:53:49Z","timestamp":1611734029000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["The Role of TSC1 in the Macrophages Against Vibrio vulnificus Infection"],"prefix":"10.3389","volume":"10","author":[{"given":"Xian-Hui","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Lou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Na","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liu-Ying","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Ju","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng-Meng","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong-Liang","family":"Lou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan-Li","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3733","DOI":"10.4049\/jimmunol.181.6.3733","article-title":"Macrophage polarization in bacterial infections","volume":"181","author":"Benoit","year":"2008","journal-title":"J. Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"R49","DOI":"10.1186\/cc5783","article-title":"Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis","volume":"11","author":"Bozza","year":"2007","journal-title":"Crit. Care"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2834","DOI":"10.1038\/ncomms3834","article-title":"The TSC-mTOR pathway regulates macrophage polarization","volume":"4","author":"Byles","year":"2013","journal-title":"Nat. Commun."},{"key":"B4","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1111\/j.1365-2249.2005.02797.x","article-title":"Differential pattern of cytokine expression by macrophages infected in vitro with different Mycobacterium tuberculosis genotypes","volume":"140","author":"Chacon-Salinas","year":"2005","journal-title":"Clin. Exp. Immunol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s12929-017-0368-2","article-title":"Vibrio vulnificus MARTX cytotoxin causes inactivation of phagocytosis-related signaling molecules in macrophages","volume":"24","author":"Chen","year":"2017","journal-title":"J. Biomed. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1002\/cbin.10955","article-title":"Pseudomonas aeruginosa infection alters the macrophage phenotype switching process during wound healing in diabetic mice","volume":"42","author":"Chen","year":"2018","journal-title":"Cell Biol. Int."},{"key":"B7","first-page":"81","article-title":"Vibrio vulnificus infection: clinical manifestations, pathogenesis, and antimicrobial therapy","volume":"36","author":"Chiang","year":"2003","journal-title":"J. Microbiol. Immunol. Infect."},{"key":"B8","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.smim.2015.08.001","article-title":"Control of macrophage metabolism and activation by mTOR and Akt signaling","volume":"27","author":"Covarrubias","year":"2015","journal-title":"Semin. Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/nrmicro2295","article-title":"Bacterial manipulation of innate immunity to promote infection","volume":"8","author":"Diacovich","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.00997","article-title":"Vibrio vulnificus: An Environmental and Clinical Burden","volume":"8","author":"Heng","year":"2017","journal-title":"Front. Microbiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"e157","DOI":"10.1016\/j.ijid.2010.11.003","article-title":"A comprehensive review of Vibrio vulnificus: an important cause of severe sepsis and skin and soft-tissue infection","volume":"15","author":"Horseman","year":"2011","journal-title":"Int. J. Infect. Dis."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.587961","article-title":"NLRP3 and mTOR Reciprocally Regulate Macrophage Phagolysosome Formation and Acidification Against Vibrio vulnificus Infection","volume":"8","author":"Huang","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/j.chom.2008.05.003","article-title":"Host innate immune receptors and beyond: making sense of microbial infections","volume":"3","author":"Ishii","year":"2008","journal-title":"Cell Host Microbe"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2018.00378","article-title":"A Critical Role of Autophagy in Regulating Microglia Polarization in Neurodegeneration","volume":"10","author":"Jin","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1128\/IAI.71.1.533-535.2003","article-title":"Vibrio vulnificus induces macrophage apoptosis in vitro and in vivo","volume":"71","author":"Kashimoto","year":"2003","journal-title":"Infect. Immun."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.02208","article-title":"Transcriptomic Identification and Biochemical Characterization of HmpA, a Nitric Oxide Dioxygenase, Essential for Pathogenesis of Vibrio vulnificus","volume":"10","author":"Kim","year":"2019","journal-title":"Front. Microbiol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.actatropica.2014.12.001","article-title":"Polarization of macrophages induced by Toxoplasma gondii and its impact on abnormal pregnancy in rats","volume":"143","author":"Kong","year":"2015","journal-title":"Acta Trop."},{"key":"B18","doi-asserted-by":"publisher","first-page":"520","DOI":"10.7150\/ijbs.8879","article-title":"Macrophage polarization in inflammatory diseases","volume":"10","author":"Liu","year":"2014","journal-title":"Int. J. Biol. Sci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1097\/QCO.0b013e328344b73e","article-title":"Macrophage polarization and bacterial infections","volume":"24","author":"Mege","year":"2011","journal-title":"Curr. Opin. Infect. Dis."},{"key":"B20","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1097\/01.shk.0000142184.49976.0c","article-title":"Infection-induced modulation of m1 and m2 phenotypes in circulating monocytes: role in immune monitoring and early prognosis of sepsis","volume":"22","author":"Mehta","year":"2004","journal-title":"Shock"},{"key":"B21","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1128\/CMR.00046-08","article-title":"Pathogen recognition and inflammatory signaling in innate immune defenses","volume":"22","author":"Mogensen","year":"2009","journal-title":"Clin. Microbiol. Rev."},{"key":"B22","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1038\/nri2448","article-title":"Exploring the full spectrum of macrophage activation","volume":"8","author":"Mosser","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1038\/nature05894","article-title":"Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance","volume":"447","author":"Odegaard","year":"2007","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3658","DOI":"10.4049\/jimmunol.1102187","article-title":"The role of tuberous sclerosis complex 1 in regulating innate immunity","volume":"188","author":"Pan","year":"2012","journal-title":"J. Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.drudis.2016.08.006","article-title":"Macrophage polarization in response to epigenetic modifiers during infection and inflammation","volume":"22","author":"Patel","year":"2017","journal-title":"Drug Discov. Today"},{"key":"B26","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1172\/JCI59643","article-title":"Macrophage plasticity and polarization: in vivo veritas","volume":"122","author":"Sica","year":"2012","journal-title":"J. Clin. Invest."},{"key":"B27","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1053\/j.ctsap.2007.02.006","article-title":"Induction of pro- and anti-inflammatory molecules in a mouse model of pneumococcal pneumonia after influenza","volume":"57","author":"Smith","year":"2007","journal-title":"Comp. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"27080","DOI":"10.1038\/srep27080","article-title":"Vibrio vulnificus VvhA induces autophagy-related cell death through the lipid raft-dependent c-Src\/NOX signaling pathway","volume":"6","author":"Song","year":"2016","journal-title":"Sci. Rep."},{"key":"B29","doi-asserted-by":"publisher","first-page":"22433","DOI":"10.1073\/pnas.0912386106","article-title":"Transcriptional response in the peripheral blood of patients infected with Salmonella enterica serovar Typhi","volume":"106","author":"Thompson","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B30","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/nri3901","article-title":"Regulation of innate immune cell function by mTOR","volume":"15","author":"Weichhart","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"14152","DOI":"10.1073\/pnas.1119744109","article-title":"Tumor suppressor TSC1 is critical for T-cell anergy","volume":"109","author":"Xie","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e0181454","DOI":"10.1371\/journal.pone.0181454","article-title":"Vibrio vulnificus induces mTOR activation and inflammatory responses in macrophages","volume":"12","author":"Xie","year":"2017","journal-title":"PloS One"},{"key":"B33","doi-asserted-by":"publisher","first-page":"e0136019","DOI":"10.1371\/journal.pone.0136019","article-title":"Correlations between Clinical Features and Mortality in Patients with Vibrio vulnificus Infection","volume":"10","author":"Zhao","year":"2015","journal-title":"PloS One"},{"key":"B34","doi-asserted-by":"publisher","first-page":"4696","DOI":"10.1038\/ncomms5696","article-title":"TSC1 controls macrophage polarization to prevent inflammatory disease","volume":"5","author":"Zhu","year":"2014","journal-title":"Nat. Commun."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2020.596609\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T07:53:52Z","timestamp":1611734032000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2020.596609\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,27]]},"references-count":34,"alternative-id":["10.3389\/fcimb.2020.596609"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2020.596609","relation":{},"ISSN":["2235-2988"],"issn-type":[{"type":"electronic","value":"2235-2988"}],"subject":[],"published":{"date-parts":[[2021,1,27]]},"article-number":"596609"}}