{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:12:28Z","timestamp":1788347548870,"version":"build-2803163510"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2017,11,14]],"date-time":"2017-11-14T00:00:00Z","timestamp":1510617600000},"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":["81501713"],"award-info":[{"award-number":["81501713"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81401679"],"award-info":[{"award-number":["81401679"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2015M570516"],"award-info":[{"award-number":["2015M570516"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2016T90547"],"award-info":[{"award-number":["2016T90547"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Leptospirosis is a global zoonotic infectious disease caused by pathogenic <jats:italic>Leptospira<\/jats:italic> species. Leptospire-induced macrophage apoptosis through the Fas\/FasL-caspase-8\/3 pathway plays an important role in the survival and proliferation of the pathogen in hosts. Although, the release of mitochondrial apoptosis-inducing factor (AIF) and endonuclease G (EndoG) in leptospire-infected macrophages has been described, the mechanisms linking caspase and mitochondrion-related host-cell apoptosis has not been determined. Here, we demonstrated that leptospire-infection induced apoptosis through mitochondrial damages in macrophages. Apoptosis was caused by the mitochondrial release and nuclear translocation of AIF and\/or EndoG, leading to nuclear DNA fragmentation. However, the mitochondrion-related CytC-caspase-9\/3 pathway was not activated. Next, we found that the release and translocation of AIF and\/or EndoG was preceded by the activation of the BH3-interacting domain death agonist (Bid). Furthermore, our data demonstrated that caspase-8 was activated during the infection and caused the activation of Bid. Meanwhile, high reactive oxygen species (ROS) trigged by the infection caused the dephosphorylation of Akt, which also activated Bid. In conclusion, Bid-mediated mitochondrial release of AIF and\/or EndoG followed by nuclear translocation is a major mechanism of leptospire- induced apoptosis in macrophages, and this process is modulated by both caspase-8 and ROS-Akt signal pathways.<\/jats:p>","DOI":"10.3389\/fcimb.2017.00471","type":"journal-article","created":{"date-parts":[[2017,11,13]],"date-time":"2017-11-13T23:20:08Z","timestamp":1510615208000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":36,"title":["Bid-Induced Release of AIF\/EndoG from Mitochondria Causes Apoptosis of Macrophages during Infection with Leptospira interrogans"],"prefix":"10.3389","volume":"7","author":[{"given":"Wei-Lin","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Yan","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Ojcius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Jun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2017,11,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.vetmic.2009.03.012","article-title":"Leptospira and leptospirosis","volume":"140","author":"Adler","year":"2010","journal-title":"Vet. Microbiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1083\/jcb.201108081","article-title":"Cell death and infection: a double-edged sword for host and pathogen survival","volume":"195","author":"Ashida","year":"2011","journal-title":"J. Cell Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1111\/j.1523-5378.2008.00646.x","article-title":"H. pylori-induced apoptosis in human gastric cancer cells mediated via the release of apoptosis-inducing factor from mitochondria","volume":"13","author":"Ashktorab","year":"2008","journal-title":"Helicobacter"},{"key":"B4","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/sj.cdd.4400823","article-title":"Host defense, viruses and apoptosis","volume":"8","author":"Barber","year":"2001","journal-title":"Cell Death Differ."},{"key":"B5","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1038\/mi.2011.3","article-title":"Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis","volume":"4","author":"Behar","year":"2011","journal-title":"Mucosal Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1016\/S1473-3099(03)00830-2","article-title":"Leptospirosis: a zoonotic disease of global importance","volume":"3","author":"Bharti","year":"2003","journal-title":"Lancet Infect. Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1189\/jlb.0506359","article-title":"Cathepsin-cleaved Bid promotes apoptosis in human neutrophils via oxidative stress-induced lysosomal membrane permeabilization","volume":"81","author":"Blomgran","year":"2007","journal-title":"J. Leukoc. Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/sj.cdd.4401400","article-title":"Apoptosis-inducing factor (AIF): caspase-independent after all","volume":"11","author":"Cande","year":"2004","journal-title":"Cell Death Differ."},{"key":"B9","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1016\/j.freeradbiomed.2009.05.024","article-title":"ROS-driven Akt dephosphorylation at Ser-473 is involved in 4-HPR-mediated apoptosis in NB4 cells","volume":"47","author":"Cao","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e0181014","DOI":"10.1371\/journal.pone.0181014","article-title":"Mononuclear-macrophages but not neutrophils act as major infiltrating anti-leptospiral phagocytes during leptospirosis","volume":"12","author":"Chen","year":"2017","journal-title":"PLoS ONE"},{"key":"B11","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.clim.2004.08.006","article-title":"Differential expression of interferon-gamma and interferon-gamma-inducing cytokines in Thai patients with scrub typhus or leptospirosis","volume":"113","author":"Chierakul","year":"2004","journal-title":"Clin. Immunol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2785","DOI":"10.1038\/sj.onc.1207517","article-title":"Role of AIF in caspase-dependent and caspase-independent cell death","volume":"23","author":"Cregan","year":"2004","journal-title":"Oncogene"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e463","DOI":"10.1371\/journal.pntd.0000463","article-title":"Leptospira interrogans stably infects zebrafish embryos, altering phagocyte behavior and homing to specific tissues","volume":"3","author":"Davis","year":"2009","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1023\/B:APPT.0000031448.64969.fa","article-title":"Modulation of phagocyte apoptosis by bacterial pathogens","volume":"9","author":"DeLeo","year":"2004","journal-title":"Apoptosis"},{"key":"B15","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1189\/jlb.1012544","article-title":"ROS production in phagocytes: why, when, and where?","volume":"94","author":"Dupre-Crochet","year":"2013","journal-title":"J. Leukoc. Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e0004403","DOI":"10.1371\/journal.pntd.0004403","article-title":"What makes a bacterial species pathogenic?:comparative genomic analysis of the genus leptospira","volume":"10","author":"Fouts","year":"2016","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B17","doi-asserted-by":"publisher","first-page":"5523","DOI":"10.1038\/onc.2010.288","article-title":"The inhibition of Bid expression by Akt leads to resistance to TRAIL-induced apoptosis in ovarian cancer cells","volume":"29","author":"Goncharenko-Khaider","year":"2010","journal-title":"Oncogene"},{"key":"B18","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1126\/science.1099320","article-title":"The pathophysiology of mitochondrial cell death","volume":"305","author":"Green","year":"2004","journal-title":"Science"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e1919","DOI":"10.1038\/cddis.2015.276","article-title":"Caspase-3 feedback loop enhances Bid-induced AIF\/endoG and Bak activation in Bax and p53-independent manner","volume":"6","author":"Guo","year":"2015","journal-title":"Cell Death Dis."},{"key":"B20","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/nrmicro1788","article-title":"Salmonellae interplay with host cells","volume":"6","author":"Haraga","year":"2008","journal-title":"Nat. Rev. Microbiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.tips.2004.03.005","article-title":"Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling","volume":"25","author":"Hong","year":"2004","journal-title":"Trends Pharmacol. Sci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1642","DOI":"10.1111\/cmi.12141","article-title":"p53 signalling controls cell cycle arrest and caspase-independent apoptosis in macrophages infected with pathogenic Leptospira species","volume":"15","author":"Hu","year":"2013","journal-title":"Cell. Microbiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1097\/QCO.0000000000000097","article-title":"Leptospira and leptospirosis in China","volume":"27","author":"Hu","year":"2014","journal-title":"Curr. Opin. Infect. Dis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1016\/j.freeradbiomed.2004.07.003","article-title":"Molecular mechanism of diclofenac-induced apoptosis of promyelocytic leukemia: dependency on reactive oxygen species, Akt, Bid, cytochrome and caspase pathway","volume":"37","author":"Inoue","year":"2004","journal-title":"Free Radic. Biol. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1128\/IAI.00914-08","article-title":"Leptospira interrogans induces apoptosis in macrophages via caspase-8- and caspase-3-dependent pathways","volume":"77","author":"Jin","year":"2009","journal-title":"Infect. Immun."},{"key":"B26","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1016\/j.bbamcr.2011.01.026","article-title":"Caspase-8 and bid: caught in the act between death receptors and mitochondria","volume":"1813","author":"Kantari","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"B27","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1038\/cdd.2011.121","article-title":"Fas death receptor signaling: roles of Bid and XIAP","volume":"19","author":"Kaufmann","year":"2012","journal-title":"Cell Death Differ."},{"key":"B28","doi-asserted-by":"publisher","first-page":"11414","DOI":"10.1128\/JVI.76.22.11414-11424.2002","article-title":"Reovirus-induced apoptosis requires mitochondrial release of Smac\/DIABLO and involves reduction of cellular inhibitor of apoptosis protein levels","volume":"76","author":"Kominsky","year":"2002","journal-title":"J. Virol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.chom.2010.06.007","article-title":"Manipulation of host cell death pathways during microbial infections","volume":"8","author":"Lamkanfi","year":"2010","journal-title":"Cell Host Microbe"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1553","DOI":"10.1038\/cdd.2008.78","article-title":"Bid-induced release of AIF from mitochondria causes immediate neuronal cell death","volume":"15","author":"Landshamer","year":"2008","journal-title":"Cell Death Differ."},{"key":"B31","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1007\/s00203-007-0280-3","article-title":"Comparison of invasion of fibroblasts and macrophages by high- and low-virulence Leptospira strains: colonization of the host-cell nucleus and induction of necrosis by the virulent strain","volume":"188","author":"Li","year":"2007","journal-title":"Arch. Microbiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/35083620","article-title":"Endonuclease G is an apoptotic DNase when released from mitochondria","volume":"412","author":"Li","year":"2001","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1016\/S1471-4922(01)02016-5","article-title":"Intracellular protozoan parasites and apoptosis: diverse strategies to modulate parasite-host interactions","volume":"17","author":"Luder","year":"2001","journal-title":"Trends Parasitol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1128\/MCB.24.2.730-740.2004","article-title":"Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases","volume":"24","author":"Majewski","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1002\/eji.200940168","article-title":"Signaling by ROS drives inflammasome activation","volume":"40","author":"Martinon","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1097\/01.qco.0000178824.05715.2c","article-title":"Leptospirosis","volume":"18","author":"McBride","year":"2005","journal-title":"Curr. Opin. Infect. Dis."},{"key":"B37","doi-asserted-by":"publisher","first-page":"936","DOI":"10.1126\/science.1214935","article-title":"Disease tolerance as a defense strategy","volume":"335","author":"Medzhitov","year":"2012","journal-title":"Science"},{"key":"B38","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1128\/iai.65.2.729-738.1997","article-title":"Invasion of Vero cells and induction of apoptosis in macrophages by pathogenic Leptospira interrogans are correlated with virulence","volume":"65","author":"Merien","year":"1997","journal-title":"Infect. Immun."},{"key":"B39","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/nri3131","article-title":"Viral infection and the evolution of caspase 8-regulated apoptotic and necrotic death pathways","volume":"12","author":"Mocarski","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1046\/j.1462-5822.2000.00056.x","article-title":"Pathogen-induced apoptosis of macrophages: a common end for different pathogenic strategies","volume":"2","author":"Navarre","year":"2000","journal-title":"Cell. Microbiol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1007\/s00210-008-0306-7","article-title":"Toxic-dise warfarin-induced apoptosis and its enhancement by gamma ionizing radiation in leukemia K562 and HL-60 cells is not mediated by induction of oxidative stress","volume":"378","author":"Onaran","year":"2008","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1111\/j.1365-2184.2012.00845.x","article-title":"Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis","volume":"45","author":"Ouyang","year":"2012","journal-title":"Cell Prolif."},{"key":"B43","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1097\/QCO.0b013e32814a5729","article-title":"Leptospirosis: pathogenesis, immunity, and diagnosis","volume":"20","author":"Palaniappan","year":"2007","journal-title":"Curr. Opin. Infect. Dis."},{"key":"B44","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1038\/nrm1496","article-title":"Molecular mechanisms of caspase regulation during apoptosis","volume":"5","author":"Riedl","year":"2004","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/nrm1104","article-title":"Phagocyte sabotage: disruption of macrophage signaling by bacterial pathogens","volume":"4","author":"Rosenberger","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/nrmicro2421","article-title":"Interactions between bacterial pathogens and mitochondrial cell death pathways","volume":"8","author":"Rudel","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1930","DOI":"10.1038\/cdd.2008.125","article-title":"Role of Smac in cephalostatin-induced cell death","volume":"15","author":"Rudy","year":"2008","journal-title":"Cell Death Differ."},{"key":"B48","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1023\/A:1009616228304","article-title":"Role of reactive oxygen species (ROS) in apoptosis induction","volume":"5","author":"Simon","year":"2000","journal-title":"Apoptosis"},{"key":"B49","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.virol.2007.05.023","article-title":"The equine arteritis virus induces apoptosis via caspase-8 and mitochondria-dependentcaspase-9 activation","volume":"367","author":"St-Louis","year":"2007","journal-title":"Virology"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1128\/IAI.01047-06","article-title":"Apoptosis-inducing factor participation in bovine macrophage Mycobacterium bovis-induced caspase-independent cell death","volume":"75","author":"Vega-Manriquez","year":"2007","journal-title":"Infect. Immun."},{"key":"B51","doi-asserted-by":"publisher","first-page":"e857","DOI":"10.1371\/journal.pntd.0000857","article-title":"Transcriptional responses of Leptospira interrogans to host innate immunity: significant changes in metabolism, oxygen tolerance, and outer membrane","volume":"4","author":"Xue","year":"2010","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B52","doi-asserted-by":"publisher","first-page":"e2477","DOI":"10.1371\/journal.pntd.0002477","article-title":"Responses of murine and human macrophages to leptospiral infection: a study using comparative array analysis","volume":"7","author":"Xue","year":"2013","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B53","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s40779-015-0039-0","article-title":"Programmed cell death and its role in inflammation","volume":"2","author":"Yang","year":"2015","journal-title":"Mil. Med. Res."}],"updated-by":[{"DOI":"10.3389\/fcimb.2025.1635286","type":"corrigendum","label":"Corrigendum","source":"publisher","updated":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000}}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2017.00471\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T09:31:32Z","timestamp":1752571892000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2017.00471\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,14]]},"references-count":53,"alternative-id":["10.3389\/fcimb.2017.00471"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2017.00471","relation":{"corrigendum":[{"id-type":"doi","id":"10.3389\/fcimb.2025.1635286","asserted-by":"object"}]},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,14]]},"article-number":"471"}}