{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:03:16Z","timestamp":1787234596894,"version":"build-2736575974"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T00:00:00Z","timestamp":1671062400000},"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":["81871239, 81771705, 82272331"],"award-info":[{"award-number":["81871239, 81771705, 82272331"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017596","name":"Natural Science Basic Research Program of Shaanxi Province","doi-asserted-by":"publisher","award":["2022JZ-45"],"award-info":[{"award-number":["2022JZ-45"]}],"id":[{"id":"10.13039\/501100017596","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Hantaan virus (HTNV) can cause endothelium injury in hemorrhagic fever with renal syndrome (HFRS) patients. Bystander activation of CD8+ T cells by virus infection has been shown that was involved in host injury, but it is unclear during HTNV infection. This project aimed to study the effect of bystander-activated CD8+ T cell responses in HTNV infection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The in vitro infection model was established to imitate the injury of endothelium in HFRS patients. Flow cytometry was performed to detect the expression of markers of tetramer+ CD8+ T cells and human umbilical vein endothelial cells (HUVECs). The levels of interleukin-15 (IL-15) in serum and supermanant were detected using ELISA kit. The expression of MICA of HUVECs was respectively determined by flow cytometry and western blot. The cytotoxicity of CD8+ T cells was assessed through the cytotoxicity assay and antibody blocking assay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>EBV or CMV-specific CD8+ T cells were bystander activated after HTNV infection in HFRS patients. HTNV-infected HUVECs in vitro could produce high levels of IL-15, which was positively correlated with disease severity and the expression of NKG2D on bystander-activated CD8+ T cells. Moreover, the elevated IL-15 could induce activation of CD122 (IL-15R\u03b2)+NKG2D+ EBV\/CMV-specific CD8+ T cells. The expression of IL-15R\u03b1 and ligand for NKG2D were upregulated on HTNV-infected HUVECs. Bystander-activated CD8+ T cells could exert cytotoxicity effects against HTNV-infected HUVECs, which could be enhanced by IL-15 stimulation and blocked by NKG2D antibody.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>IL-15 induced bystander activation of CD8+ T cells through NKG2D, which may mediate endothelium injury during HTNV infection in HFRS patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2022.1084841","type":"journal-article","created":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T01:55:40Z","timestamp":1671069340000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["IL-15 induced bystander activation of CD8+ T cells may mediate endothelium injury through NKG2D in Hantaan virus infection"],"prefix":"10.3389","volume":"12","author":[{"given":"Xiyue","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunmei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manling","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhou","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifeng","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boquan","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanglin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e6","DOI":"10.1111\/1469-0691.12291","article-title":"Hantavirus infections","author":"Avsic-Zupanc","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"B2","doi-asserted-by":"publisher","first-page":"892","DOI":"10.4049\/jimmunol.1403046","article-title":"Increased CD226 expression on CD8+ T cells is associated with upregulated cytokine production and endothelial cell injury in patients with systemic sclerosis","volume":"195","author":"Ayano","year":"2015","journal-title":"J. Immunol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1111\/j.1365-2249.2006.02996.x","article-title":"NK cells, displaying early activation, cytotoxicity and adhesion molecules, are associated with mild dengue disease","volume":"143","author":"Azeredo","year":"2006","journal-title":"Clin. Exp. Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1111\/j.0105-2896.2010.00893.x","article-title":"Effect of NKG2D ligand expression on host immune responses","volume":"235","author":"Champsaur","year":"2010","journal-title":"Immunol. Rev."},{"key":"B5","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1016\/j.imbio.2010.09.012","article-title":"IL-15 induces CD8+ T cells to acquire functional NK receptors capable of modulating cytotoxicity and cytokine secretion","volume":"216","author":"Correia","year":"2011","journal-title":"Immunobiology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1086\/592714","article-title":"Respiratory syncytial virus persistence in the lungs correlates with airway hyperreactivity in the mouse model","volume":"198","author":"Estripeaut","year":"2008","journal-title":"J. Infect. Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1038\/ni1524","article-title":"NKG2D signaling is coupled to the interleukin 15 receptor signaling pathway","volume":"8","author":"Horng","year":"2007","journal-title":"Nat. Immunol."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004241","article-title":"Innate immune responses and rapid control of inflammation in African green monkeys treated or not with interferon-alpha during primary SIVagm infection","volume":"10","author":"Jacquelin","year":"2014","journal-title":"PloS Pathog."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2339","DOI":"10.3390\/cancers14092339","article-title":"Regulation of NKG2D stress ligands and its relevance in cancer progression","volume":"14","author":"Jones","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.167230","article-title":"Innate immunity to orthohantaviruses: Could divergent immune interactions explain host-specific disease outcomes","volume":"434","author":"Kell","year":"2022","journal-title":"J. Mol. Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.immuni.2017.11.025","article-title":"Innate-like cytotoxic function of bystander-activated CD8(+) T cells is associated with liver injury in acute hepatitis a","volume":"48","author":"Kim","year":"2018","journal-title":"Immunity"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.532388","article-title":"Genomic epidemiology and active surveillance to investigate outbreaks of hantaviruses","volume":"10","author":"Kim","year":"2020","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-019-0316-1","article-title":"The activation of bystander CD8(+) T cells and their roles in viral infection","volume":"51","author":"Kim","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.virusres.2013.03.020","article-title":"Serum TNF-alpha, sTNFR1, IL-6, IL-8 and IL-10 levels in hemorrhagic fever with renal syndrome","volume":"175","author":"Kyriakidis","year":"2013","journal-title":"Virus Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1146\/annurev.immunol.23.021704.115526","article-title":"NK cell recognition","volume":"23","author":"Lanier","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1097\/COH.0b013e32835c7134","article-title":"Soluble biomarkers of HIV transmission, disease progression and comorbidities","volume":"8","author":"Leeansyah","year":"2013","journal-title":"Curr. Opin. HIV AIDS"},{"key":"B17","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/s41590-021-00985-3","article-title":"Significance of bystander T cell activation in microbial infection","volume":"23","author":"Lee","year":"2022","journal-title":"Nat. Immunol."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00298","article-title":"Structure and function of HLA-A*02-Restricted hantaan virus cytotoxic T-cell epitope that mediates effective protective responses in HLA-A2.1\/K(b) transgenic mice","volume":"7","author":"Ma","year":"2016","journal-title":"Front. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1084\/jem.191.8.1269","article-title":"The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis b virus infection","volume":"191","author":"Maini","year":"2000","journal-title":"J. Exp. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1186\/s12985-020-01421-y","article-title":"Protective CD8(+) T-cell response against hantaan virus infection induced by immunization with designed linear multi-epitope peptides in HLA-A2.1\/K(b) transgenic mice","volume":"17","author":"Ma","year":"2020","journal-title":"Virol. J."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.795340","article-title":"Hantavirus induced kidney disease","volume":"8","author":"Mir","year":"2021","journal-title":"Front. Med. (Lausanne)"},{"key":"B22","doi-asserted-by":"publisher","first-page":"724","DOI":"10.18632\/aging.101774","article-title":"CD56-negative NK cells with impaired effector function expand in CMV and EBV co-infected healthy donors with age","volume":"11","author":"Muller-Durovic","year":"2019","journal-title":"Aging (Albany NY)"},{"key":"B23","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.molimm.2019.11.011","article-title":"Control of memory CD8(+) T cell longevity and effector functions by IL-15","volume":"117","author":"Nolz","year":"2020","journal-title":"Mol. Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1084\/jem.20112401","article-title":"Primary Epstein-Barr virus infection does not erode preexisting CD8(+) T cell memory in humans","volume":"209","author":"Odumade","year":"2012","journal-title":"J. Exp. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"43230","DOI":"10.18632\/oncotarget.6462","article-title":"The NKG2D-IL-15 signaling pathway contributes to T-cell mediated pathology in inflammatory myopathies","volume":"6","author":"Ruck","year":"2015","journal-title":"Oncotarget"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001051","article-title":"Contribution of herpesvirus specific CD8 T cells to anti-viral T cell response in humans","volume":"6","author":"Sandalova","year":"2010","journal-title":"PloS Pathog."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1007\/s00705-018-3786-x","article-title":"Involvement of CD8(+) T cells in the development of renal hemorrhage in a mouse model of hemorrhagic fever with renal syndrome","volume":"163","author":"Shimizu","year":"2018","journal-title":"Arch. Virol."},{"key":"B28","unstructured":"Epidemic situation of infectious diseases in China2021"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.591255","article-title":"Oral dysbiosis and autoimmunity: From local periodontal responses to an imbalanced systemic immunity. a review","volume":"11","author":"Suarez","year":"2020","journal-title":"Front. Immunol."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01797","article-title":"Novel identified HLA-A*0201-Restricted hantaan virus glycoprotein cytotoxic T-cell epitopes could effectively induce protective responses in HLA-A2.1\/K(b) transgenic mice may associate with the severity of hemorrhagic fever with renal syndrome","volume":"8","author":"Tang","year":"2017","journal-title":"Front. Immunol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3947\/ic.2021.0148","article-title":"Hemorrhagic fever with renal syndrome: Literature review, epidemiology, clinical picture and pathogenesis","volume":"54","author":"Tariq","year":"2022","journal-title":"Infect. Chemother."},{"key":"B32","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1007\/s12253-018-0444-2","article-title":"IL-2 and IL-15 induced NKG2D, CD158a and CD158b expression on T, NKT- like and NK cell lymphocyte subsets from regional lymph nodes of melanoma patients","volume":"26","author":"Vuletic","year":"2020","journal-title":"Pathol. Oncol. Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1086\/595834","article-title":"Cellular immune response to hantaan virus nucleocapsid protein in the acute phase of hemorrhagic fever with renal syndrome: correlation with disease severity","volume":"199","author":"Wang","year":"2009","journal-title":"J. Infect. Dis."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1016\/j.it.2018.10.003","article-title":"Bystander T cells: A balancing act of friends and foes","volume":"39","author":"Whiteside","year":"2018","journal-title":"Trends Immunol."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.849020","article-title":"LncRNA NEAT1 potentiates SREBP2 activity to promote inflammatory macrophage activation and limit hantaan virus propagation","volume":"13","author":"Yang","year":"2022","journal-title":"Front. Microbiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"3586","DOI":"10.3390\/cancers12123586","article-title":"Immunomodulatory effects of IL-2 and IL-15; implications for cancer immunotherapy","volume":"12","author":"Yang","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1093\/infdis\/jis475","article-title":"Hantaan virus RNA load in patients having hemorrhagic fever with renal syndrome: correlation with disease severity","volume":"207","author":"Yi","year":"2013","journal-title":"J. Infect. Dis."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2745","DOI":"10.1172\/JCI85996","article-title":"IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection","volume":"126","author":"Younes","year":"2016","journal-title":"J. Clin. Invest."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.665410","article-title":"The presence of circulating nucleated red blood cells is associated with disease severity in patients of hemorrhagic fever with renal syndrome","volume":"8","author":"Zhang","year":"2021","journal-title":"Front. Med. (Lausanne)"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003514","article-title":"IL-33\/ST2 correlates with severity of haemorrhagic fever with renal syndrome and regulates the inflammatory response in hantaan virus-infected endothelial cells","volume":"9","author":"Zhang","year":"2015","journal-title":"PloS Negl. Trop. Dis."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.1084841\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,15]],"date-time":"2022-12-15T01:55:45Z","timestamp":1671069345000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.1084841\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,15]]},"references-count":40,"alternative-id":["10.3389\/fcimb.2022.1084841"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.1084841","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,15]]},"article-number":"1084841"}}