{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T17:58:15Z","timestamp":1791655095308,"version":"4.3.4"},"update-to":[{"DOI":"10.1371\/journal.pntd.0010006","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T00:00:00Z","timestamp":1640649600000}}],"reference-count":29,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T00:00:00Z","timestamp":1638748800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Infections with the <jats:italic>Puumala orthohantavirus<\/jats:italic> (PUUV) in humans may cause hemorrhagic fever with renal syndrome (HFRS), known as nephropathia epidemica (NE), which is associated with acute renal failure in severe cases. In response to PUUV-infections, a subset of potent antiviral NKG2C<jats:sup>+<\/jats:sup> NK cells expand, whose role in virus defence and pathogenesis of NE is unclear. NKG2C<jats:sup>+<\/jats:sup> NK cell proliferation is mediated by binding of NKG2C\/CD94 to HLA-E on infected cells. The proliferation and activation of NKG2C<jats:sup>+<\/jats:sup> NK cells via the NKG2C\/HLA-E axis is affected by different NKG2C (NKG2C<jats:sup>wt\/del<\/jats:sup>) and HLA-E (HLA-E*0101\/0103) alleles, which naturally occur in the human host. Homozygous (NKG2C<jats:sup>del\/del<\/jats:sup>) and heterozygous (NKG2C<jats:sup>wt\/del<\/jats:sup>) deletions of the NKG2C receptor results in an impaired NKG2C\/CD94 mediated proliferation and activation of NKG2C<jats:sup>+<\/jats:sup> cells. We therefore analyzed the PUUV-mediated NKG2C<jats:sup>+<\/jats:sup> NK cell responses and the impact of different NKG2C and HLA-E alleles in NE patients.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methodology\/Principal findings<\/jats:title>\n<jats:p>NKG2C<jats:sup>+<\/jats:sup> NK cell expansion and effector functions in PUUV-infected cells were investigated using flow cytometry and it was shown that PUUV-infected endothelial cells led to a NKG2C\/CD94 mediated NKG2C<jats:sup>+<\/jats:sup> NK cell activation and expansion, dependent on the HLA-G-mediated upregulation of HLA-E. Furthermore, the NKG2C<jats:sup>del<\/jats:sup> and HLA-E*0101\/0103 alleles were determined in 130 NE patients and 130 matched controls, and it was shown that in NE patients the NKG2C<jats:sup>wt\/del<\/jats:sup> allele was significantly overrepresented, compared to the NKG2C<jats:sup>wt\/wt<\/jats:sup> variant (p = 0.01). In addition, <jats:italic>in vitro<\/jats:italic> analysis revealed that NKG2C<jats:sup>wt\/del<\/jats:sup> NK cells exhibited on overall a lower proliferation (p = 0.002) and lower IFN\u03b3 expression (p = 0.004) than NKG2C<jats:sup>wt\/wt<\/jats:sup> NK cells.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions\/Significance<\/jats:title>\n<jats:p>Our results corroborate the substantial impact of the NKG2C\/HLA-E axis on PUUV-specific NK cell responses. A weak NKG2C<jats:sup>+<\/jats:sup> NK cell response, as reflected by NKG2C<jats:sup>wt\/del<\/jats:sup> variant, may be associated with a higher risk for a severe hantavirus infections.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0010006","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T18:26:47Z","timestamp":1638815207000},"page":"e0010006","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dissection of the NKG2C NK cell response against Puumala Orthohantavirus"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3993-6538","authenticated-orcid":true,"given":"Hannes","family":"Vietzen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"Hartenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan W.","family":"Aberle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0673-8335","authenticated-orcid":true,"given":"Elisabeth","family":"Puchhammer-St\u00f6ckl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,12,6]]},"reference":[{"issue":"1","key":"pntd.0010006.ref001","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1111\/1440-1681.13403","article-title":"Hantavirus diseases pathophysiology, their diagnostic strategies and therapeutic approaches: A review","volume":"48","author":"N Munir","year":"2021","journal-title":"Clinical and Experimental Pharmacology and Physiology"},{"issue":"1","key":"pntd.0010006.ref002","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12898-017-0118-z","article-title":"Puumala hantavirus infections in bank vole populations: host and virus dynamics in Central Europe","volume":"17","author":"D Reil","year":"2017","journal-title":"BMC Ecol."},{"issue":"1","key":"pntd.0010006.ref003","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/rmv.1722","article-title":"Hantavirus infections in Europe and their impact on public health","volume":"23","author":"A Vaheri","year":"2013","journal-title":"Reviews in medical virology"},{"issue":"Pt 3","key":"pntd.0010006.ref004","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1099\/0022-1317-74-3-515","article-title":"Susceptibility of human cells to Puumala virus infection","volume":"74","author":"M Temonen","year":"1993","journal-title":"The Journal of general virology"},{"issue":"220","key":"pntd.0010006.ref005","article-title":"Effect of Puumala hantavirus infection on human umbilical vein endothelial cell hemostatic function: platelet interactions, increased tissue factor expression and fibrinolysis regulator release","volume":"6","author":"M Goeijenbier","year":"2015","journal-title":"Frontiers in Microbiology"},{"issue":"6","key":"pntd.0010006.ref006","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1093\/infdis\/jix650","article-title":"Delayed Interferon Type 1-Induced Antiviral State Is a Potential Factor for Hemorrhagic Fever With Renal Syndrome Severity","volume":"217","author":"K Resman Rus","year":"2017","journal-title":"The Journal of infectious diseases"},{"key":"pntd.0010006.ref007","article-title":"Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus-associated syndromes","author":"J Klingstrom","year":"2019","journal-title":"Journal of internal medicine"},{"issue":"1","key":"pntd.0010006.ref008","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1084\/jem.20100762","article-title":"Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus","volume":"208","author":"NK Bjorkstrom","year":"2011","journal-title":"The Journal of experimental medicine"},{"key":"pntd.0010006.ref009","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.3389\/fimmu.2019.02865","article-title":"Phenotypic and Functional Analysis of Human NK Cell Subpopulations According to the Expression of Fc\u03b5RI\u03b3 and NKG2C","volume":"10","author":"KH Kim","year":"2019","journal-title":"Frontiers in Immunology"},{"issue":"7","key":"pntd.0010006.ref010","first-page":"5082","article-title":"HLA-E allelic variants. 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