{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:51:51Z","timestamp":1792788711030,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.pntd.0012074","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T00:00:00Z","timestamp":1713225600000}}],"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T00:00:00Z","timestamp":1711497600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Netherlands Centre for One Health"}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>Seoul orthohantavirus (SEOV) is a rat-borne zoonotic virus that is transmitted via inhalation of aerosolized infectious excreta, and can cause hemorrhagic fever with renal syndrome (HFRS) in humans worldwide. In rats, SEOV predominantly exists as a persistent infection in the absence of overt clinical signs. Lack of disease in rats is attributed to downregulation of pro-inflammatory and upregulation of regulatory host responses. As lung microvascular endothelial cells (LMECs) represent a primary target of infection in both human and rats, infections in these cells provide a unique opportunity to study the central role of LMECs in the dichotomy between pathogenicity in both species. In this study, host responses to SEOV infection in primary human and rat LMECs were directly compared on a transcriptional level. As infection of rat LMECs was more efficient than human LMECs, the majority of anti-viral defense responses were observed earlier in rat LMECs. Most prominently, SEOV-induced processes in both species included responses to cytokine stimulus, negative regulation of innate immune responses, responses to type I and II interferons, regulation of pattern recognition receptor signaling and MHC-I signaling. However, over time, in the rat LMECs, responses shifted from an anti-viral state towards a more immunotolerant state displayed by a PD-L1, B2M-, JAK2-focused interaction network aiding in negative regulation of cytotoxic CD8-positive T cell activation. This suggests a novel mechanism by which species-specific orthohantavirus-induced endothelium and T cell crosstalk may play a crucial role in the development of acute disease in humans and persistence in rodents.<\/jats:p>","DOI":"10.1371\/journal.pntd.0012074","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T13:58:26Z","timestamp":1711547906000},"page":"e0012074","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Species-specific responses during Seoul orthohantavirus infection in human and rat lung microvascular endothelial cells"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1845-7511","authenticated-orcid":true,"given":"Danny","family":"Noack","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam C. G. N.","family":"van den Hout","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen W. E.","family":"Embregts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilfred F. J.","family":"van IJcken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion P. G.","family":"Koopmans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2463-027X","authenticated-orcid":true,"given":"Barry","family":"Rockx","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,3,27]]},"reference":[{"issue":"2","key":"pntd.0012074.ref001","doi-asserted-by":"crossref","first-page":"387","DOI":"10.3201\/eid2502.181643","article-title":"Clinical Characteristics of Ratborne Seoul Hantavirus Disease","volume":"25","author":"J Clement","year":"2019","journal-title":"Emerg Infect Dis"},{"issue":"9","key":"pntd.0012074.ref002","doi-asserted-by":"crossref","DOI":"10.2807\/ese.18.09.20415-en","article-title":"Pet rats as a source of hantavirus in England and Wales, 2013.","volume":"18","author":"LJ Jameson","year":"2013","journal-title":"Euro Surveill."},{"issue":"7","key":"pntd.0012074.ref003","doi-asserted-by":"crossref","DOI":"10.3390\/v11070652","article-title":"Wild Rats, Laboratory Rats, Pet Rats: Global Seoul Hantavirus Disease Revisited.","volume":"11","author":"J Clement","year":"2019","journal-title":"Viruses"},{"issue":"6","key":"pntd.0012074.ref004","doi-asserted-by":"crossref","DOI":"10.3390\/v11060531","article-title":"Seoul Virus Tropism and Pathology in Naturally Infected Feeder Rats.","volume":"11","author":"M Maas","year":"2019","journal-title":"Viruses."},{"issue":"8","key":"pntd.0012074.ref005","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1093\/infdis\/jiaa307","article-title":"Seoul Virus Infection and Spread in United States Home-Based Ratteries: Rat and Human Testing Results From a Multistate Outbreak Investigation","volume":"222","author":"B Knust","year":"2020","journal-title":"J Infect Dis"},{"key":"pntd.0012074.ref006","first-page":"15","article-title":"Pet Rats as the Likely Reservoir for Human SeoulOrthohantavirus Infection","author":"E Heuser","year":"2023"},{"issue":"7","key":"pntd.0012074.ref007","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1002\/jmv.21213","article-title":"Seoul virus enhances regulatory and reduces proinflammatory responses in male Norway rats","volume":"80","author":"JD Easterbrook","year":"2008","journal-title":"J Med Virol"},{"key":"pntd.0012074.ref008","doi-asserted-by":"crossref","first-page":"399","DOI":"10.3389\/fcimb.2020.00399","article-title":"Orthohantavirus Pathogenesis and Cell Tropism","volume":"10","author":"D Noack","year":"2020","journal-title":"Front Cell Infect Microbiol"},{"issue":"12","key":"pntd.0012074.ref009","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1111\/j.1348-0421.1984.tb00792.x","article-title":"Experimental infection in newborn mice and rats by hemorrhagic fever with renal syndrome (HFRS) virus.","volume":"28","author":"T Yamanouchi","year":"1984","journal-title":"Microbiol Immunol"},{"issue":"7","key":"pntd.0012074.ref010","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1007\/s00705-004-0294-y","article-title":"Persistent Seoul virus infection in Lewis rats","volume":"149","author":"SR Compton","year":"2004","journal-title":"Arch Virol"},{"issue":"5","key":"pntd.0012074.ref011","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s10096-010-1141-6","article-title":"Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus","volume":"30","author":"J Rasmuson","year":"2011","journal-title":"Eur J Clin Microbiol Infect Dis"},{"issue":"39","key":"pntd.0012074.ref012","doi-asserted-by":"crossref","first-page":"15502","DOI":"10.1073\/pnas.0707453104","article-title":"Regulatory T cells enhance persistence of the zoonotic pathogen Seoul virus in its reservoir host","volume":"104","author":"JD Easterbrook","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"pntd.0012074.ref013","doi-asserted-by":"crossref","first-page":"e1000172","DOI":"10.1371\/journal.ppat.1000172","article-title":"Immunological mechanisms mediating hantavirus persistence in rodent reservoirs.","volume":"4","author":"JD Easterbrook","year":"2008","journal-title":"PLoS Pathog."},{"issue":"1","key":"pntd.0012074.ref014","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.virol.2010.01.027","article-title":"Seoul virus suppresses NF-kappaB-mediated inflammatory responses of antigen presenting cells from Norway rats","volume":"400","author":"RY Au","year":"2010","journal-title":"Virology"},{"issue":"21","key":"pntd.0012074.ref015","doi-asserted-by":"crossref","first-page":"11845","DOI":"10.1128\/JVI.01233-12","article-title":"Seoul virus-infected rat lung endothelial cells and alveolar macrophages differ in their ability to support virus replication and induce regulatory T cell phenotypes","volume":"86","author":"W Li","year":"2012","journal-title":"J Virol"},{"key":"pntd.0012074.ref016","first-page":"1151524","article-title":"The pathogenesis of zoonotic viral infections: Lessons learned by studying reservoir hosts.","volume":"14","author":"L Begeman","year":"2023","journal-title":"Front Microbiol.PubMed Central PMCID"},{"issue":"2","key":"pntd.0012074.ref017","doi-asserted-by":"crossref","DOI":"10.3390\/v15020532","article-title":"Characterization of a Panel of Cross-Reactive Hantavirus Nucleocapsid Protein-Specific Monoclonal Antibodies.","volume":"15","author":"A Aviziniene","year":"2023","journal-title":"Viruses."},{"issue":"4","key":"pntd.0012074.ref018","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.","volume":"25","author":"KJ Livak","year":"2001","journal-title":"Methods"},{"issue":"1","key":"pntd.0012074.ref019","article-title":"Cutadapt Removes Adapter Sequences From High-Throughput Sequencing Reads.","volume":"17","author":"M. Martin","year":"2011","journal-title":"EMBnetjournal."},{"issue":"4","key":"pntd.0012074.ref020","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: a fast spliced aligner with low memory requirements.","volume":"12","author":"D Kim","year":"2015","journal-title":"Nat Methods.PubMed Central PMCID"},{"issue":"2","key":"pntd.0012074.ref021","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq\u2014a Python framework to work with high-throughput sequencing data","volume":"31","author":"S Anders","year":"2015","journal-title":"Bioinformatics"},{"issue":"1","key":"pntd.0012074.ref022","doi-asserted-by":"crossref","DOI":"10.1093\/genetics\/iyad042","article-title":"2022 updates to the Rat Genome Database: a Findable, Accessible, Interoperable, and Reusable (FAIR) resource.","volume":"224","author":"M Vedi","year":"2023","journal-title":"Genetics"},{"key":"pntd.0012074.ref023","volume-title":"R: A language and environment for satistical computing.","author":"R Core Team","year":"2014"},{"issue":"12","key":"pntd.0012074.ref024","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"MI Love","year":"2014","journal-title":"Genome Biol"},{"key":"pntd.0012074.ref025","unstructured":"GitHub, Inc. Tidyverse. URL: https:\/\/www.github.com\/tidyverse. 2023."},{"issue":"1","key":"pntd.0012074.ref026","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1186\/s12859-015-0611-3","article-title":"InteractiVenn: a web-based tool for the analysis of sets through Venn diagrams","volume":"16","author":"H Heberle","year":"2015","journal-title":"BMC Bioinformatics"},{"issue":"1","key":"pntd.0012074.ref027","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets.","volume":"10","author":"Y Zhou","year":"2019","journal-title":"Nat Commun."},{"issue":"1","key":"pntd.0012074.ref028","article-title":"The Gene Ontology knowledgebase in 2023","volume":"224","author":"C Gene Ontology","year":"2023","journal-title":"Genetics"},{"issue":"D1","key":"pntd.0012074.ref029","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"D Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"pntd.0012074.ref030","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1093\/infdis\/161.5.1016","article-title":"Abnormalities of T cell immunoregulation in hemorrhagic fever with renal syndrome","volume":"161","author":"LB Chen","year":"1990","journal-title":"J Infect Dis"},{"issue":"5","key":"pntd.0012074.ref031","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1084\/jem.20011255","article-title":"Long-lived memory T lymphocyte responses after hantavirus infection","volume":"196","author":"HL Van Epps","year":"2002","journal-title":"J Exp Med"},{"issue":"19","key":"pntd.0012074.ref032","doi-asserted-by":"crossref","first-page":"10252","DOI":"10.1128\/JVI.05548-11","article-title":"Longitudinal analysis of the human T cell response during acute hantavirus infection","volume":"85","author":"T Lindgren","year":"2011","journal-title":"J Virol"},{"issue":"5","key":"pntd.0012074.ref033","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1089\/vim.2014.0135","article-title":"Kinetics and Immunodominance of Virus-Specific T Cell Responses During Hantaan Virus Infection","volume":"28","author":"M Wang","year":"2015","journal-title":"Viral Immunol"},{"issue":"1","key":"pntd.0012074.ref034","first-page":"652","article-title":"HTNV infection of CD8(+) T cells is associated with disease progression in HFRS patients.","volume":"4","author":"R Liu","year":"2021","journal-title":"Commun Biol.PubMed Central PMCID"},{"issue":"2","key":"pntd.0012074.ref035","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1002\/jmv.20266","article-title":"Andes virus stimulates interferon-inducible MxA protein expression in endothelial cells","volume":"75","author":"SF Khaiboullina","year":"2005","journal-title":"J Med Virol"},{"issue":"12","key":"pntd.0012074.ref036","doi-asserted-by":"crossref","first-page":"6143","DOI":"10.1128\/JVI.78.12.6143-6150.2004","article-title":"Differential antiviral response of endothelial cells after infection with pathogenic and nonpathogenic hantaviruses","volume":"78","author":"AA Kraus","year":"2004","journal-title":"J Virol"},{"issue":"2","key":"pntd.0012074.ref037","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.imlet.2007.08.003","article-title":"Immunopathogenesis of hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome: Do CD8+ T cells trigger capillary leakage in viral hemorrhagic fevers","volume":"113","author":"M Terajima","year":"2007","journal-title":"Immunol Lett"},{"issue":"1","key":"pntd.0012074.ref038","doi-asserted-by":"crossref","first-page":"14644","DOI":"10.1038\/s41598-019-50878-7","article-title":"Epidemiological and time series analysis of haemorrhagic fever with renal syndrome from 2004 to 2017 in Shandong Province, China.","volume":"9","author":"C Zhang","year":"2019","journal-title":"Sci Rep"},{"issue":"21","key":"pntd.0012074.ref039","doi-asserted-by":"crossref","first-page":"13837","DOI":"10.1073\/pnas.192298899","article-title":"Pathogenic and nonpathogenic hantaviruses differentially regulate endothelial cell responses","volume":"99","author":"E Geimonen","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"pntd.0012074.ref040","doi-asserted-by":"crossref","first-page":"e1008483","DOI":"10.1371\/journal.ppat.1008483","article-title":"RIG-I-like receptor activation drives type I IFN and antiviral signaling to limit Hantaan orthohantavirus replication","volume":"16","author":"AM Kell","year":"2020","journal-title":"PLoS Pathog"},{"issue":"19","key":"pntd.0012074.ref041","doi-asserted-by":"crossref","first-page":"9676","DOI":"10.1128\/JVI.00508-06","article-title":"The pathogenic NY-1 hantavirus G1 cytoplasmic tail inhibits RIG-I- and TBK-1-directed interferon responses","volume":"80","author":"PJ Alff","year":"2006","journal-title":"J Virol"},{"issue":"4","key":"pntd.0012074.ref042","doi-asserted-by":"crossref","DOI":"10.3390\/v12040457","article-title":"Orthohantavirus Isolated in Reservoir Host Cells Displays Minimal Genetic Changes and Retains Wild-Type Infection Properties.","volume":"12","author":"T Strandin","year":"2020","journal-title":"Viruses"},{"issue":"12","key":"pntd.0012074.ref043","doi-asserted-by":"crossref","first-page":"e28992","DOI":"10.1371\/journal.pone.0028992","article-title":"A model system for in vitro studies of bank vole borne viruses.","volume":"6","author":"M Stoltz","year":"2011","journal-title":"PLoS One."},{"issue":"1","key":"pntd.0012074.ref044","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.jacc.2013.08.694","article-title":"SOCS1 prevents graft arteriosclerosis by preserving endothelial cell function","volume":"63","author":"L Qin","year":"2014","journal-title":"J Am Coll Cardiol"},{"issue":"4","key":"pntd.0012074.ref045","doi-asserted-by":"crossref","first-page":"e21388","DOI":"10.1096\/fj.202001477RR","article-title":"Microtubule-dependent mechanism of anti-inflammatory effect of SOCS1 in endothelial dysfunction and lung injury","volume":"35","author":"P Karki","year":"2021","journal-title":"FASEB J"},{"issue":"6","key":"pntd.0012074.ref046","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1002\/eji.201343955","article-title":"The WT hemochromatosis protein HFE inhibits CD8(+) T-lymphocyte activation.","volume":"44","author":"A Reuben","year":"2014","journal-title":"Eur J Immunol"},{"key":"pntd.0012074.ref047","doi-asserted-by":"crossref","first-page":"207","DOI":"10.3389\/fcimb.2019.00207","article-title":"The PD-1\/PD-L1 Axis and Virus Infections: A Delicate Balance.","volume":"9","author":"G Schonrich","year":"2019","journal-title":"Front Cell Infect Microbiol"},{"issue":"5","key":"pntd.0012074.ref048","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.4049\/jimmunol.0802893","article-title":"Hantaan virus triggers TLR3-dependent innate immune responses","volume":"182","author":"W Handke","year":"2009","journal-title":"J Immunol"},{"key":"pntd.0012074.ref049","first-page":"2560","article-title":"Hantavirus-Driven PD-L1\/PD-L2 Upregulation: An Imperfect Viral Immune Evasion Mechanism","volume":"9","author":"MJ Raftery","year":"2018"},{"issue":"4","key":"pntd.0012074.ref050","doi-asserted-by":"crossref","DOI":"10.3390\/v13040665","article-title":"Immunological Responses to Seoul Orthohantavirus in Experimentally and Naturally Infected Brown Rats (Rattus norvegicus).","volume":"13","author":"SP Yasuda","year":"2021","journal-title":"Viruses."},{"issue":"10","key":"pntd.0012074.ref051","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1093\/oxfordjournals.molbev.a026254","article-title":"Evolutionary diversification of protein-coding genes of hantaviruses","volume":"17","author":"AL Hughes","year":"2000","journal-title":"Mol Biol Evol"},{"issue":"2","key":"pntd.0012074.ref052","doi-asserted-by":"crossref","first-page":"e1003159","DOI":"10.1371\/journal.ppat.1003159","article-title":"Phylogeny and origins of hantaviruses harbored by bats, insectivores, and rodents.","volume":"9","author":"WP Guo","year":"2013","journal-title":"PLoS Pathog."}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0012074","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T00:00:00Z","timestamp":1713225600000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0012074","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T14:35:22Z","timestamp":1713278122000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0012074"}},"subtitle":[],"editor":[{"given":"Jonas","family":"Klingstr\u00f6m","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,3,27]]},"references-count":52,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0012074","relation":{},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,27]]}}}