{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:49:48Z","timestamp":1789753788584,"version":"4.0.1"},"reference-count":43,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Hantaviruses are emerging zoonotic pathogens responsible for two severe clinical syndromes: (i) haemorrhagic fever with renal syndrome (HFRS) and (ii) hantavirus cardiopulmonary syndrome (HCPS), collectively causing more than 200,000 human cases annually worldwide. Despite their public-health importance, the molecular mechanisms governing the host response and the population-level dynamics of rodent-to-human spillover remain incompletely characterised. The timeliness of this framework is underscored by the April\u2013May 2026 outbreak of Andes orthohantavirus aboard the MV Hondius cruise ship, the first such cluster in a maritime setting, with three deaths reported across multiple countries. This event revealed critical gaps in existing models that treat humans solely as dead-end spillover hosts. Our coupled Susceptible-Exposed-Infectious-Recovered-Dead (SEIRD) model assumes no human-to-human transmission and is therefore designed for hantavirus strains where spillover does not lead to secondary human cases, specifically Hantaan virus (HTNV), Puumala virus (PUUV), Sin Nombre virus (SNV), and Dobrava-Belgrade virus (DOBV). The Andes virus (ANDV) outbreak aboard the MV Hondius is used as a real-world case study to assess the boundaries of our model and to motivate future extensions, not as a direct validation target for its quantitative predictions. Here, we present an integrated computational study combining three complementary analyses. First, we performed a preliminary phylogenetic analysis of the viral sequence, identifying Orthohantavirus andesense as the likely etiological agent responsible for the vessel-associated outbreak. Second, we carried out a downstream transcriptomic analysis of Hantaan virus (HTNV)-infected human umbilical vein endothelial cells (HUVECs), using publicly available RNA-seq data (GEO accession GSE133751, n=3 per group). This analysis identified 184 upregulated and 19 downregulated genes, highlighting a transcriptional response dominated by interferon-stimulated genes (ISGs), including CXCL10, CXCL11, MX2, DDX58, IRF7, STAT1, OASL, and CMPK2. We then constructed a protein\u2013protein interaction (PPI) network using STRING, comprising 176 nodes and 3210 edges, and applied a composite network centrality score to rank putative regulatory hubs. This analysis identified ISG15, IRF1, CXCL10, STAT1, and DDX58 as the most central nodes. Pathway enrichment analysis confirmed a strong activation of interferon signalling (Reactome, p=1.3\u00d710\u221263), antiviral defence mechanisms (Gene Ontology, p=3.8\u00d710\u221258), and NF-\u03baB-related pathways, together with a concurrent suppression of ribosomal translation. Finally, we developed a coupled SEIRD epidemiological model that explicitly represents rodent-to-rodent and rodent-to-human transmission with logistic rodent population growth. Preliminary simulation analysis demonstrates that reducing human exposure to rodent excreta is substantially more effective than rodent population control alone for reducing human disease burden, and that rodent control in isolation can paradoxically increase human cases through a dilution-like effect. The integrated framework provides molecular and epidemiological insights relevant to hantavirus surveillance, therapeutic target identification, and public-health intervention design.<\/jats:p>","DOI":"10.3390\/pathogens15060601","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T09:33:14Z","timestamp":1780479194000},"page":"601","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Integrated Downstream Analysis and Epidemiological Modelling of Hantavirus Infection: From Host Transcriptomics to Transmission Dynamics"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5542-2997","authenticated-orcid":false,"given":"Pietro Hiram","family":"Guzzi","sequence":"first","affiliation":[{"name":"Department of Surgical and Medical Sciences, University \u201cMagna Graecia\u201d of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9485-3877","authenticated-orcid":false,"given":"Francesco","family":"Branda","sequence":"additional","affiliation":[{"name":"Unit of Medical Statistics and Molecular Epidemiology, Universit\u00e0 Campus Bio-Medico di Roma, Via \u00c1lvaro del Portillo 21, 00128 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3501-714X","authenticated-orcid":false,"given":"Fabio","family":"Scarpa","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5921-3180","authenticated-orcid":false,"given":"Giancarlo","family":"Ceccarelli","sequence":"additional","affiliation":[{"name":"Department of Public Health and Infectious Diseases, University Hospital Policlinico Umberto I, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3866-9239","authenticated-orcid":false,"given":"Massimo","family":"Ciccozzi","sequence":"additional","affiliation":[{"name":"Unit of Medical Statistics and Molecular Epidemiology, Universit\u00e0 Campus Bio-Medico di Roma, Via \u00c1lvaro del Portillo 21, 00128 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7325-9908","authenticated-orcid":false,"given":"Federico Manuel","family":"Giorgi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2494-0294","authenticated-orcid":false,"given":"Pierangelo","family":"Veltri","sequence":"additional","affiliation":[{"name":"DIMES, University of Calabria, 88100 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e371","DOI":"10.1016\/S1473-3099(23)00128-7","article-title":"Hantavirus in humans: A review of clinical aspects and management","volume":"23","author":"Vial","year":"2023","journal-title":"Lancet Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8041","DOI":"10.1073\/pnas.1701777114","article-title":"Interannual cycles of Hantaan virus outbreaks at the human\u2013animal interface in central China are controlled by temperature and rainfall","volume":"114","author":"Tian","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Tortosa, F., Perre, F., Tognetti, C., Lossetti, L., Carrasco, G., Guaresti, G., Iglesias, A., Espasandin, Y., and Izcovich, A. (2024). Seroprevalence of hantavirus infection in non-epidemic settings over four decades: A systematic review and meta-analysis. BMC Public Health, 24.","DOI":"10.1186\/s12889-024-20014-w"},{"key":"ref_4","first-page":"S285","article-title":"Human-to-human transmission of Andes virus: A systematic review","volume":"224","author":"Toledo","year":"2021","journal-title":"J. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s42522-025-00136-w","article-title":"Ecological determinants driving orthohantavirus prevalence in small mammals of Europe: A systematic review","volume":"7","author":"Fabbri","year":"2025","journal-title":"One Health Outlook"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.3201\/eid1112.050501","article-title":"Person-to-person transmission of Andes virus","volume":"11","author":"Bellomo","year":"2005","journal-title":"Emerg. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"792","DOI":"10.3201\/eid2604.190799","article-title":"Person-to-person transmission of Andes virus in hantavirus pulmonary syndrome, Argentina, 2014","volume":"26","author":"Alonso","year":"2020","journal-title":"Emerg. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1006\/viro.1997.8976","article-title":"Hantavirus pulmonary syndrome outbreak in Argentina: Molecular evidence for person-to-person transmission of Andes virus","volume":"241","author":"Padula","year":"1998","journal-title":"Virology"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Pizarro, E., Navarrete, M., Mendez, C., Zaror, L., Mansilla, C., Tapia, M., Carrasco, C., Salazar, P., Murua, R., and Padula, P. (2020). Immunocytochemical and ultrastructural evidence supporting that Andes hantavirus (ANDV) is transmitted person-to-person through the respiratory and\/or salivary pathways. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.02992"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1056\/NEJMoa2009040","article-title":"\u201cSuper-spreaders\u201d and person-to-person transmission of Andes virus in Argentina","volume":"383","author":"Alonso","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Coelho, R.M., Kehl, S., Periolo, N., Alonso, D.O., Bellomo, C.M., and Mart\u00ednez, V.P. (2025). Virological characterization of a new isolated strain of Andes virus involved in the recent person-to-person transmission outbreak reported in Argentina. PLoS Negl. Trop. Dis., 19.","DOI":"10.1371\/journal.pntd.0013205"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e00018","DOI":"10.1128\/msphere.00018-23","article-title":"Andes virus genome mutations that are likely associated with animal model attenuation and human person-to-person transmission","volume":"8","author":"Bellomo","year":"2023","journal-title":"mSphere"},{"key":"ref_13","unstructured":"World Health Organization (2026, May 10). Hantavirus Cluster Linked to Cruise Ship Travel, Multi-Country\u2014Disease Outbreak News DON599. Technical Report, World Health Organization, 2026. Published 5 May 2026. Available online: https:\/\/www.who.int\/emergencies\/disease-outbreak-news\/item\/2026-DON599."},{"key":"ref_14","unstructured":"Public Health Agency of Canada (2026, May 10). Rapid Risk Assessment: Hantavirus (Andes Virus) Outbreak on International Cruise Ship. Technical Report; Public Health Agency of Canada, 2026. Assessment Completed 8 May 2026, Available online: https:\/\/www.canada.ca\/en\/public-health\/services\/emergency-preparedness-response\/rapid-risk-assessments-public-health-professionals\/rapid-risk-assessment-hantavirus-andes-virus-outbreak-international-cruise-ship.html."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e02250\u201316","DOI":"10.1128\/JVI.02250-16","article-title":"The long noncoding RNA NEAT1 exerts antihantaviral effects by acting as positive feedback for RIG-I signaling","volume":"91","author":"Ma","year":"2017","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1111\/j.1365-2656.2009.01646.x","article-title":"The effect of seasonality, density and climate on the population dynamics of Montana deer mice, important reservoir hosts for Sin Nombre hantavirus","volume":"79","author":"Luis","year":"2010","journal-title":"J. Anim. Ecol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4349874","DOI":"10.1155\/2023\/9578283","article-title":"A mathematical model for the transmission of hantavirus between rodents and humans","volume":"2023","author":"Supriatna","year":"2023","journal-title":"Comput. Math. Methods Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Guti\u00e9rrez-Jara, J.P., Mu\u00f1oz-Quezada, M.T., C\u00f3rdova-Lepe, F., and Silva-Guzm\u00e1n, A. (2023). Mathematical model of the dynamics of hantavirus infection in rodents and humans with the effect of rodent mobility. Pathogens, 12.","DOI":"10.3390\/pathogens12091147"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Guzzi, P.H., Mercatelli, D., Ceraolo, C., and Giorgi, F.M. (2020). Master regulator analysis of the SARS-CoV-2\/Human interactome. J. Clin. Med., 9.","DOI":"10.1101\/2020.03.15.992925"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s13278-025-01556-2","article-title":"Exdiff: A modular and explainable framework combining network simulation and graph neural networks for diffusion modelling","volume":"16","author":"Defilippo","year":"2026","journal-title":"Soc. Netw. Anal. Min."},{"key":"ref_21","first-page":"2813","article-title":"Using graph models to understand West Nile virus epidemics: A computational approach","volume":"5","author":"Branda","year":"2016","journal-title":"F1000Research"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Royster, A., Ren, S., Ali, S., Mir, S., and Mir, M. (2024). Modulations in the host cell proteome by the hantavirus nucleocapsid protein. PLoS Pathog., 20.","DOI":"10.1371\/journal.ppat.1011925"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1093\/clinids\/13.1.97","article-title":"Mechanisms of disease in Hantavirus infection: Pathophysiology of hemorrhagic fever with renal syndrome","volume":"13","author":"Cosgriff","year":"1991","journal-title":"Rev. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Wang, M., Wang, J., Wang, T., Li, J., Hui, L., and Ha, X. (2013). Thrombocytopenia as a predictor of severe acute kidney injury in patients with Hantaan virus infections. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053236"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1080\/23744235.2016.1192719","article-title":"Thrombocytopenia associates with the severity of inflammation and variables reflecting capillary leakage in Puumala Hantavirus infection, an analysis of 546 Finnish patients","volume":"48","author":"Outinen","year":"2016","journal-title":"Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lupusoru, G.E., Ailincai, I.G., Andronesi, A.G., Lupusoru, M., Bernea, L.M., Berechet, A.I., Banu, M., Andronesi, D., and Ismail, G. (2021). MO426 hanta hemorrhagic fever with renal syndrome caused by hantaan serotipe in balkan peninsula\u2014An unespected finding. Nephrol. Dial. Transplant., 36.","DOI":"10.1093\/ndt\/gfab083.0018"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1309\/CNWF-DC72-QYMR-M8DA","article-title":"Rapid presumptive diagnosis of hantavirus cardiopulmonary syndrome by peripheral blood smear review","volume":"116","author":"Koster","year":"2001","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.virs.2023.08.006","article-title":"RIPK3 promotes hantaviral replication by restricting JAK-STAT signaling without triggering necroptosis","volume":"38","author":"Si","year":"2023","journal-title":"Virol. Sin."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1086\/513874","article-title":"Hantavirus infection induces a typical myocarditis that may be responsible for myocardial depression and shock in hantavirus pulmonary syndrome","volume":"195","author":"Saggioro","year":"2007","journal-title":"J. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1093\/infdis\/jiv161","article-title":"Increased thrombopoiesis and platelet activation in hantavirus-infected patients","volume":"212","author":"Sundberg","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"STRING v11.5: Protein\u2013protein association networks with increased coverage supporting functional discovery in genome-wide experimental datasets","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: A comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_33","unstructured":"Phylo, Inc. (2026, May 05). Biomni: AI-Powered Scientific Research Platform. Available online: https:\/\/phylo.bio\/."},{"key":"ref_34","unstructured":"Bloemberg, G., Chudzinski, V., Cordey, S., Huber, M., Laubscher, F., P\u00e9rez-Rodr\u00edguez, F.J., Pichler, I., Schibler, M., Thomasson, V., and Ziltener, G. (2026, May 13). Complete Sequence of Orthohantavirus Andesense Virus: Swiss Resident 2026. Available online: https:\/\/virological.org\/t\/complete-sequence-of-orthohantavirus-andesense-virus-swiss-resident-2026\/1023."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1093\/nar\/gkh340","article-title":"MUSCLE: Multiple sequence alignment with high accuracy and high throughput","volume":"32","author":"Edgar","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"msae263","DOI":"10.1093\/molbev\/msae263","article-title":"MEGA12: Molecular evolutionary genetic analysis version 12 for adaptive and green computing","volume":"41","author":"Kumar","year":"2024","journal-title":"Mol. Biol. Evol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"D571","DOI":"10.1093\/nar\/gku1207","article-title":"NCBI viral genomes resource","volume":"43","author":"Brister","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Lu, S., Zhu, N., Guo, W., Wang, X., Li, K., Yan, J., Jiang, C., Han, S., Xiang, H., and Wu, X. (2020). RNA-Seq Revealed a Circular RNA-microRNA-mRNA Regulatory Network in Hantaan Virus Infection. Front. Cell. Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.00097"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0168-1702(02)00129-6","article-title":"Complete nucleotide sequence of a Chilean hantavirus","volume":"89","author":"Meissner","year":"2002","journal-title":"Virus Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3765","DOI":"10.1128\/JVI.76.8.3765-3773.2002","article-title":"Analysis of hantavirus genetic diversity in Argentina: S segment-derived phylogeny","volume":"76","author":"Bohlman","year":"2002","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Clay, C.A., Lehmer, E.M., Jeor, S.S., and Dearing, M.D. (2009). Sin Nombre virus and rodent species diversity: A test of the dilution and amplification hypotheses. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0006467"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.meegid.2016.03.036","article-title":"Phylogenetic analysis of a newfound bat-borne hantavirus supports a laurasiatherian host association for ancestral hantaviruses","volume":"41","author":"Witkowski","year":"2016","journal-title":"Infect. Genet. Evol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Kim, W.K., Cho, S., Lee, S.H., No, J.S., Lee, G.Y., Park, K., Lee, D., Jeong, S.T., and Song, J.W. (2021). Genomic epidemiology and active surveillance to investigate outbreaks of hantaviruses. Front. Cell. Infect. Microbiol., 10.","DOI":"10.3389\/fcimb.2020.532388"}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/6\/601\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T09:55:32Z","timestamp":1780480532000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/15\/6\/601"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,3]]},"references-count":43,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["pathogens15060601"],"URL":"https:\/\/doi.org\/10.3390\/pathogens15060601","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,3]]}}}