{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T02:36:19Z","timestamp":1787884579823,"version":"build-2784847793"},"reference-count":62,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001805","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001805","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Innovation Saskatchewan and the Ministry of Agriculture"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Kyasanur Forest disease virus (KFDV) and the closely related Alkhurma hemorrhagic disease virus (AHFV) are emerging flaviviruses that cause severe viral hemorrhagic fevers in humans. Increasing geographical expansion and case numbers, particularly of KFDV in southwest India, class these viruses as a public health threat. Viral pathogenesis is not well understood and additional vaccines and antivirals are needed to effectively counter the impact of these viruses. However, current animal models of KFDV pathogenesis do not accurately reproduce viral tissue tropism or clinical outcomes observed in humans. Here, we show that pigtailed macaques (\n                    <jats:italic>Macaca nemestrina<\/jats:italic>\n                    ) infected with KFDV or AHFV develop viremia that peaks 2 to 4 days following inoculation. Over the course of infection, animals developed lymphocytopenia, thrombocytopenia, and elevated liver enzymes. Infected animals exhibited hallmark signs of human disease characterized by a flushed appearance, piloerection, dehydration, loss of appetite, weakness, and hemorrhagic signs including epistaxis. Virus was commonly present in the gastrointestinal tract, consistent with human disease caused by KFDV and AHFV where gastrointestinal symptoms (hemorrhage, vomiting, diarrhea) are common. Importantly, RNAseq of whole blood revealed that KFDV downregulated gene expression of key clotting factors that was not observed during AHFV infection, consistent with increased severity of KFDV disease observed in this model. This work characterizes a nonhuman primate model for KFDV and AHFV that closely resembles human disease for further utilization in understanding host immunity and development of antiviral countermeasures.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009678","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T13:44:22Z","timestamp":1638452662000},"page":"e1009678","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["A pigtailed macaque model of Kyasanur Forest disease virus and Alkhurma hemorrhagic disease virus pathogenesis"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3740-5442","authenticated-orcid":true,"given":"Rebecca M.","family":"Broeckel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friederike","family":"Feldmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin L.","family":"McNally","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhilash I.","family":"Chiramel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail L.","family":"Sturdevant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline M.","family":"Leung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick W.","family":"Hanley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7567-446X","authenticated-orcid":true,"given":"Jamie","family":"Lovaglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Rosenke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana P.","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg","family":"Saturday","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadila","family":"Bouamr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela L.","family":"Rasmussen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelly J.","family":"Robertson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0206-297X","authenticated-orcid":true,"given":"Sonja M.","family":"Best","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"issue":"2","key":"ppat.1009678.ref001","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1029\/2018GH000164","article-title":"Historical Expansion of Kyasanur Forest Disease in India From 1957 to 2017: A Retrospective Analysis","volume":"3","author":"S Chakraborty","year":"2019","journal-title":"Geohealth"},{"issue":"2","key":"ppat.1009678.ref002","doi-asserted-by":"crossref","first-page":"145","DOI":"10.4103\/ijmr.IJMR_688_17","article-title":"Clinical & epidemiological significance of Kyasanur forest disease","volume":"148","author":"A Munivenkatappa","year":"2018","journal-title":"Indian J Med Res"},{"key":"ppat.1009678.ref003","first-page":"248","article-title":"Russian spring-summer virus in India: Kyasanur Forest disease","volume":"1","author":"TH WORK","year":"1958","journal-title":"Prog Med Virol"},{"issue":"2","key":"ppat.1009678.ref004","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0035-9203(97)90215-7","article-title":"Isolation of a flavivirus related to the tick-borne encephalitis complex from human cases in Saudi Arabia","volume":"91","author":"AM Zaki","year":"1997","journal-title":"Trans R Soc Trop Med Hyg"},{"issue":"10","key":"ppat.1009678.ref005","doi-asserted-by":"crossref","first-page":"e1352","DOI":"10.1371\/journal.pntd.0001352","article-title":"Ancient ancestry of KFDV and AHFV revealed by complete genome analyses of viruses isolated from ticks and mammalian hosts","volume":"5","author":"KA Dodd","year":"2011","journal-title":"PLoS Negl Trop 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A preliminary report on the nature of the infection and clinical manifestations in human beings","volume":"11","author":"TH WORK","year":"1957","journal-title":"Indian J Med Sci"},{"issue":"5","key":"ppat.1009678.ref032","first-page":"124","article-title":"Clinical study of 100 cases of Kyasanur Forest disease with clinicopathological correlation","volume":"47","author":"MR Adhikari Prabha","year":"1993","journal-title":"Indian J Med Sci"},{"issue":"11","key":"ppat.1009678.ref033","first-page":"1462","article-title":"CD14","volume":"2","author":"D Michlmayr","year":"2017","journal-title":"Nat Microbiol"},{"issue":"2","key":"ppat.1009678.ref034","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.virol.2008.03.028","article-title":"Phenotyping of peripheral blood mononuclear cells during acute dengue illness demonstrates infection and increased activation of monocytes in severe cases compared to classic dengue fever","volume":"376","author":"AP Durbin","year":"2008","journal-title":"Virology"},{"issue":"1","key":"ppat.1009678.ref035","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41426-018-0177-z","article-title":"Kyasanur Forest disease virus infection activates human vascular endothelial cells and monocyte-derived dendritic cells","volume":"7","author":"J Sirmarova","year":"2018","journal-title":"Emerg Microbes Infect"},{"issue":"8","key":"ppat.1009678.ref036","doi-asserted-by":"crossref","first-page":"e1002885","DOI":"10.1371\/journal.ppat.1002885","article-title":"Measles immune suppression: lessons from the macaque model","volume":"8","author":"RD de Vries","year":"2012","journal-title":"PLoS Pathog"},{"issue":"6","key":"ppat.1009678.ref037","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1089\/aid.2016.0253","article-title":"HIV Persistence in Gut-Associated Lymphoid Tissues: Pharmacological Challenges and Opportunities","volume":"33","author":"CG Thompson","year":"2017","journal-title":"AIDS Res Hum Retroviruses"},{"issue":"20","key":"ppat.1009678.ref038","doi-asserted-by":"crossref","first-page":"4172","DOI":"10.1182\/blood-2012-06-437608","article-title":"Differential infection patterns of CD4+ T cells and lymphoid tissue viral burden distinguish progressive and nonprogressive lentiviral infections","volume":"120","author":"JM Brenchley","year":"2012","journal-title":"Blood"},{"issue":"3","key":"ppat.1009678.ref039","doi-asserted-by":"crossref","first-page":"e1006219","DOI":"10.1371\/journal.ppat.1006219","article-title":"Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues","volume":"13","author":"AJ Hirsch","year":"2017","journal-title":"PLoS Pathog."},{"issue":"1","key":"ppat.1009678.ref040","doi-asserted-by":"crossref","first-page":"15306","DOI":"10.1038\/s41598-020-72205-1","article-title":"Dynamics of human B and T cell adaptive immune responses to Kyasanur Forest disease virus infection","volume":"10","author":"S Devadiga","year":"2020","journal-title":"Sci Rep."},{"key":"ppat.1009678.ref041","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/0035-9203(61)90067-0","article-title":"RL. 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