{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T19:09:17Z","timestamp":1774033757255,"version":"3.50.1"},"reference-count":56,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T00:00:00Z","timestamp":1628121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM103648"],"award-info":[{"award-number":["P20GM103648"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The emergence and ensuing dominance of COVID-19 on the world stage has emphasized the urgency of efficient animal models for the development of therapeutics for and assessment of immune responses to SARS-CoV-2 infection. Shortcomings of current animal models for SARS-CoV-2 include limited lower respiratory disease, divergence from clinical COVID-19 disease, and requirements for host genetic modifications to permit infection. In this study, n = 12 specific-pathogen-free domestic cats were infected intratracheally with SARS-CoV-2 to evaluate clinical disease, histopathologic lesions, and viral infection kinetics at 4 and 8 days post-inoculation; n = 6 sham-inoculated cats served as controls. Intratracheal inoculation of SARS-CoV-2 produced a significant degree of clinical disease (lethargy, fever, dyspnea, and dry cough) consistent with that observed in the early exudative phase of COVID-19. Pulmonary lesions such as diffuse alveolar damage, hyaline membrane formation, fibrin deposition, and proteinaceous exudates were also observed with SARS-CoV-2 infection, replicating lesions identified in people hospitalized with ARDS from COVID-19. A significant correlation was observed between the degree of clinical disease identified in infected cats and pulmonary lesions. Viral loads and ACE2 expression were also quantified in nasal turbinates, distal trachea, lungs, and other organs. Results of this study validate a feline model for SARS-CoV-2 infection that results in clinical disease and histopathologic lesions consistent with acute COVID-19 in humans, thus encouraging its use for future translational studies.<\/jats:p>","DOI":"10.3390\/v13081550","type":"journal-article","created":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T21:43:53Z","timestamp":1628199833000},"page":"1550","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Clinical and Histopathologic Features of a Feline SARS-CoV-2 Infection Model Are Analogous to Acute COVID-19 in Humans"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4532-3458","authenticated-orcid":false,"given":"Jennifer M.","family":"Rudd","sequence":"first","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miruthula","family":"Tamil Selvan","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shannon","family":"Cowan","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun-Fan","family":"Kao","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecily C.","family":"Midkiff","sequence":"additional","affiliation":[{"name":"Division of Comparative Pathology, Tulane National Primate Research Center, Tulane University, Covington, LA 70433, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sai","family":"Narayanan","sequence":"additional","affiliation":[{"name":"Oklahoma Animal Disease Diagnostic Laboratory, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akhilesh","family":"Ramachandran","sequence":"additional","affiliation":[{"name":"Oklahoma Animal Disease Diagnostic Laboratory, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jerry W.","family":"Ritchey","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3638-5665","authenticated-orcid":false,"given":"Craig A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,5]]},"reference":[{"key":"ref_1","unstructured":"WHO (2021, July 08). World Health Organization Coronavirus (COVID-19) Dashboard. Available online: https:\/\/covid19.who.int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1001\/jamainternmed.2020.0994","article-title":"Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China","volume":"80","author":"Wu","year":"2020","journal-title":"JAMA Intern. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2620","DOI":"10.1172\/JCI137244","article-title":"Clinical and immunologic features in severe and moderate Coronavirus Disease 2019","volume":"130","author":"Chen","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1172\/JCI137647","article-title":"SARS-CoV-2: A storm is raging","volume":"130","author":"Pedersen","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s13337-020-00637-4","article-title":"Selection of animal models for COVID-19 research","volume":"31","author":"Kumar","year":"2020","journal-title":"VirusDisease"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.coviro.2015.06.009","article-title":"Animal models for SARS and MERS coronaviruses","volume":"13","author":"Gretebeck","year":"2015","journal-title":"Curr. Opin. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e9610","DOI":"10.15252\/msb.20209610","article-title":"The protein expression profile of ACE2 in human tissues","volume":"16","author":"Hikmet","year":"2020","journal-title":"Mol. Syst. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/s12985-020-01416-9","article-title":"COVID-19 pandemic: Current knowledge about the role of pets and other animals in disease transmission","volume":"17","author":"Kiros","year":"2020","journal-title":"Virol. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2001005","DOI":"10.2807\/1560-7917.ES.2020.25.23.2001005","article-title":"SARS-CoV-2 infection in farmed minks, the Netherlands, April and May 2020","volume":"25","author":"Oreshkova","year":"2020","journal-title":"Eurosurveillance"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"710","DOI":"10.15585\/mmwr.mm6923e3","article-title":"First reported cases of SARS-CoV-2 infection in companion animals\u2014New York, March\u2013April 2020","volume":"69","author":"Newman","year":"2020","journal-title":"Morb. Mortal. Wkly. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1177\/0300985820943535","article-title":"Clinical and Pathological Findings in SARS-CoV-2 Disease Outbreaks in Farmed Mink (Neovison vison)","volume":"57","author":"Molenaar","year":"2020","journal-title":"Vet. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.bbrc.2020.03.047","article-title":"Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection","volume":"526","author":"Luan","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e2025373118","DOI":"10.1073\/pnas.2025373118","article-title":"Functional and genetic analysis of viral receptor ACE2 orthologs reveals a broad potential host range of SARS-CoV-2","volume":"118","author":"Liu","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1080\/01652176.2020.1823522","article-title":"Highly conserved binding region of ACE2 as a receptor for SARS-CoV-2 between humans and mammals","volume":"40","author":"Hayashi","year":"2020","journal-title":"Vet. Q."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e02220-20","DOI":"10.1128\/mBio.02220-20","article-title":"From people to panthera: Natural SARS-CoV-2 infection in tigers and lions at the Bronx Zoo","volume":"11","author":"McAloose","year":"2020","journal-title":"mBio"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1126\/science.abb7015","article-title":"Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2","volume":"358","author":"Shi","year":"2020","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1080\/22221751.2020.1817796","article-title":"A serological survey of SARS-CoV-2 in cat in Wuhan","volume":"9","author":"Zhang","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1126\/science.abc6141","article-title":"The search for a COVID-19 animal model","volume":"368","author":"Lakdawala","year":"2020","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez, M., Abad, D., Eiros, J.M., and Rodr\u00edguez-L\u00e1zaro, D. (2020). Are animals a neglected transmission route of SARS-CoV-2?. Pathogens, 9.","DOI":"10.3390\/pathogens9060480"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1017\/S0007114513000226","article-title":"The cat as a model for human obesity: Insights into depot-specific inflammation associated with feline obesity","volume":"110","author":"Janssens","year":"2013","journal-title":"Br. J. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"T1","DOI":"10.1530\/JOE-14-0202","article-title":"Animal models of disease: Classification and etiology of diabetes in dogs and cats","volume":"222","author":"Nelson","year":"2014","journal-title":"J. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1111\/age.12799","article-title":"The Burmese cat as a genetic model of type 2 diabetes in humans","volume":"50","author":"Samaha","year":"2019","journal-title":"Anim. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1177\/193229681200600306","article-title":"The cat as a model for human obesity and diabetes","volume":"6","author":"Hoenig","year":"2012","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"16587","DOI":"10.1038\/s41598-017-15851-2","article-title":"A Feline HFpEF Model with Pulmonary Hypertension and Compromised Pulmonary Function","volume":"7","author":"Wallner","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1007\/s10741-017-9645-0","article-title":"Human heart failure with preserved ejection versus feline cardiomyopathy: What can we learn from both veterinary and human medicine?","volume":"22","author":"Prat","year":"2017","journal-title":"Heart Fail. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.1080\/22221751.2020.1833687","article-title":"SARS-CoV-2 infection, disease and transmission in domestic cats","volume":"9","author":"Gaudreault","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"26382","DOI":"10.1073\/pnas.2013102117","article-title":"Experimental infection of domestic dogs and cats with SARS-CoV-2: Pathogenesis, transmission, and response to reexposure in cats","volume":"117","author":"Hartwig","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1080\/22221751.2021.1902753","article-title":"Experimental re-infected cats do not transmit SARS-CoV-2","volume":"10","author":"Gaudreault","year":"2021","journal-title":"Emerg. Microbes Infect."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1354\/vp.45-4-551","article-title":"Pathology of experimental SARS coronavirus infection in cats and ferrets","volume":"45","author":"Haagmans","year":"2008","journal-title":"Vet. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.jcpa.2014.01.004","article-title":"The pathology and pathogenesis of experimental severe acute respiratory syndrome and influenza in animal models","volume":"151","author":"Haagmans","year":"2014","journal-title":"J. Comp. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1002\/9780471729259.mc15e02s37","article-title":"Growth and quantification of MERS-CoV infection","volume":"37","author":"Coleman","year":"2015","journal-title":"Curr. Protoc. Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1093\/oxfordjournals.aje.a118408","article-title":"A simple method of estimating fifty per cent endpoints","volume":"27","author":"Reed","year":"1938","journal-title":"Am. J. Epidemiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0165-2427(01)00250-1","article-title":"Constitutive expression of types 1 and 2 cytokines by alveolar macrophages from feline immunodeficiency virus-infected cats","volume":"79","author":"Ritchey","year":"2001","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1038\/s41379-020-0603-3","article-title":"A systematic review of pathological findings in COVID-19: A pathophysiological timeline and possible mechanisms of disease progression","volume":"33","author":"Polak","year":"2020","journal-title":"Mod. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1038\/s41379-020-0536-x","article-title":"Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies","volume":"33","author":"Tian","year":"2020","journal-title":"Mod. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e13259","DOI":"10.1111\/eci.13259","article-title":"Histopathology and genetic susceptibility in COVID-19 pneumonia","volume":"50","year":"2020","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/S2213-2600(20)30076-X","article-title":"Pathological findings of COVID-19 associated with acute respiratory distress syndrome","volume":"8","author":"Xu","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.vetimm.2011.06.006","article-title":"Strain-specific viral distribution and neuropathology of feline immunodeficiency virus","volume":"143","author":"Miller","year":"2011","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Miller, C., Boegler, K., Carver, S., MacMillan, M., Bielefeldt-Ohmann, H., and VandeWoude, S. (2017). Pathogenesis of oral FIV infection. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185138"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"18764","DOI":"10.1038\/s41598-020-75958-x","article-title":"Assessment of the direct quantitation of SARS-CoV-2 by droplet digital PCR","volume":"10","author":"Deiana","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.jbi.2015.01.008","article-title":"HBLAST: Parallelised sequence similarity\u2014A Hadoop MapReducable basic local alignment search tool","volume":"54","author":"Belogrudov","year":"2015","journal-title":"J. Biomed. Inf."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.cell.2020.04.023","article-title":"Genomic epidemiology of SARS-CoV-2 in Guangdong province, China","volume":"181","author":"Lu","year":"2020","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1101\/gr.215087.116","article-title":"Canu: Scalable and accurate long-read assembly via adaptive k-mer weighting and repeat separation","volume":"27","author":"Koren","year":"2017","journal-title":"Genome Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"giab008","DOI":"10.1093\/gigascience\/giab008","article-title":"Twelve years of SAMtools and BCFtools","volume":"10","author":"Danecek","year":"2021","journal-title":"Gigascience"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3094","DOI":"10.1093\/bioinformatics\/bty191","article-title":"Minimap2: Pairwise alignment for nucleotide sequences","volume":"34","author":"Li","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/nmeth.3444","article-title":"A complete bacterial genome assembled de novo using only nanopore sequencing data","volume":"12","author":"Loman","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1097\/SHK.0b013e3182939831","article-title":"Ensuring animal welfare while meeting scientific aims using a murine pneumonia model of septic shock","volume":"39","author":"Huet","year":"2013","journal-title":"Shock"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/j.1939-1676.2007.0012.x","article-title":"Efficacy of pradofloxacin in cats with feline upper respiratory tract disease due to Chlamydophila felis or Mycoplasma infections","volume":"22","author":"Hartmann","year":"2008","journal-title":"J. Vet. Intern. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1177\/1098612X18808103","article-title":"Acute pain in cats: Recent advances in clinical assessment","volume":"21","author":"Steagall","year":"2019","journal-title":"J. Feline Med. Surg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.ajpath.2020.10.016","article-title":"Acute respiratory distress in aged, SARS-CoV-2\u2013infected African green monkeys but not rhesus macaques","volume":"191","author":"Blair","year":"2021","journal-title":"Am. J. Pathol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.ajpath.2011.03.026","article-title":"Pathogenesis of Influenza A\/H5N1 virus infection in ferrets differs between intranasal and intratracheal routes of inoculation","volume":"179","author":"Bodewes","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"176","DOI":"10.2353\/ajpath.2006.050466","article-title":"Influenza A virus (H5N1) infection in cats causes systemic disease with potential novel routes of virus spread within and between hosts","volume":"168","author":"Rimmelzwaan","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.2460\/javma.2003.223.1142","article-title":"Clinicopathologic and radiographic features and etiologic agents in cats with histologically confirmed infectious pneumonia: 39 cases (1991\u20132000)","volume":"223","author":"Macdonald","year":"2003","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1001\/jama.2020.12839","article-title":"Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): A Review","volume":"324","author":"Wiersinga","year":"2020","journal-title":"JAMA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/S2213-2600(20)30243-5","article-title":"Pulmonary and cardiac pathology in African American patients with COVID-19: An autopsy series from New Orleans","volume":"8","author":"Fox","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.1038\/s41379-020-00661-1","article-title":"COVID-19 pulmonary pathology: A multi-institutional autopsy cohort from Italy and New York City","volume":"33","author":"Borczuk","year":"2020","journal-title":"Mod. Pathol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/8\/1550\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:41:13Z","timestamp":1760164873000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/8\/1550"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,5]]},"references-count":56,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["v13081550"],"URL":"https:\/\/doi.org\/10.3390\/v13081550","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.04.14.439863","asserted-by":"object"}]},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,5]]}}}