{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T18:11:54Z","timestamp":1791655914044,"version":"4.3.4"},"reference-count":48,"publisher":"MDPI AG","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":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020","award":["643476 (COMPARE)"],"award-info":[{"award-number":["643476 (COMPARE)"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["-398066876\/GRK 2485\/1"],"award-info":[{"award-number":["-398066876\/GRK 2485\/1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Canine kobuvirus (CaKV) is a globally distributed pathogen of dogs and is predominantly associated with infection of the gastrointestinal tract. However, an etiological link to enteric disease has not been established since CaKV has been identified in both asymptomatic dogs and animals with diarrheic symptoms. In this study, an extraintestinal CaKV infection was detected by next-generation sequencing in a fox (Vulpes vulpes) in Germany concomitant with a canine distemper virus (canine morbillivirus; CDV) co-infection. Phylogenetic analysis of the complete coding region sequence showed that this strain was most closely related to a CaKV strain detected in a dog in the United Kingdom in 2008. The tissue and cellular tropism of CaKV was characterized by the detection of viral antigens and RNA. CaKV RNA was detected by in situ hybridization in different tissues, including epithelial cells of the stomach and ependymal cells in the brain. The use of a new RT-qPCR assay for CaKV confirmed the systemic distribution of CaKV with viral RNA also detected in the lymph nodes, bladder, trachea, and brain. The detection of a CDV infection in this fox suggests that immunosuppression should be further investigated as a contributing factor to the enhanced extraintestinal spread of CaKV.<\/jats:p>","DOI":"10.3390\/microorganisms9122521","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T22:18:42Z","timestamp":1638829122000},"page":"2521","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Detection of Systemic Canine Kobuvirus Infection in Peripheral Tissues and the Central Nervous System of a Fox Infected with Canine Distemper Virus"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7758-9605","authenticated-orcid":false,"given":"Franziska K.","family":"Kaiser","sequence":"first","affiliation":[{"name":"Research Center for Infectious Disease and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"van Dyck","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy K.","family":"Jo","sequence":"additional","affiliation":[{"name":"Research Center for Infectious Disease and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0978-2067","authenticated-orcid":false,"given":"Tom","family":"Schreiner","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa M.","family":"Pfankuche","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9184-4134","authenticated-orcid":false,"given":"Peter","family":"Wohlsein","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilka","family":"Baumann","sequence":"additional","affiliation":[{"name":"Research Center for Infectious Disease and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Peters","sequence":"additional","affiliation":[{"name":"Chemisches und Veterin\u00e4runtersuchungsamt Westfalen, 59821 Arnsberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Baumg\u00e4rtner","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert D. M. E.","family":"Osterhaus","sequence":"additional","affiliation":[{"name":"Research Center for Infectious Disease and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0061-1106","authenticated-orcid":false,"given":"Martin","family":"Ludlow","sequence":"additional","affiliation":[{"name":"Research Center for Infectious Disease and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1007\/s00705-017-3358-5","article-title":"Changes to taxonomy and the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses","volume":"162","author":"Adams","year":"2017","journal-title":"Arch. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s00705-017-3614-8","article-title":"Picornaviridae\u2014the ever-growing virus family","volume":"163","author":"Zell","year":"2018","journal-title":"Arch. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1099\/vir.0.034611-0","article-title":"Viruses in diarrhoeic dogs include novel kobuviruses and sapoviruses","volume":"92","author":"Li","year":"2011","journal-title":"J. Gen. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s13337-014-0200-5","article-title":"Epidemiology of human and animal kobuviruses","volume":"25","author":"Khamrin","year":"2014","journal-title":"Virusdisease"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1093\/infdis\/164.5.954","article-title":"Isolation of Cytopathic Small Round Viruses with BS-C-l Cells from Patients with Gastroenteritis","volume":"164","author":"Yamashita","year":"1991","journal-title":"J. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8408","DOI":"10.1128\/JVI.72.10.8408-8412.1998","article-title":"Complete Nucleotide Sequence and Genetic Organization of Aichi Virus, a Distinct Member of the Picornaviridae Associated with Acute Gastroenteritis in Humans","volume":"72","author":"Yamashita","year":"1998","journal-title":"J. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"11520","DOI":"10.1128\/JVI.05317-11","article-title":"Characterization of a Canine Homolog of Human Aichivirus","volume":"85","author":"Kapoor","year":"2011","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Phan, T., Kapusinszky, B., Wang, C., Rose, R.K., Lipton, H.L., and Delwart, E.L. (2011). The Fecal Viral Flora of Wild Rodents. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002218"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12161","DOI":"10.1128\/JVI.00869-12","article-title":"High Variety of Known and New RNA and DNA Viruses of Diverse Origins in Untreated Sewage","volume":"86","author":"Ng","year":"2012","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s00705-014-2228-7","article-title":"Identification and complete genome analysis of kobuvirus in faecal samples of European roller (Coracias garrulus): For the first time in a bird","volume":"160","author":"Pankovics","year":"2015","journal-title":"Arch. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/s11262-013-0953-8","article-title":"Detection and genetic characterization of feline kobuviruses","volume":"47","author":"Chung","year":"2013","journal-title":"Virus Genes"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1099\/jmm.0.070987-0","article-title":"Molecular detection and nucleotide sequence analysis of a new Aichi virus closely related to canine kobuvirus in sewage samples","volume":"63","author":"Yamashita","year":"2014","journal-title":"J. Med. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1007\/s00705-014-1975-9","article-title":"Molecular evidence of kobuviruses in free-ranging red foxes (Vulpes vulpes)","volume":"159","author":"Melegari","year":"2014","journal-title":"Arch. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s00705-017-3637-1","article-title":"First molecular identification of kobuviruses in wolves (Canis lupus) in Italy","volume":"163","author":"Melegari","year":"2018","journal-title":"Arch. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.virol.2015.01.010","article-title":"Molecular characterization of canine kobuvirus in wild carnivores and the domestic dog in Africa","volume":"477","author":"Heeger","year":"2015","journal-title":"Virology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2751","DOI":"10.1007\/s00705-014-2136-x","article-title":"Canine kobuvirus infections in Korean dogs","volume":"159","author":"Oem","year":"2014","journal-title":"Arch. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1007\/s00705-020-04727-y","article-title":"Epidemiological and phylogenetic analysis of canine kobuviruses in Tangshan, China","volume":"165","author":"Wang","year":"2020","journal-title":"Arch. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1007\/s42770-019-00095-1","article-title":"Detection of canine kobuvirus RNA in diarrheic fecal samples of dogs with parvoviruses","volume":"50","author":"Miyabe","year":"2019","journal-title":"Braz. J. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.vetmic.2013.02.014","article-title":"Phylogeny and prevalence of kobuviruses in dogs and cats in the UK","volume":"164","author":"Buesa","year":"2013","journal-title":"Vet. Microbiol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Charoenkul, K., Janetanakit, T., Chaiyawong, S., Bunpapong, N., Boonyapisitsopa, S., Tangwangvivat, R., and Amonsin, A. (2019). First detection and genetic characterization of canine Kobuvirus in domestic dogs in Thailand. BMC Vet. Res., 15.","DOI":"10.1186\/s12917-019-1994-6"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/j.meegid.2010.06.001","article-title":"Molecular detection of kobuvirus sequences in stool samples collected from healthy pigs in Japan","volume":"10","author":"Khamrin","year":"2010","journal-title":"Infect. Genet. Evol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.3201\/eid1412.080797","article-title":"Candidate New Species of Kobuvirusin Porcine Hosts","volume":"14","author":"Reuter","year":"2008","journal-title":"Emerg. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3069","DOI":"10.1099\/vir.0.19266-0","article-title":"Isolation and characterization of a new species of kobuvirus associated with cattle","volume":"84","author":"Yamashita","year":"2003","journal-title":"J. Gen. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"985","DOI":"10.3201\/eid1406.070784","article-title":"Bovine Kobuviruses from Cattle with Diarrhea","volume":"14","author":"Khamrin","year":"2008","journal-title":"Emerg. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4011","DOI":"10.1128\/JCM.01044-08","article-title":"Aichi Virus, Norovirus, Astrovirus, Enterovirus, and Rotavirus Involved in Clinical Cases from a French Oyster-Related Gastroenteritis Outbreak","volume":"46","author":"Krol","year":"2008","journal-title":"J. Clin. Microbiol."},{"key":"ref_26","first-page":"1544","article-title":"Aichi Virus Shedding in High Concentrations in Patients with Acute Diarrhea","volume":"17","author":"Drexler","year":"2011","journal-title":"Emerg. Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1128\/JCM.02140-07","article-title":"Prevalence and Genetic Diversity of Aichi Virus Strains in Stool Samples from Community and Hospitalized Patients","volume":"46","author":"Lorrot","year":"2008","journal-title":"J. Clin. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1007\/s00705-020-04773-6","article-title":"Identification and full-genome sequencing of canine kobuvirus in canine fecal samples collected from Anhui Province, eastern China","volume":"165","author":"Wang","year":"2020","journal-title":"Arch. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12579","DOI":"10.1128\/JVI.77.23.12579-12591.2003","article-title":"A Ferret Model of Canine Distemper Virus Virulence and Immunosuppression","volume":"77","author":"Springfeld","year":"2003","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.3201\/eid2312.161634","article-title":"New Avian Hepadnavirus in Palaeognathous Bird, Germany","volume":"23","author":"Jo","year":"2017","journal-title":"Emerg. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1080\/22221751.2019.1664940","article-title":"An evolutionary divergent pestivirus lacking the N(pro) gene systemically infects a whale species","volume":"8","author":"Jo","year":"2019","journal-title":"Emerg. Microbes Infect."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1093\/molbev\/mst010","article-title":"MAFFT Multiple Sequence Alignment Software Version 7: Improvements in Performance and Usability","volume":"30","author":"Katoh","year":"2013","journal-title":"Mol. Biol. Evol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1093\/molbev\/msw054","article-title":"MEGA7: Molecular Evolutionary Genetics Analysis Version 7.0 for Bigger Datasets","volume":"33","author":"Kumar","year":"2016","journal-title":"Mol. Biol. Evol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1007\/s00401-007-0307-5","article-title":"Vimentin-positive astrocytes in canine distemper: A target for canine distemper virus especially in chronic demyelinating lesions?","volume":"114","author":"Seehusen","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1111\/j.1439-0450.1997.tb00983.x","article-title":"In vivo and in vitro Detection of Canine Distemper Virus Nucleoprotein Gene with Digoxigenin-Labelled RNA, Double-Stranded DNA Probes and Oligonucleotides by in situ Hybridization","volume":"44","author":"Gaedke","year":"1997","journal-title":"J. Vet. Med. Ser. B"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1007\/s00436-015-4382-6","article-title":"Pearsonema plica (Capillaria plica) infection and associated urinary bladder pathology in red foxes (Vulpes vulpes) from Bosnia and Herzegovina","volume":"114","year":"2015","journal-title":"Parasitol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Jo, W.K., Peters, M., Kydyrmanov, A., Van De Bildt, M.W.G., Kuiken, T., Osterhaus, A., and Ludlow, M. (2019). The Canine Morbillivirus Strain Associated with An Epizootic in Caspian Seals Provides New Insights into the Evolutionary History of this Virus. Viruses, 11.","DOI":"10.3390\/v11100894"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1007\/s00705-016-3164-5","article-title":"Extra-intestinal detection of canine kobuvirus in a puppy from Southern Brazil","volume":"162","author":"Ribeiro","year":"2016","journal-title":"Arch. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.vetimm.2008.09.023","article-title":"Pathogenesis and immunopathology of systemic and nervous canine distemper","volume":"127","author":"Beineke","year":"2009","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1126\/science.aaa3662","article-title":"Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality","volume":"348","author":"Mina","year":"2015","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"16386","DOI":"10.1155\/2012\/163860","article-title":"Immunopathogenic and Neurological Mechanisms of Canine Distemper Virus","volume":"2012","author":"Carvalho","year":"2012","journal-title":"Adv. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"14216","DOI":"10.1073\/pnas.0403597101","article-title":"Tropism illuminated: Lymphocyte-based pathways blazed by lethal morbillivirus through the host immune system","volume":"101","author":"Milosevic","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.3201\/eid1908.130312","article-title":"Aichi Virus in Sewage and Surface Water, the Netherlands","volume":"19","author":"Lodder","year":"2013","journal-title":"Emerg. Infect. Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4113","DOI":"10.1128\/AEM.00501-10","article-title":"Molecular Detection and Characterization of Aichi Viruses in Sewage-Polluted Waters of Venezuela","volume":"76","author":"Ana","year":"2010","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1007\/s00705-010-0744-7","article-title":"First molecular detection of Aichi virus in sewage and shellfish samples in the Monastir region of Tunisia","volume":"155","author":"Hassine","year":"2010","journal-title":"Arch. Virol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1128\/CVI.00382-09","article-title":"Seroprevalence of Aichi Virus in a Spanish Population from 2007 to 2008","volume":"17","author":"Ribes","year":"2010","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1007\/s00705-005-0706-7","article-title":"Molecular characterization of the first Aichi viruses isolated in Europe and in South America","volume":"151","author":"Oh","year":"2006","journal-title":"Arch. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1007\/s00705-008-0091-0","article-title":"Seroprevalence distribution of Aichi virus among a French population in 2006\u20132007","volume":"153","author":"Goyer","year":"2008","journal-title":"Arch. Virol."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/9\/12\/2521\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:40:17Z","timestamp":1760168417000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/9\/12\/2521"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,6]]},"references-count":48,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["microorganisms9122521"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms9122521","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,6]]}}}