A novel orally infected hamster model for Coxsackievirus A16 hand-foot-and-mouth disease and encephalomyelitis.
Animals
Antigens, Viral
/ metabolism
Child
Cricetinae
/ virology
Disease Models, Animal
Encephalomyelitis
/ diagnosis
Enterovirus A, Human
/ genetics
Feces
/ virology
Hand, Foot and Mouth Disease
/ diagnosis
Humans
Immunohistochemistry
In Situ Hybridization
Mouth
/ pathology
Mouth Mucosa
/ pathology
RNA, Viral
/ genetics
Sensitivity and Specificity
Journal
Laboratory investigation; a journal of technical methods and pathology
ISSN: 1530-0307
Titre abrégé: Lab Invest
Pays: United States
ID NLM: 0376617
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
24
02
2020
accepted:
11
06
2020
revised:
06
06
2020
pubmed:
1
7
2020
medline:
24
11
2020
entrez:
1
7
2020
Statut:
ppublish
Résumé
Coxsackievirus A16 (CV-A16) is one of the major causes of mild and self-limiting hand-foot-and-mouth disease (HFMD) in young children, which may occasionally leads to serious neurological complications. In this study, we had developed a novel, consistent, orally infected CV-A16 HFMD hamster model with encephalomyelitis. Four groups of 7-day-old hamsters in a kinetic study were orally infected with mouse-adapted CV-A16 strains and sacrificed at 1-4 days post infection (dpi), respectively. Tissues were studied by light microscopy, immunohistochemistry to detect viral antigens, in situ hybridization to detect viral RNA, and by viral titration. In a separate transmission experiment, orally infected index hamsters were housed together with contact hamsters to investigate oral and fecal viral shedding by virus culture and reverse transcription polymerase chain reaction (RT-PCR). At severe infection/death endpoints, index and contact hamster infection were also histopathologically analyzed. In the kinetic study, infected hamsters developed signs of infection at 4 dpi. Viral antigens/RNA were localized to brainstem (medulla/pons; reticular formation and motor trigeminal nucleus) and spinal cord anterior horn neurons, oral squamous epithelia and epidermis from 3 to 4 dpi. Salivary and lacrimal glands, myocardium, brown adipose tissue, intestinal smooth muscle, and skeletal muscle infection was also demonstrated. Viremia at 1 dpi and increasing viral titers in various tissues were observed from 2 dpi. In the transmission study, all contact hamsters developed disease 3-5 days later than index hamsters, but demonstrated similar histopathological findings at endpoint. Viral culture and RT-PCR positive oral washes and feces confirmed viral shedding. Our hamster model, orally infected by the natural route for human infection, confirmed CV-A16 neurotropism and demonstrated squamous epitheliotropism reminiscent of HFMD, attributes not found in other animal models. It should be useful to investigate neuropathogenesis, model person-to-person transmission, and for testing antiviral drugs and vaccines.
Identifiants
pubmed: 32601355
doi: 10.1038/s41374-020-0456-x
pii: S0023-6837(22)00369-5
doi:
Substances chimiques
Antigens, Viral
0
RNA, Viral
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1262-1275Références
Goto K, Sanefuji M, Kusuhara K, Nishimura Y, Shimizu H, Kira R, et al. Rhombencephalitis and Coxsackievirus A16. Emerg Infect Dis. 2009;15:1689–91.
pubmed: 19861078
pmcid: 2866411
Eyckmans T, Wollants E, Janssens A, Schoemans H, Lagrou K, Wauters J, et al. Coxsackievirus A16 encephalitis during Obinutuzumab therapy, Belgium, 2013. Emerg Infect Dis. 2014;20:913–5.
pubmed: 24751368
pmcid: 4012818
Zhang SY, Xu MY, Xu HM, Li XJ, Ding SJ, Wang XJ, et al. Immunologic characterization of cytokine responses to Enterovirus 71 and Coxsackievirus A16 infection in children. Medicine. 2015;94:e1137.
pubmed: 26166120
pmcid: 4504596
Luo M, Gong C, Zhang TG, Zhang ZJ. Study on the prevalence of acute flaccid paralysis and hand foot mouth disease in Beijing 2006–2008. Zhonghua Liu Xing Bing Xue Za Zhi. 2011;32:681–4.
pubmed: 21933539
Tao Z, Wang H, Li Y, Liu G, Xu A, Lin X, et al. Molecular epidemiology of human enterovirus associated with aseptic meningitis in Shandong Province, China, 2006-2012. PLoS ONE. 2014;9:e89766.
pubmed: 24587020
pmcid: 3931826
Legay F, Leveque N, Gacouin A, Tattevin P, Bouet J, Thomas R, et al. Fatal Coxsackievirus A-16 pneumonitis in adult. Emerg Infect Dis. 2007;13:1084–6.
pubmed: 18214187
pmcid: 2878248
Goldberg MF, McAdams AJ. Myocarditis possibly due to Coxsackie Group A, type 16, virus. J Pediatr. 1965;62:762–5.
Wang CY, Li LuF, Wu MH, Lee CY, Huang LM. Fatal Coxsackievirus A16 infection. Pediatr Infect Dis J. 2004;23:275–6.
pubmed: 15014311
Wright HT Jr., Landing BH, Lennette EH, Mc AR. Fatal infection in an infant associated with Coxsackie virus group A, type 16. N Engl J Med. 1963;268:1041–4.
pubmed: 14001956
Yang WS. Clinical characteristic analysis of 104 cases of children severe hand, foot and mouth disease. Chongqing Med J. 2011;40:1722–7.
Ong KC, Wong KT. Understanding Enterovirus 71 neuropathogenesis and its impact on other neurotropic enteroviruses. Brain Pathol. 2015;25:614–24.
pubmed: 26276025
Mao Q, Wang Y, Gao R, Shao J, Yao X, Lang S, et al. A neonatal mouse model of Coxsackievirus A16 for vaccine evaluation. J Virol. 2012;86:11967–76.
pubmed: 22951825
pmcid: 3486452
Cai Y, Liu Q, Huang X, Li D, Ku Z, Zhang Y, et al. Active immunization with a Coxsackievirus A16 experimental inactivated vaccine induces neutralizing antibodies and protects mice against lethal infection. Vaccine. 2013;31:2215–21.
pubmed: 23499596
Li JP, Liao Y, Zhang Y, Wang JJ, Wang LC, Feng K, et al. Experimental infection of tree shrews (Tupaia belangeri) with Coxsackie virus A16. Dongwuxue Yanjiu. 2014;35:485–91.
pubmed: 25465084
pmcid: 4790277
Liu Q, Shi J, Huang X, Liu F, Cai Y, Lan K, et al. A murine model of Coxsackievirus A16 infection for anti-viral evaluation. Antiviral Res. 2014;105:26–31.
pubmed: 24583030
Caine EA, Fuchs J, Das SC, Partidos CD, Osorio JE. Efficacy of a trivalent hand, foot, and mouth disease vaccine against Enterovirus 71 and Coxsackieviruses A16 and A6 in mice. Viruses. 2015;7:5919–32.
pubmed: 26593938
pmcid: 4664989
Sun YS, Li YJ, Xia Y, Xu F, Wang WW, Yang ZN, et al. Coxsackievirus A16 induced neurological disorders in young gerbils which could serve as a new animal model for vaccine evaluation. Sci Rep. 2016;6:34299.
pubmed: 27667023
pmcid: 5035925
Li J, Chang J, Liu X, Yang J, Guo H, Wei W, et al. Protection from lethal challenge in a neonatal mouse model by circulating recombinant form Coxsackievirus A16 vaccine candidates. J Gen Virol. 2014;95:1083–93.
pubmed: 24496826
pmcid: 3983757
Hooi YT, Ong KC, Perera D, Wong KT. Pathological findings in a mouse model for Coxsackievirus A16 infection. Neurology Asia. 2015;20:343–7.
Phyu WK, Ong KC, Wong KT. A consistent orally-infected hamster model for Enterovirus A71 encephalomyelitis demonstrates squamous lesions in the paws, skin and oral cavity reminiscent of hand-foot-and-mouth disease. PLoS ONE. 2016;11:e0147463.
pubmed: 26815859
pmcid: 4729525
Arita M, Nagata N, Sata T, Miyamura T, Shimizu H. Quantitative analysis of poliomyelitis-like paralysis in mice induced by a poliovirus replicon. J Gen Virol. 2006;87:3317–27.
pubmed: 17030866
Kärber G. Beitrag zur kollektiven Behandlung pharmakologischer Reihenversuche. Archiv für experimentelle Pathologie und Pharmakologie. 1931;162:480–3.
Tan SH, Ong KC, Wong KT. Enterovirus 71 can directly infect the brainstem via cranial nerves and infection can be ameliorated by passive immunization. J Neuropathol Exp Neurol. 2014;73:999–1008.
pubmed: 25289894
Hooi YT, Ong KC, Tan SH, Perera D, Wong KT. Coxsackievirus A16 in a 1-day-old mouse model of central nervous system infection shows lower neurovirulence than Enterovirus A71. J Comp Pathol. 2020;176:19–32.
pubmed: 32359633
Cameron Smail R, O’Neill JH, Andresen D. Brainstem encephalitis caused by Coxsackie A16 virus in a rituximab-immunosuppressed patient. BMJ Case Rep. 2019;12:e230177.
pubmed: 31451462
Xu W, Liu CF, Yan L, Li JJ, Wang LJ, Qi Y, et al. Distribution of enteroviruses in hospitalized children with hand, foot and mouth disease and relationship between pathogens and nervous system complications. Virol J. 2012;9:8.
pubmed: 22230340
pmcid: 3268717
Fan YK, Liu YP. Magnetic resonance imaging features of pediatric coxsackievirus encephalitis. J Belg Soc Radiol. 2019;103:6.
pubmed: 30637372
pmcid: 6328711
Brecht M, Jyoti R, McGuire W, Chauhan M. A case of neonatal Coxsackie B virus brainstem encephalitis. J Paediatr Child Health. 2010;46:699–701.
pubmed: 21077981
Lum LC, Chua KB, McMinn PC, Goh AY, Muridan R, Sarji SA, et al. Echovirus 7 associated encephalomyelitis. J Clin Virol. 2002;23:153–60.
pubmed: 11595594
Lian ZY, Li HH, Zhang B, Dong YH, Deng WX, Liu J, et al. Neuro-magnetic resonance imaging in hand, foot, and mouth disease: finding in 412 patients and prognostic features. J Comput Assist Tomogr. 2017;41:861–7.
pubmed: 28463891
pmcid: 5704669
Cree BC, Bernardini GL, Hays AP, Lowe G. A fatal case of Coxsackievirus B4 meningoencephalitis. Arch Neurol. 2003;60:107–12.
pubmed: 12533096
Shen WC, Chiu HH, Chow KC, Tsai CH. MR imaging findings of enteroviral encephaloymelitis: an outbreak in Taiwan. Am J Neuroradiol. 1999;20:1889–95.
pubmed: 10588115
Chen F, Li JJ, Liu T, Wen GQ, Xiang W. Clinical and neuroimaging features of Enterovirus71 related acute flaccid paralysis in patients with hand-foot-mouth disease. Asian Pac J Trop Med. 2013;6:68–72.
pubmed: 23317889
Li J, Chen F, Liu T, Wang L. MRI findings of neurological complications in hand-foot-mouth disease by Enterovirus 71 infection. Int J Neurosci. 2012;122:338–44.
pubmed: 22248036
Wong KT, Munisamy B, Ong KC, Kojima H, Noriyo N, Chua KB, et al. The distribution of inflammation and virus in human Enterovirus 71 encephalomyelitis suggests possible viral spread by neural pathways. J Neuropathol Exp Neurol. 2008;67:162–9.
pubmed: 18219253
Xing J, Liu D, Shen S, Su Z, Zhang L, Duan Y, et al. Pathologic studies of fatal encephalomyelitis in children caused by Enterovirus 71. Am J Clin Pathol. 2016;146:95–106.
pubmed: 27357294
He Y, Ong KC, Gao Z, Zhao X, Anderson VM, McNutt MA, et al. Tonsillar crypt epithelium is an important extra-central nervous system site for viral replication in EV71 encephalomyelitis. Am J Pathol. 2014;184:714–20.
pubmed: 24378407
Ong KC, Badmanathan M, Devi S, Leong KL, Cardosa MJ, Wong KT. Pathologic characterization of a murine model of human Enterovirus 71 encephalomyelitis. J Neuropathol Exp Neurol. 2008;67:532–42.
pubmed: 18520772
Muehlenbachs A, Bhatnagar J, Zaki SR. Tissue tropism, pathology and pathogenesis of enterovirus infection. J Pathol. 2015;235:217–28.
pubmed: 25211036
Phyu WK, Ong KC, Kong CK, Alizan AK, Ramanujam TM, Wong KT. Squamous epitheliotropism of Enterovirus A71 in human epidermis and oral mucosa. Sci Rep. 2017;7:45069.
pubmed: 28322333
pmcid: 5359612
Ooi MH, Solomon T, Podin Y, Mohan A, Akin W, Yusuf MA, et al. Evaluation of different clinical sample types in diagnosis of human Enterovirus 71-associated hand-foot-and-mouth disease. J Clin Microbiol. 2007;45:1858–66.
pubmed: 17446325
pmcid: 1933032
Chen X, Tan X, Li J, Jin Y, Gong L, Hong M, et al. Molecular epidemiology of Coxsackievirus A16: intratype and prevalent intertype recombination identified. PLoS ONE. 2013;8:e82861.
pubmed: 24340064
pmcid: 3858299
Pallansch MA, Ross RP. Enteroviruses: polioviruses, coxsackieviruses, echoviruses, and newer enteroviruses. In: Knipe David Mahan, Howley P.M., (eds.) Fields’ virology. 1.5th ed. USA: Lippincott, Williams & Wilkins; 2007. p 723–75.
Chen KT, Lee TC, Chang HL, Yu MC, Tang LH. Human Enterovirus 71 disease: clinical features, epidemiology, virology, and management. Open Epidemiol J. 2008;1:10–6.
Hoang CQ, Nguyen TTT, Ho NX, Nguyen HD, Nguyen AB, Nguyen THT, et al. Transmission and serotype features of hand foot mouth disease in household contacts in Dong Thap, Vietnam. BMC Infect Dis. 2019;19:933.
pubmed: 31690269
pmcid: 6833133
Fredricks DN, Relman DA. Sequence-based identification of microbial pathogens: a reconsideration of Koch’s postulates. Clin Microbiol Rev. 1996;9:18–33.
pubmed: 8665474
Phyu WK, Ong KC, Wong KT. Modelling person-to-person transmission in an Enterovirus A71 orally infected hamster model of hand-foot-and-mouth disease and encephalomyelitis. Emerg Microb Infect. 2017;6:e62.
Chen YC, Yu CK, Wang YF, Liu CC, Su IJ, Lei HY. A murine oral Enterovirus 71 infection model with central nervous system involvement. J Gen Virol. 2004;85:69–77.
pubmed: 14718621
Wang YF, Chou CT, Lei HY, Liu CC, Wang SM, Yan JJ, et al. A mouse-adapted Enterovirus 71 strain causes neurological disease in mice after oral infection. J Virol. 2004;78:7916–24.
pubmed: 15254164
pmcid: 446098
Yang X, Li G, Wen K, Bui T, Liu F, Kocher J, et al. A neonatal gnotobiotic pig model of human Enterovirus 71 infection and associated immune responses. Emerg Microb Infect. 2014;3:e35.
Tam PE. Coxsackievirus myocarditis: interplay between virus and host in the pathogenesis of heart disease. Viral Immunol. 2006;19:133–46.
pubmed: 16817756
Kearney MT, Cotton JM, Richardson PJ, Shah AM. Viral myocarditis and dilated cardiomyopathy: mechanisms, manifestations, and management. Postgrad Med J. 2001;77:4–10.
pubmed: 11123385
pmcid: 1741887
Liu L, Zhao H, Zhang Y, Wang J, Che Y, Dong C, et al. Neonatal rhesus monkey is a potential animal model for studying pathogenesis of EV71 infection. Virology. 2011;412:91–100.
pubmed: 21262515
Grodums EI, Dempster G. Changes in brown adipose tissues and Coxsackievirus B pathogenesis in mice on acute and chronic cold exposure. Can J Microbiol. 1970;16:833–9.
pubmed: 5506087
Li Z, Liu X, Wang S, Li J, Hou M, Liu G, et al. Identification of a nucleotide in 5’ untranslated region contributing to virus replication and virulence of Coxsackievirus A16. Sci Rep. 2016;6:20839.
pubmed: 26861413
pmcid: 4748407