title: A clinically authentic mouse model of enterovirus 71 (EV-A71)-induced neurogenic pulmonary oedema.
abstract: Enterovirus 71 (EV-A71) is a neurotropic virus that sporadically causes fatal neurologic illness among infected children. Animal models of EV-A71 infection exist, but they do not recapitulate in animals the spectrum of disease and pathology observed in fatal human cases. Specifically, neurogenic pulmonary oedema (NPE)-the main cause of EV-A71 infection-related mortality-is not observed in any of these models. This limits their utility in understanding viral pathogenesis of neurologic infections. We report the development of a mouse model of EV-A71 infection displaying NPE in severely affected animals. We inoculated one-week-old BALB/c mice with an adapted EV-A71 strain and identified clinical signs consistent with observations in human cases and other animal models. We also observed respiratory distress in some mice. At necropsy, we found their lungs to be heavier and incompletely collapsed compared to other mice. Serum levels of catecholamines and histopathology of lung and brain tissues of these mice strongly indicated onset of NPE. The localization of virally-induced brain lesions also suggested a potential pathogenic mechanism for EV-A71-induced NPE. This novel mouse model of virally-induced NPE represents a valuable resource for studying viral mechanisms of neuro-pathogenesis and pre-clinical testing of potential therapeutics and prophylactics against EV-A71-related neurologic complications.
authors.affiliation: Temasek Lifesciences Laboratory, 1 Research Link, National University of Singapore, Singapore.|Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Carla Bianca Luena
authors.initials: CB
authors.lastname: Victorio
authors.affiliation: Temasek Lifesciences Laboratory, 1 Research Link, National University of Singapore, Singapore.|Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Yishi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Temasek Lifesciences Laboratory, 1 Research Link, National University of Singapore, Singapore.
authors.forename: Qimei
authors.initials: Q
authors.lastname: Ng
authors.affiliation: Office of Research and Development, Curtin University, Perth, Western Australia, Australia.
authors.forename: Beng Hooi
authors.initials: BH
authors.lastname: Chua
authors.affiliation: Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Alonso
authors.affiliation: Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Vincent T K
authors.initials: VT
authors.lastname: Chow
authors.affiliation: Temasek Lifesciences Laboratory, 1 Research Link, National University of Singapore, Singapore.
authors.forename: Kaw Bing
authors.initials: KB
authors.lastname: Chua
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002395:Catecholamines / Q000378:metabolism; D004195:Disease Models, Animal; D029821:Enterovirus A, Human / Q000276:immunology / Q000502:physiology*; D004769:Enterovirus Infections / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000821:virology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D011654:Pulmonary Edema / Q000378:metabolism / Q000401:mortality / Q000473:pathology* / Q000821:virology; D012720:Severity of Illness Index
chemical_list: D057134:Antibodies, Neutralizing; D002395:Catecholamines