Characterization of enterovirus D68 infection in four nonhuman primate species

Dearing, J.; Conte, A.; Brooks, C.; Zimina, A.; Birch, S. M.; Adney, D. R.; Li, M.; Rascon, A.; Belov, G. A.; Pekosz, A.; Vermillion, M. S.

doi:10.1101/2022.04.16.487524

bioRxiv · 10.1101/2022.04.16.487524

Characterization of enterovirus D68 infection in four nonhuman primate species

Dearing, J.·Conte, A.·Brooks, C.·Zimina, A.·Birch, S. M.·Adney, D. R.·Li, M.·Rascon, A.·Belov, G. A.·Pekosz, A.·Vermillion, M. S.

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Abstract

Human enterovirus D68 (EV-D68) is a globally reemerging respiratory pathogen that is associated with the development of acute flaccid myelitis (AFM) in children. Currently, there are no approved vaccines or treatments for EV-D68 infection, and there is a paucity of data related to the virus and host specific factors that predict disease severity and progression to the neurologic syndrome. Published animal models of EV-D68 infection to date have been limited to mice, cotton rat and ferrets, and investigation of the susceptibility of nonhuman primate (NHP) species to contemporary EV-D68 isolates has not yet been reported. In this study, we challenged juvenile NHPs - cynomolgus macaques, rhesus macaques, pigtailed macaques, and African green monkeys - with one of five different 2014 or 2018 EV-D68 isolates by the respiratory route. Animals were monitored for clinical respiratory and neurologic signs, and serially collected nasal swabs, bronchoalveolar lavage fluid (BALF) and cerebrospinal fluid (CSF) were evaluated for EV-D68 RNA and infectious virus. Infection with 2014 and 2018 EV-D68 isolates resulted in mild respiratory and gastrointestinal disease in some animals, but no evidence of neurological disease. Neither EV-D68 RNA nor infectious virus could be detected from any sample collected from animals challenged with 2014 EV-D68 isolates. Limited viral shedding - based on viral RNA quantified from nasal swabs and BALF - was detected from some animals infected with 2018 EV-D68 isolates. No virus was detectable in CSF. The rate of seroconversion was 100% for cynomolgus macaques infected with the 2018 EV-D68 isolates, but averaged between 0-50% for the 2014 isolates. Based on the results of this study, there is some evidence that infection with 2018 EV-D68 isolates may be more reliable at establishing limited infection than 2014 EV-D68 isolates. Regardless of virus isolate, however, EV-D68 infection of juvenile NHP species resulted in mild and nonspecific clinical disease and limited viral shedding. These data suggest that further refinements to the NHP model system (e.g., immunosuppression and/or direct viral inoculation) may be required to reproduce EV-D68 infection of the central nervous system and the associated AFM phenotype.

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Dearing, J., Conte, A., Brooks, C., Zimina, A., Birch, S. M., Adney, D. R., Li, M., Rascon, A., Belov, G. A., Pekosz, A., Vermillion, M. S.. 2022-04-17. Characterization of enterovirus D68 infection in four nonhuman primate species. https://doi.org/10.1101/2022.04.16.487524

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