Enterovirus D68 (EV-D68) has been implicated in outbreaks of severe respiratory illness and acute flaccid myelitis (AFM) and is detected in patient respiratory samples and from stool and wastewater, suggesting both respiratory and enteric routes of transmission. Here, we used a panel of EV-D68 isolates, including a historical isolate and multiple contemporary isolates from AFM outbreak years, to define the dynamics of viral replication and the host response to infection in primary human airway cells and stem cell-derived enteroids. We show that some recent EV-D68 isolates have decreased sensitivity to acid and temperature compared with an earlier isolate and that the respiratory, but not intestinal, epithelium induces a robust type III interferon (IFN) response that restricts infection. Our findings define the differential responses of the respiratory and intestinal epithelium to contemporary EV-D68 isolates and suggest that some isolates have the potential to target both the human airway and gastrointestinal tracts.
Background Enterovirus D68 (EV-D68) has been implicated in outbreaks of severe respiratory illness and associated with acute flaccid myelitis (AFM), a disease which causes paralysis in previously healthy patients, mostly children. AFM peaked in even numbered years, at least 2014–2018. While 2020 was expected to be a peak AFM year, few cases were seen, likely due to non-specific social distancing measures due to SARS-CoV-2. EV-D68 is primarily described as a respiratory pathogen, in contrast to ‘classic’ enteroviruses that are spread via the fecal-oral route. However, similar to other enteroviruses, EV-D68 has been detected in wastewater, suggesting it might also have an enteric route of transmission. Methods We used a panel of EV-D68 isolates, including a historic isolate from 2009 and multiple contemporary isolates from AFM peak years to define dynamics of viral replication and host response to infection. We performed comparative studies in primary human bronchial epithelial cells grown at an air-liquid interface and in primary human stem-cell derived intestinal enteroids. These human primary cell-based models more accurately reflect the cells targeted by EV-D68 in vivo. We defined growth characteristics, temperature sensitivity, infection polarity, and acid sensitivity in these parallel models. We used unbiased Luminex-based multianalyte profiling and bulk RNA-sequencing to define the innate immune response in each model. Results Conclusions Our findings suggest that a subset of contemporary isolates of EV-D68 have the potential to target both the human airway and gastrointestinal tracts as a potential route of infection, identifying a previously unrecognized potential route of infection as well as defining, for the first time, the innate immune response to infection in multiple relevant primary epithelial models. These findings are highly significant and are the first to characterize the viral replication and host innate immune response to a diverse panel of historic and contemporary EV-D68 isolates in both the respiratory and intestinal tracts.
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