Respiratory and intestinal epithelial cells exhibit differential susceptibility and innate immune responses to contemporary EV-D68 isolates

Abstract

Enterovirus D68 (EV-D68) has been implicated in outbreaks of severe respiratory illness and is associated with acute flaccid myelitis (AFM). EV-D68 is often detected in patient respiratory samples but has also been detected in stool and wastewater, suggesting the potential for both respiratory and enteric routes of transmission. Here, we used a panel of EV-D68 isolates, including a historical pre-2014 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 earlier isolates 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 a subset of isolates have the potential to target both the human airway and gastrointestinal tracts.

Comparison of tissue tropism and host response to enteric and respiratory enteroviruses

“…Similarly, their infections were also run at 33˚C [27]. Therefore, tolerance to higher body temperatures certainly represents a critical prerequisite for CNS invasion, which is supported by the lower temperature sensitivity of recent EV-D68 neurotropic strains [28]. Of note, contemporary EV-D68 strains also exhibit greater acid tolerance [28].…”

“…The ability of old EV-D68 strains to grow in intestinal tissues at 33˚C seems to depend on the tissue culture model. Freeman et al recently showed that historical EV-D68 strains do not replicate in stem cell-derived enteroids [28]. However, in this model, the apical tissue side, where the infection occurs, is enclosed within the organoid, making it hardly accessible for the virus.…”

“…Therefore, tolerance to higher body temperatures certainly represents a critical prerequisite for CNS invasion, which is supported by the lower temperature sensitivity of recent EV-D68 neurotropic strains [28]. Of note, contemporary EV-D68 strains also exhibit greater acid tolerance [28]. Whether this would allow the virus to survive the acidic environment of the gastrointestinal tract in vivo remains to be determined.…”

Neutralizing Enterovirus D68 Antibodies in Children after 2014 Outbreak, Kansas City, Missouri, USA

“…Indeed, the low rates of seronegativity to both B2 and the 2014 D virus in our current and prior studies suggest that antibodies induced by the 2014 B1 virus cross-neutralize B2 and D viruses. Such cross-neutralization seems reasonable given the close relatedness of the B1 and B2 viruses and the less but still relatively close relatedness of the D virus ( 27 ).…”

An in vivo model of echovirus-induced meningitis in neonates

“…However, because we used brain tissue homogenates and human studies can are restricted to CSF, it is unclear which cytokines induced by echovirus infections mediate the influx of immune cells observed in echovirus-induced meningitis. Although the differential roles of type I and III IFNs has been established in the respiratory and intestinal epithelium during enterovirus infection (30,(38)(39)(40), whether these IFNs play distinct roles in enterovirus-induced meningitis has remained unclear. Our data suggest that type I IFNs are the sole barrier to echovirus infection of the CNS, which is consistent with previous work defining indicating that these IFNs form at least one bottleneck to poliovirus access to the CNS (41).…”