Biology subjects

Wells, A. I.

Publications and source records attributed to Wells, A. I..

3 recordsLinked to original sources

bioRxiv2022

An in vivo model of echovirus-induced meningitis in neonates

Echoviruses are amongst the most common causes of aseptic meningitis worldwide, which can cause long-term sequelae and death, particularly in neonates. However, the mechanisms by which these viruses induce meningeal inflammation is poorly understood, owing at least in part to the lack of in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we developed an in vivo neonatal mouse model that recapitulates key aspects of echovirus-induced meningitis. We found that expression of the human homologue of the neonatal Fc receptor (FcRn), the primary echovirus receptor, in neonatal mice was not sufficient for infection of the brain. However, ablation of type I, but not III, IFN signaling in mice expressing human FcRn permitted high levels of echovirus replication in the brain, with corresponding clinical symptoms including delayed motor skills and hind limb weakness. We also defined the immunological response of the brain to echovirus infections and identified key cytokines induced by this infection. Lastly, we found that echoviruses robustly replicate in the leptomeninges, where they induce profound inflammation and cell death. Together, this work establishes an in vivo model of aseptic meningitis associated with echovirus infections and defines the specificity of echoviral infections within the meninges. Significance StatementEchoviruses are amongst the most common causes of aseptic meningitis worldwide, which can cause long-term sequelae or even death. The mechanisms by which echoviruses infect the brain are poorly understood, largely owing to the lack of robust in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we establish a neonatal mouse model of echovirus-induced aseptic meningitis and show that expression of the human homologue of the neonatal Fc receptor (FcRn), the primary receptor for echoviruses, and ablation of type I interferon (IFN) signaling are required to recapitulate echovirus-induced meningitis and clinical disease. These findings provide key insights into the host factors that control echovirus-induced meningitis and a model that could be used to test anti-echovirus therapeutics.

microbiology↗

bioRxiv2022

Enterovirus replication and dissemination are differentially controlled by type I and III interferons in the GI tract

Enteroviruses are amongst the most common viral infectious agents of humans and cause a broad spectrum of mild-to-severe illness. Enteroviruses are primarily transmitted by the fecal-oral route, but the events associated with their intestinal replication in vivo are poorly defined. Here, we developed a neonatal mouse model of enterovirus infection by the enteral route using echovirus 5 and used this model to define the differential roles of type I and III interferons (IFNs) in enterovirus replication in the intestinal epithelium and subsequent dissemination to secondary tissues. We show that human FcRn, the primary receptor for echoviruses, is essential for intestinal infection by the enteral route and that type I IFNs control dissemination to secondary sites, including the liver. In contrast, type III IFNs limit enterovirus infection in the intestinal epithelium and mice lacking this pathway exhibit persistent epithelial replication. Finally, we show that echovirus infection in the small intestine is cell-type specific and occurs exclusively in enterocytes. These studies define the type-specific roles of IFNs in enterovirus infection of the GI tract and the cellular tropism of echovirus intestinal replication.

microbiology↗

bioRxiv2021

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

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.

microbiology↗