Enterovirus Replication and Dissemination Are Differentially Controlled by Type I and III Interferons in the Gastrointestinal Tract.

Enteroviruses are among the most common viral infectious agents of humans and cause a broad spectrum of mild-to-severe illness. Enteroviruses are transmitted primarily 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 neonatal Fc receptor (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 echovirus infection in the intestinal epithelium, and mice lacking this pathway exhibit extended 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 gastrointestinal (GI) tract and the cellular tropism of echovirus replication in the intestinal epithelium. IMPORTANCE Echovirus infections are associated with a broad spectrum of illness, particularly in neonates, and are primarily transmitted through the fecal-oral route. Little is known regarding how echoviruses infect the gastrointestinal tract and how the intestinal epithelium controls echoviral replication. Here, we establish an in vivo mouse model of echovirus infection by the enteral route and define the differential roles of type I and III interferons (IFNs) in controlling viral replication in the intestine. These findings provide important insights into the mechanisms by which echoviruses infect the GI tract and the epithelium-specific antiviral pathways that control this infection.

Echovirus 30 induced neuronal cell death through TRIO-RhoA signaling activation.

BACKGROUND: Echovirus 30 (Echo30) is one of the most frequently identified human enteroviruses (EVs) causing aseptic meningitis and encephalitis. However the mechanism underlying the pathogenesis of Echo30 infection with significant clinical outcomes is not completely understood. The aim of this investigation is to illustrate molecular pathologic alteration in neuronal cells induced by Echo30 infection using clinical isolate from young patient with neurologic involvement. METHODOLOGY/PRINCIPAL FINDINGS: To characterize the neuronal cellular response to Echo30 infection, we performed a proteomic analysis based on two-dimensional gel electrophoresis (2-DE) and MALDI-TOF/TOF Mass Spectrophotometric (MS) analysis. We identified significant alteration of several protein expression levels in Echo30-infected SK-N-SH cells. Among these proteins, we focused on an outstanding up-regulation of Triple functional domain (TRIO) in Echo30-infected SK-N-SH cells. Generally, TRIO acts as a key component in the regulation of axon guidance and cell migration. In this study, we determined that TRIO plays a role in the novel pathways in Echo30 induced neuronal cell death. CONCLUSIONS/SIGNIFICANCE: Our finding shows that TRIO plays a critical role in neuronal cell death by Echo30 infection. Echo30 infection activates TRIO-guanine nucleotide exchange factor (GEF) domains (GEFD2) and RhoA signaling in turn. These results suggest that Echo30 infection induced neuronal cell death by activation of the TRIO-RhoA signaling. We expect the regulation of TRIO-RhoA signaling may represent a new therapeutic approach in treating aseptic meningitis and encephalitis induced by Echo30.

Interaction of decay-accelerating factor with echovirus 7.

Echovirus 7 (EV7) belongs to the Enterovirus genus within the family Picornaviridae. Many picornaviruses use IgG-like receptors that bind in the viral canyon and are required to initiate viral uncoating during infection. However, in addition, some of the enteroviruses use an alternative or additional receptor that binds outside the canyon. Decay-accelerating factor (DAF) has been identified as a cellular receptor for EV7. The crystal structure of EV7 has been determined to 3.1-Å resolution and used to interpret the 7.2-Å-resolution cryo-electron microscopy reconstruction of EV7 complexed with DAF. Each DAF binding site on EV7 is near a 2-fold icosahedral symmetry axis, which differs from the binding site of DAF on the surface of coxsackievirus B3, indicating that there are independent evolutionary processes by which DAF was selected as a picornavirus accessory receptor. This suggests that there is an advantage for these viruses to recognize DAF during the initial process of infection.

Role of class I human leukocyte antigen molecules in early steps of echovirus infection of rhabdomyosarcoma cells.

Several echoviruses use decay accelerating factor (DAF) as a cell surface receptor. However, most of them require additional cell surface coreceptors. We investigated the respective roles of DAF and class I human leukocyte antigen (HLA) molecules in the early steps of the echovirus 11 (EV11) lifecycle in rhabdomyosarcoma (RD) cells. EV11 infection was inhibited at an early stage by anti-beta2-microglobulin (beta2m) and anti-HLA monoclonal antibodies and by a soluble monochain HLA class I molecule. Expression of class I HLA molecules restored the early steps of the EV11 lifecycle, but its expression was not sufficient for EV11 replication and particle production. Expression of HLA class I molecules was associated with leukocyte cell line permissiveness to EV11 infection. In conclusion, HLA class I molecules are involved in the early steps of EV11 infection of RD cells and appear to participate in a complex interplay of surface molecules acting as coreceptors, including DAF.

In vitro (1)H NMR studies of RD human cell infection with echovirus 11.

The effects of echovirus 11 infection on RD human cell line (derived from rhabdomyosarcoma) were studied using (1)H NMR spectroscopy and optical microscopy. Both uninfected and infected cells consumed glucose and produced lactate, acetate and formate as extracellular metabolites. In infected whole cells, phosphocholine and uridine-sugar were observed in addition to the metabolites observed in uninfected cells. Water-soluble intracellular metabolites of infected cells showed glutamine, phosphocholine and glycine which were not observed in uninfected cells. Cellular metabolites except lipid components gradually decreased and disappeared during 24-48 h of viral infection. The quantity of lipid components in infected cells was comparable with that in uninfected cells, indicating that echovirus 11 does not utilize cell lipid molecules. Unlike optical microscopy, (1)H NMR spectroscopy identified early stages of infection through metabolic changes. These results may have potential implications in probing virus-cell interactions using NMR-based metabolomics.

[Severe manifestations of non-poliomyelitic enterovirus infections in newborn infants]. / Manifestations sévères des infections à entérovirus non poliomyélitiques chez le nouveau-né.

The authors report eight cases of severe neonatal infections with Coxsackie and Echo virus. Meningo-encephalitis, aseptic meningitis, myocarditis and sepsis-like state were the most frequent presenting conditions. A high mortality rate was associated with meningo-encephalitis and low birth weight.