Commensal microbes profoundly impact host immunity to enteric viral infections 1 . We have shown that the bacterial microbiota and host antiviral cytokine interferon-lambda (IFN-λ) determine the persistence of murine norovirus in the gut 2 , 3 . However, the effects of the virome in modulating enteric infections remain unexplored. Here we report that murine astrovirus can complement primary immunodeficiency to protect against murine norovirus and rotavirus infections. Protection against infection was horizontally transferable between immunocompromised mouse strains by cohousing and fecal transplantation. Furthermore, protection against enteric pathogens corresponded with the presence of a specific strain of murine astrovirus in the gut, and this complementation of immunodeficiency required IFN-λ signaling in gut epithelial cells. Our study demonstrates that elements of the virome can protect against enteric pathogens in an immunodeficient host.

Central Nervous System inflammation has been implicated in neurodegenerative disorders including Parkinson’s disease (Ransohoff, Science 353: 777–783, 2016; Kannarkat et al. J. Parkinsons Dis. 3: 493–514, 2013). Here, we examined if the H1N1 influenza virus (Studahl et al. Drugs 73: 131–158, 2013) could synergize with the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Jackson-Lewis et al. in Mark LeDoux (ed) Movement Disorders: Genetics and Models: 287–306, Elsevier, 2015) to induce a greater microglial activation and loss of substantia nigra pars compacta dopaminergic neurons than either insult alone. H1N1-infected animals administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exhibit a 20% greater loss of substantia nigra pars compacta dopaminergic neurons than occurs from the additive effects of H1N1 or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine alone (p < 0.001). No synergistic effects were found in microglial activation. The synergistic dopaminergic neuron loss is eliminated by influenza vaccination or treatment with oseltamivir carboxylate. This work shows that multiple insults can induce synergistic effects; and even these small changes can be significant as it might allow one to cross a phenotypic disease threshold that would not occur from individual non-interacting exposures. Our observations also have important implications for public health, providing impetus for influenza vaccination or prompt treatment with anti-viral medications upon influenza diagnosis.

Little is known about intrinsic epithelial cell responses against astrovirus infection. Here we show that human astrovirus type 1 (HAstV-1) infection induces type I interferon (beta interferon [IFN-␤]) production in differentiated Caco2 cells, which not only inhibits viral replication by blocking positive-strand viral RNA and capsid protein synthesis but also protects against HAstV-1-increased barrier permeability. Excitingly, we found similar results in vivo using a murine astrovirus (MuAstV) model, providing new evidence that virus-induced type I IFNs may protect against astrovirus replication and pathogenesis in vivo. IMPORTANCEHuman astroviruses are a major cause of pediatric diarrhea, yet little is known about the immune response. Here we show that type I interferon limits astrovirus infection and preserves barrier permeability both in vitro and in vivo. Importantly, we characterized a new mouse model for studying astrovirus replication and pathogenesis. The successful replication and spread of many enteric viruses depend upon modulating immune factors produced by intestinal epithelial cells (IECs) including interferons (IFNs) (1, 2). For instance, enteric adenoviruses are sensitive to IEC-produced type I IFNs, unlike respiratory adenoviruses (3), while rotavirus exploits type I IFN signaling in IECs to promote early viral replication (4). However, nothing is known about the impact of IFN on astrovirus infection.Astroviruses are small, nonenveloped, RNA viruses that are one of the most important causes of pediatric acute gastroenteritis worldwide (5-8). Infection begins by binding to an unidentified receptor(s) on epithelial cells after fecal-oral transmission followed by entry via endosomes (9). After viral uncoating, the positive-sense, single-stranded RNA genome is translated into a polyprotein precursor that is subsequently cleaved into proteins required for replication and the assembly of progeny virions. The genome contains three open reading frames: ORF1a, ORF1b, and ORF2. ORF1a and ORF1b encode nonstructural proteins involved in transcription and replication of the virus, while ORF2 encodes the capsid protein (10, 11). Negative-strand RNA is produced from the positive genomic strand, which can be detected 6 to 12 h postinfection (hpi) (12). Transcription of the negativestrand genome yields the genomic and subgenomic RNA. Human astrovirus (HAstV) proteins have been associated with membranes in infected cells likely serving as the site for replication and assembly (13-15). After assembly, the progeny virions egress from the cell, a process promoted by caspase activation (16).Recently, Guix et al. found that HAstV type 4 (HAstV-4) replication induces type I IFN production and that pretreatment of Caco2 cells with beta interferon (IFN-␤) reduced HAstV-4 capsid protein synthesis and progeny virion production (17). However, whether the IFN-␤ produced during astrovirus infection is sufficient to limit astrovirus replication, and at what step in the viral life cycle IFN-␤ affects astrovirus, remains...

Astroviruses are a global cause of pediatric diarrhea, but they are largely understudied, and it is unclear how and where they replicate in the gut. Using an in vivo model, here we report that murine astrovirus preferentially infects actively secreting small intestinal goblet cells, specialized epithelial cells that maintain the mucus barrier. Consequently, virus infection alters mucus production, leading to an increase in mucus-associated bacteria and resistance to enteropathogenic E. coli colonization. These studies establish the main target cell type and region of the gut for productive murine astrovirus infection. They further define a mechanism by which an enteric virus can regulate the mucus barrier, induce functional changes to commensal microbial communities, and alter host susceptibility to pathogenic bacteria.

West Africa might be an animal influenza–free zone.