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Background Rotaviruses are the major etiological agents of gastroenteritis and diarrheal outbreaks in plenty of mammalian species. The genus Rotavirus is highly diverse and currently comprises nine genetically distinct species, and four of them (A, B, C, and H) are common for humans and pigs. There is a strong necessity to comprehend phylogenetic relationships among rotaviruses from different host species to assess interspecies transmission, specifically between humans and livestock. To reveal the genetic origin of rotaviruses from Russian pig farms, nanopore-based metagenomic sequencing was performed on the PCR-positive specimens. Methods Samples were selected among the cases submitted to routine diagnostic or monitoring studies to the Laboratory of Biochemistry and Molecular Biology of “Federal Scientific Center VIEV” (Moscow, Russia). The selected positive samples were genotyped using nanopore sequencing method. Results Five porcine RVA isolates were completely sequenced, and genotype analysis revealed various porcine G/P genogroups: G2, G3, G4, G5, G11 and P[6], P[7], P[13], P[23], P[27] with a typical backbone constellation I5-R1-C1-M1-A8-N1-T1/7-E1-H1. The RVB isolate was detected in combination with RVA in a rectal swab from a diseased pig in Krasnoyarsk Krai. It was characterized by the following genogroups: G15-P[X]-I11-R4-C4-M4-A8-N10-T4-E4-H7. The first complete porcine RVC genome from Russia was obtained with genomic constellation G6-P[5]-I14-R1-C1-M1-A7-N9-T6-E1-H1, and the phylogenetic analysis revealed putative novel genotype group for the VP6 gene-I14. Additionally, the first porcine kobuvirus isolate from Russia was phylogenetically characterized. Conclusions The applied nanopore sequencing method successfully genotyped the RV isolates and additionally revealed co-circulated species. The study demonstrates high genetic variability of Russian RVA isolates in VP4/VP7 genes and phylogenetically describes local RVB and RVC. Complete characterization of genomic segments is a crucial methodology in tracing the rotavirus's evolution and evaluating interspecies transmissions.

The inflammasome receptor Nlrp9b defends against enteric viruses by interacting with double-stranded viral RNA-bound helicase Dhx9, triggering gasdermin-D-dependent pyroptotic cell death of infected cells and secretion of Il-18. Inflammasome defends against gastric bug Rotaviruses cause severe and often fatal gastroenterological illnesses in young children. The mechanism by which such enteric viruses are detected and restricted in vivo is largely unknown. Richard Flavell and colleagues report how the inflammasome receptor Nlrp9 helps to defend against enteric viruses, via RNA helicase Dhx9, by interacting with double-stranded viral RNA. This interaction triggers gasdermin-D-dependent pyroptotic cell death of infected cells and secretion of IL-18. This innate immune signalling functions uniquely in intestinal epithelial cells and could reveal useful targets in the modulation of viral defences. Rotavirus, a leading cause of severe gastroenteritis and diarrhoea in young children, accounts for around 215,000 deaths annually worldwide 1 . Rotavirus specifically infects the intestinal epithelial cells in the host small intestine and has evolved strategies to antagonize interferon and NF-κB signalling 2 , 3 , 4 , 5 , raising the question as to whether other host factors participate in antiviral responses in intestinal mucosa. The mechanism by which enteric viruses are sensed and restricted in vivo , especially by NOD-like receptor (NLR) inflammasomes, is largely unknown. Here we uncover and mechanistically characterize the NLR Nlrp9b that is specifically expressed in intestinal epithelial cells and restricts rotavirus infection. Our data show that, via RNA helicase Dhx9, Nlrp9b recognizes short double-stranded RNA stretches and forms inflammasome complexes with the adaptor proteins Asc and caspase-1 to promote the maturation of interleukin (Il)-18 and gasdermin D (Gsdmd)-induced pyroptosis. Conditional depletion of Nlrp9b or other inflammasome components in the intestine in vivo resulted in enhanced susceptibility of mice to rotavirus replication. Our study highlights an important innate immune signalling pathway that functions in intestinal epithelial cells and may present useful targets in the modulation of host defences against viral pathogens.

Rotaviruses infect cells by delivering into the cytosol a transcriptionally active inner capsid particle (a \"double-layer particle\": DLP). Delivery is the function of a third, outer layer, which drives uptake from the cell surface into small vesicles from which the DLPs escape. In published work, we followed stages of rhesus rotavirus (RRV) entry by live-cell imaging and correlated them with structures from cryogenic electron microscopy and tomography (cryo-EM and cryo-ET). The virus appears to wrap itself in membrane, leading to complete engulfment and loss of Ca.sup.2+ from the vesicle produced by the wrapping. One of the outer-layer proteins, VP7, is a Ca.sup.2+ -stabilized trimer; loss of Ca.sup.2+ releases both VP7 and the other outer-layer protein, VP4, from the particle. VP4, activated by cleavage into VP8* and VP5*, is a trimer that undergoes a large-scale conformational rearrangement, reminiscent of the transition that viral fusion proteins undergo to penetrate a membrane. The rearrangement of VP5* thrusts a 250-residue, C-terminal segment of each of the three subunits outward, while allowing the protein to remain attached to the virus particle and to the cell being infected. We proposed that this segment inserts into the membrane of the target cell, enabling Ca.sup.2+ to cross. In the work reported here, we show the validity of key aspects of this proposed sequence. By cryo-EM studies of liposome-attached virions (\"triple-layer particles\": TLPs) and single-particle fluorescence imaging of liposome-attached TLPs, we confirm insertion of the VP4 C-terminal segment into the membrane and ensuing generation of a Ca.sup.2+ \"leak\". The results allow us to formulate a molecular description of early events in entry. We also discuss our observations in the context of other work on double-strand RNA virus entry.

Rotavirus (RV) is the foremost enteric pathogen associated with severe diarrheal illness in young children (<5years) and animals worldwide. RV primarily infects mature enterocytes in the intestinal epithelium causing villus atrophy, enhanced epithelial cell turnover and apoptosis. Intestinal epithelial cells (IECs) being the first physical barrier against RV infection employs a range of innate immune strategies to counteract RVs invasion, including mucus production, toll-like receptor signaling and cytokine/chemokine production. Conversely, RVs have evolved numerous mechanisms to escape/subvert host immunity, seizing translation machinery of the host for effective replication and transmission. RV cell entry process involve penetration through the outer mucus layer, interaction with cell surface molecules and intestinal microbiota before reaching the IECs. For successful cell attachment and entry, RVs use sialic acid, histo-blood group antigens, heat shock cognate protein 70 and cell-surface integrins as attachment factors and/or (co)-receptors. In this review, a comprehensive summary of the existing knowledge of mechanisms underlying RV-IECs interactions, including the role of gut microbiota, during RV infection is presented. Understanding these mechanisms is imperative for developing efficacious strategies to control RV infections, including development of antiviral therapies and vaccines that target specific immune system antagonists within IECs.

Rotaviruses (RVs) are a major cause of acute viral gastroenteritis in young animals and children worldwide. Immunocompetent adults of different species become resistant to clinical disease due to post-infection immunity, immune system maturation and gut physiological changes. Of the 9 RV genogroups (A–I), RV A, B, and C (RVA, RVB, and RVC, respectively) are associated with diarrhea in piglets. Although discovered decades ago, porcine genogroup E RVs (RVE) are uncommon and their pathogenesis is not studied well. The presence of porcine RV H (RVH), a newly defined distinct genogroup, was recently confirmed in diarrheic pigs in Japan, Brazil, and the US. The complex epidemiology, pathogenicity and high genetic diversity of porcine RVAs are widely recognized and well-studied. More recent data show a significant genetic diversity based on the VP7 gene analysis of RVB and C strains in pigs. In this review, we will summarize previous and recent research to provide insights on historic and current prevalence and genetic diversity of porcine RVs in different geographic regions and production systems. We will also provide a brief overview of immune responses to porcine RVs, available control strategies and zoonotic potential of different RV genotypes. An improved understanding of the above parameters may lead to the development of more optimal strategies to manage RV diarrheal disease in swine and humans.

Background Rotavirus causes severe gastroenteritis in infants and young children worldwide. The UK introduced the monovalent rotavirus vaccine (Rotarix®) in July 2013. Vaccination is free of charge to parents, with two doses delivered at 8 and 12 weeks of age. We evaluated vaccine impact across a health system in relation to socioeconomic deprivation. Methods We used interrupted time-series analyses to assess changes in monthly health-care attendances in Merseyside, UK, for all ages, from July 2013 to June 2016, compared to predicted counterfactual attendances without vaccination spanning 3–11 years pre-vaccine. Outcome measures included laboratory-confirmed rotavirus gastroenteritis (RVGE) hospitalisations, acute gastroenteritis (AGE) hospitalisations, emergency department (ED) attendances for gastrointestinal conditions and consultations for infectious gastroenteritis at community walk-in centres (WIC) and general practices (GP). All analyses were stratified by age. Hospitalisations were additionally stratified by vaccine uptake and small-area-level socioeconomic deprivation. Results The uptake of the first and second doses of rotavirus vaccine was 91.4% (29,108/31,836) and 86.7% (27,594/31,836), respectively. Among children aged < 5 years, the incidence of gastrointestinal disease decreased across all outcomes post-vaccine introduction: 80% (95% confidence interval [CI] 70–87%; p  < 0.001) for RVGE hospitalisation, 44% (95% CI 35–53%; p  < 0.001) for AGE hospitalisations, 23% (95% CI 11–33%; p  < 0.001) for ED, 32% (95% CI 7–50%; p  = 0.02) for WIC and 13% (95% CI -3–26%; p  = 0.10) for GP. The impact was greatest during the rotavirus season and for vaccine-eligible age groups. In adults aged 65+ years, AGE hospitalisations fell by 25% (95% CI 19–30%; p  < 0.001). The pre-vaccine risk of AGE hospitalisation was highest in the most socioeconomically deprived communities (adjusted incident rate ratio 1.57; 95% CI 1.51–1.64; p  < 0.001), as was the risk for non-vaccination (adjusted risk ratio 1.54; 95% CI 1.34–1.75; p  < 0.001). The rate of AGE hospitalisations averted per 1,000 first doses of vaccine was higher among infants in the most deprived communities compared to the least deprived in 2014/15 (28; 95% CI 25–31 vs. 15; 95% CI 12–17) and in 2015/16 (26; 95% CI 23–30 vs. 13; 95% CI 11–16). Conclusions Following the introduction of rotavirus vaccination, incidence of gastrointestinal disease reduced across the health-care system. Vaccine impact was greatest among the most deprived populations, despite lower vaccine uptake. Prioritising vaccine uptake in socioeconomically deprived communities should give the greatest health benefit in terms of population disease burden.

We previously demonstrated that in Ifnar1 -/- Ifngr1 -/- or Stat1 -/- suckling mice lacking intact type I and type II interferon (IFN) signaling, rhesus rotavirus (RRV) infection causes a lethal disease with clinical manifestations similar to biliary atresia, including acholic stools, oily fur, growth retardation, and excess mortality. Elevated levels of viral RNA are detected in the bile ducts and liver of diseased pups together with severe inflammatory responses in these tissues. However, the viral determinants and the molecular mechanisms driving this process remain incompletely understood. Using an optimized rotavirus (RV) reverse genetics system, we generated a panel of recombinant RVs that encode non-structural protein 1 (NSP1) derived from different RV strains. We found that compared to the parental simian SA11 strain that is less biliary pathogenic, SA11 containing an RRV-derived NSP1 resulted in severe biliary obstructive disease comparable to that associated with RRV infection, reflected by high levels of viral RNA and inflammation in the biliary tract, liver, and pancreas. In contrast, RRV containing an SA11-originated NSP1 showed only mild biliary obstruction comparable to what was observed during SA11 infection. Infection with a monoreassortant RRV virus carrying NSP1 from the bovine RV UK strain also showed substantially reduced viral replication in extra-intestinal organs and did not develop clinical biliary diseases. Mechanistically, RRV NSP1 seemed to promote active viral replication in hepatocytes and this expanded tropism led to enhanced infiltration of CD4 and CD8 T cells, causing immunopathology and damage in the hepatobiliary system. These results highlight an unexpectedly important role of RV NSP1 in viral replication and disease progression in extra-intestinal tissues.

Rotaviruses (RVs) are non-enveloped multilayered dsRNA viruses that are major etiologic agents of diarrheal disease in humans and in the young in a large number of animal species. The viral particle is composed of three different protein layers that enclose the segmented dsRNA genome and the transcriptional complexes. Each layer defines a unique subparticle that is associated with a different phase of the replication cycle. Thus, while single- and double-layered particles are associated with the intracellular processes of selective packaging, genome replication, and transcription, the viral machinery necessary for entry is located in the third layer. This modular nature of its particle allows rotaviruses to control its replication cycle by the disassembly and assembly of its structural proteins. In this review, we examine the significant advances in structural, molecular, and cellular RV biology that have contributed during the last few years to illuminating the intricate details of the RV particle disassembly and assembly processes.

Rotavirus species A (RVA) is a pathogen mainly affecting children under five years old and young animals. The infection produces acute diarrhea in its hosts and, in intensively reared livestock animals, can cause severe economic losses. In this study, we analyzed all RVA genomic constellations described in animal hosts. This review included animal RVA strains in humans. We compiled detection methods, hosts, genotypes and complete genomes. RVA was described in 86 animal species, with 52% (45/86) described by serology, microscopy or the hybridization method; however, strain sequences were not described. All of these reports were carried out between 1980 and 1990. In 48% (41/86) of them, 9251 strain sequences were reported, with 28% being porcine, 27% bovine, 12% equine and 33% from several other animal species. Genomic constellations were performed in 80% (32/40) of hosts. Typical constellation patterns were observed in groups such as birds, domestic animals and artiodactyls. The analysis of the constellations showed RVA’s capacity to infect a broad range of species, because there are RVA genotypes (even entire constellations) from animal species which were described in other studies. This suggests that this virus could generate highly virulent variants through gene reassortments and that these strains could be transmitted to humans as a zoonotic disease, making future surveillance necessary for the prevention of future outbreaks.