Analysis of complete capsid sequences of the emerging norovirus GII.17 Kawasaki 308 from 13 countries demonstrated that they originated from a single haplotype since the initial emergence in China in late 2014. Global spread of a sublineage SL2 was identified. A new sublineage SL3 emerged in China in 2016.
Norovirus is estimated to cause 677 million annual cases of gastroenteritis worldwide, resulting in 210,000 deaths. As viral gastroenteritis is generally self-limiting, clinical samples for epidemiological studies only partially represent circulating noroviruses in the population and is biased towards severe symptomatic cases. As infected individuals from both symptomatic and asymptomatic cases shed viruses into the sewerage system at a high concentration, waste water samples are useful for the molecular epidemiological analysis of norovirus genotypes at a population level. Using Illumina MiSeq and Sanger sequencing, we surveyed circulating norovirus within Australia and New Zealand, from July 2014 to December 2016. Importantly, norovirus genomic diversity during 2016 was compared between clinical and waste water samples to identify potential pandemic variants, novel recombinant viruses and the timing of their emergence. Although the GII.4 Sydney 2012 variant was prominent in 2014 and 2015, its prevalence significantly decreased in both clinical and waste water samples over 2016. This was concomitant with the emergence of multiple norovirus strains, including two GII.4 Sydney 2012 recombinant viruses, GII.P4 New Orleans 2009/GII.4 Sydney 2012 and GII.P16/GII.4 Sydney 2012, along with three other emerging strains GII.17, GII.P12/GII.3 and GII.P16/GII.2. This is unusual, as a single GII.4 pandemic variant is generally responsible for 65–80% of all human norovirus infections at any one time and predominates until it is replaced by a new pandemic variant. In sumary, this study demonstrates the combined use of clinical and wastewater samples provides a more complete picture of norovirus circulating within the population.
For the past two decades, norovirus pandemic variants have emerged every 3–5 years, and dominate until they are replaced by alternate strains. However, this scenario changed in 2016 with the co-circulation of six prevalent viruses, three of which possessed the pandemic GII.4 Sydney 2012 capsid. An increased number of institutional gastroenteritis outbreaks were reported within the Oceania region in mid-2017. This study identified emerging noroviruses circulating in Australia and New Zealand in 2017 to assess the changing dynamics of the virus infection. RT-PCR-based methods, next generation sequencing, and phylogenetic analyses were used to genotype noroviruses from both clinical and wastewater samples. Antigenic changes were observed between the capsid of pandemic Sydney 2012 variant and the two new Sydney recombinant viruses. The combination of these antigenic changes and the acquisition of a new ORF1 through recombination could both facilitate their ongoing persistence in the population. Overall, an increased prevalence of GII.P16/GII.4 Sydney 2012 viruses was observed in 2017, replacing the GII.P16/GII.2 recombinant that dominated in the region at the end of 2016. This shift in strain dominance was also observed in wastewater samples, demonstrating the reliability of wastewater as a molecular surveillance tool.
Viruses of the Caliciviridae cause significant and sometimes lethal diseases, however despite substantial research efforts, specific antivirals are lacking. Broad-spectrum antivirals could combat multiple viral pathogens, offering a rapid solution when no therapies exist. The RNA-dependent RNA polymerase (RdRp) is an attractive antiviral target as it is essential for viral replication and lacks mammalian homologs. To focus the search for pan-Caliciviridae antivirals, the RdRp was probed with non-nucleoside inhibitors (NNIs) developed against hepatitis C virus (HCV) to reveal both allosteric ligands for structure-activity relationship enhancement, and highly-conserved RdRp pockets for antiviral targeting. The ability of HCV NNIs to inhibit calicivirus RdRp activities was assessed using in vitro enzyme and murine norovirus cell culture assays. Results revealed that three NNIs which bound the HCV RdRp Thumb I (TI) site also inhibited transcriptional activities of six RdRps spanning the Norovirus, Sapovirus and Lagovirus genera of the Caliciviridae. These NNIs included JTK-109 (RdRp inhibition range: IC 4.3-16.6 μM), TMC-647055 (IC range: 18.8-45.4 μM) and Beclabuvir (IC range: 23.8->100 μM). In silico studies and site-directed mutagenesis indicated the JTK-109 binding site was within the calicivirus RdRp thumb domain, in a pocket termed Site-B, which is highly-conserved within all calicivirus RdRps. Additionally, RdRp inhibition assays revealed that JTK-109 was antagonistic with the previously reported RdRp inhibitor pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) tetrasodium salt (PPNDS), that also binds to Site-B. Moreover, like JTK-109, PPNDS was also a potent inhibitor of polymerases from six viruses spanning the three Caliciviridae genera tested (IC range: 0.1-2.3 μM). Together, this study demonstrates the potential for de novo development of broad-spectrum antivirals that target the highly-conserved RdRp thumb pocket, Site-B. We also revealed three broad-spectrum HCV NNIs that could be used as antiviral scaffolds for further development against caliciviruses and other viruses.
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