Phylodynamic Reconstruction Reveals Norovirus GII.4 Epidemic Expansions and their Molecular Determinants

Abstract

Noroviruses are the most common cause of viral gastroenteritis. An increase in the number of globally reported norovirus outbreaks was seen the past decade, especially for outbreaks caused by successive genogroup II genotype 4 (GII.4) variants. Whether this observed increase was due to an upswing in the number of infections, or to a surveillance artifact caused by heightened awareness and concomitant improved reporting, remained unclear. Therefore, we set out to study the population structure and changes thereof of GII.4 strains detected through systematic outbreak surveillance since the early 1990s. We collected 1383 partial polymerase and 194 full capsid GII.4 sequences. A Bayesian MCMC coalescent analysis revealed an increase in the number of GII.4 infections during the last decade. The GII.4 strains included in our analyses evolved at a rate of 4.3–9.0×10−3 mutations per site per year, and share a most recent common ancestor in the early 1980s. Determinants of adaptation in the capsid protein were studied using different maximum likelihood approaches to identify sites subject to diversifying or directional selection and sites that co-evolved. While a number of the computationally determined adaptively evolving sites were on the surface of the capsid and possible subject to immune selection, we also detected sites that were subject to constrained or compensatory evolution due to secondary RNA structures, relevant in virus-replication. We highlight codons that may prove useful in identifying emerging novel variants, and, using these, indicate that the novel 2008 variant is more likely to cause a future epidemic than the 2007 variant. While norovirus infections are generally mild and self-limiting, more severe outcomes of infection frequently occur in elderly and immunocompromized people, and no treatment is available. The observed pattern of continually emerging novel variants of GII.4, causing elevated numbers of infections, is therefore a cause for concern.

Acute norovirus gastroenteritis in children in a highly rotavirus-vaccinated population in Northeast Brazil

“…In Brazil, GII.4 NoV is most frequently reported from emergency departments [5,6,29,30]. The presence of a variety of genotypes in Sergipe and the periodic shift of GII.4 variants (i.e., GII.4 New-Orleans_2009 and GII.4 Sydney_2012) reflects the emergence worldwide of GII.4 variants [29,[31][32][33][34][35][36], confirming that the NoV genotypes have a wide geographical distribution. The increased detection of GII.4 could be explained by GII.4 theoretically causing more severe disease than other genotypes [31,37], but GII.4 diarrhoea severity in our patients was similar to other genotypes and we do not have evidence of an increased severity.…”

Structural Basis for Norovirus Inhibition and Fucose Mimicry by Citrate

“…Most studies agreed that a dominant GII.4 norovirus was replaced the following year or next by a new GII.4 "variant" norovirus that had ϳ5% amino acid change in the capsid gene (6,9,10,30,31,47). The reason that the GII.4 variants dominated and not some other genotype was unknown, but studies have shown specific mutations at or surrounding the HBGA binding site were capable of altering the HBGA binding patterns (15,30,31,52).…”

The estimated disease burden of norovirus in The Netherlands

“…hospitalizations, and there is an implicit assumption that community cases have also increased by the same proportion. Nevertheless, an actual increase is likely as a result of the emergence of new variants, as described by Siebenga et al [13]. The updated number of 1285 estimated discounted DALYs is higher compared to y500 in 1999 [6] and 2004 [7].…”