Mutation Distribution in the NSP4 Protein in Rotaviruses Isolated from Mexican Children with Moderate to Severe Gastroenteritis

Abstract

The NSP4 protein is a multifunctional protein that plays a role in the morphogenesis and pathogenesis of the rotavirus. Although NSP4 is considered an enterotoxin, the relationship between gastroenteritis severity and amino acid variations in NSP4 of the human rotavirus remains unclear. In this study, we analyzed the sequence diversity of NSP4 and the severity of gastroenteritis of children with moderate to severe gastroenteritis. The rotavirus-infected children were hospitalized before the rotavirus vaccine program in Mexico. All children had diarrhea within 1−4 days, 44 (88%) were vomiting and 35 (70%) had fevers. The severity analysis showed that 13 (26%) cases had mild gastroenteritis, 23 (46%) moderate gastroenteritis and 14 (28%) severe. NSP4 phylogenetic analysis showed three clusters within the genotype E1. Sequence analysis revealed similar mutations inside each cluster, and an uncommon variation in residue 144 was found in five of the Mexican NSP4 sequences. Most of the amino acid variations were located in the VP4 and VP6 binding site domains, with no relationship to different grades of gastroenteritis. This finding indicates that severe gastroenteritis caused by the rotavirus appears to be related to diverse viral or cellular factors instead of NSP4 activity as a unique pathogenic factor.

Molecular characterisation of the NSP4 gene of group A human rotavirus G2P[4] strains circulating in São Paulo, Brazil, from 1994 and 2006 to 2010

“…Most of the variations in NSP4 aas from E2 strains occurred in the carboxy-terminal region, including the VP4-binding domain, and the same result has been observed in studies comparing NSP4 aas from E1 strains ( González-Ochoa et al 2013 , Fredj et al 2014 ). This finding suggests that NSP4 is involved in viral morphogenesis and that additional studies are necessary to understand how these variations in the NSP4 protein may interfere with the structural conformation of the interaction sites between NSP4 and VP4.…”

“…The phylogenetic tree showed E2 intragenotype variation due to the presence of different branches formed by the strains from the same collection year. The same pattern of intragenotypic variation has been observed in E1 strains in Mexico and the authors attributed this finding to the accumulation of single point mutations in the NSP4 gene ( González-Ochoa et al 2013 ).…”

Genotyping and sequence characterization of the NSP4 gene of human group A rotavirus strains in Northern Iran

“…Besides, the E1 genotype was the dominant genotype (87% of samples), while the E2 genotype was less frequent (13% of samples). While it seems that E1 and E2 are not the only human genotypes, the diversity of NSP4 genes among human RVAs in some studies is restricted to genotypes E1 or E2 9–11 . In other studies, unusual E‐genotypes in human RVA strains have been identified.…”

Whole-genome analysis of human group A rotaviruses in 1980s Japan and evolutionary assessment of global Wa-like strains across half a century

“…The post-2010 strains (lineage II) had lineage-specific aa mutations at residues 141 and 145 within the VP4-binding domain (aa 112–146) and at residue 169 within the double-layered particle (DLP)-binding region (aa 161–175) () [42, 43]. These residues are known to be susceptible to aa variation [44]. Of particular interest, residue 141 showed sequential mutation (valine→alanine→isoleucine→tyrosine) corresponding to changes in the sublineage from lineage Ie to If to IIa to IIb.…”