Abstract
Noroviruses are the leading cause of acute gastroenteritis, and they can affect humans of all age groups. In immunocompromised patients, norovirus infections can develop into chronic diarrhea or show prolonged asymptomatic virus shedding. Chronic norovirus infections are frequently reported for solid organ transplant recipients, with rapid intrahost norovirus evolution seen. In this report, we describe a case of chronic norovirus infection in an immunocompromised patient who was followed up for over 5 years. The purpose of the study was to specify the norovirus evolution in a chronically infected immunocompromised host and identify possible selection sites in norovirus capsid protein. During the follow-up period, 25 sequential stool samples were collected and nine of them were selected to generate amplicons covering viral RNA-dependent RNA polymerase (RdRp) and viral capsid protein (VP1) genes. Amplicons were sequenced using next-generation sequencing. Single nucleotide polymorphisms were defined, which demonstrated a nearly 3-fold greater mutation rate in the VP1 genome region compared to the RdRp genome region (7.9 vs. 2.8 variable sites/100 nucleotides, respectively). This indicates that mutations in the virus genome were not accumulated randomly, but are rather the result of mutant selection during the infection cycle. Using ShoRAH software we were able to reconstruct haplotypes occurring in each of the nine selected samples. The deduced amino-acid haplotype sequences were aligned and the positions were analyzed for selective pressure using the Datamonkey program. Only 12 out of 25 positive selection sites were within the commonly described epitopes A, B, C, and D of the VP1 protein. New positive selection sites were determined that have not been described before and might reflect adaptation of the norovirus toward optimal histo-blood-group antigen binding, or modification of the norovirus antigenic properties. These data provide new insights into norovirus evolutionary dynamics and indicate new putative epitope “hot-spots” of modified and optimized norovirus–host interactions.
Highlights
Noroviruses (NVs) are the leading cause of sporadic and epidemic acute gastroenteritis in humans, with the young and the elderly being the most vulnerable populations
The NV genotype was GII.4_Den Haag 2006 in all of the samples analyzed. During this recorded shedding period of 2,125 days, the 25 samples were analyzed for the presence of enteric pathogens, and all of these were positive for GII NVs
We examined the potential influence of changes at site 393 on Leb histo-blood-group antigens (HBGAs) binding [with the patient phenotype of Le(a−b+)]
Summary
Noroviruses (NVs) are the leading cause of sporadic and epidemic acute gastroenteritis in humans, with the young and the elderly being the most vulnerable populations. NVs are small, non-enveloped, icosahedral viruses with a genome of 7,500 nucleotides of positive polar single-stranded RNA. The NV genome encodes several non-structural proteins within openreading frame (ORF), the major structural viral capsid protein (VP) within ORF2, and minor capsid proteins within ORF3 (Thorne and Goodfellow, 2014). NVs are known to interact with human histo-blood-group antigens (HBGAs) and to show high specificity for certain types of these antigens (Rockx et al, 2005b; Schroten et al, 2016). NV pathogenesis is dependent on the host secretor (α1,2l-fucosyltransferase) status, and the ABO and Lewis (LE) blood groups. NV pathogenesis is dependent on the host secretor (α1,2l-fucosyltransferase) status, and the ABO and Lewis (LE) blood groups. Shanker et al (2011) showed that temporal sequence variations do not affect the binding of monofucosyl ABH HBGAs, but that they can modulate the binding strength of difucosyl Lewis (Le) HBGAs, and can contribute to epochal evolution through the potentiated targeting of new variants to Le-positive, secretor-positive individuals (Shanker et al, 2011)
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