Intra-Host Evolution of Norovirus GII.4 in a Chronic Infected Patient With Hematopoietic Stem Cell Transplantation

Abstract

Human noroviruses (NVs) are the leading cause of acute gastroenteritis outbreaks worldwide. The majority of outbreaks are caused by genogroup II.4 (GII.4), with new variants emerging every 2 to 4 years. Immunocompromised patients are hypothesized to be important reservoirs where new NV variants emerge. Here, we examined intrahost NV variants and assessed immune-driven NV evolution in chronically infected immunocompromised hosts. Three NV GII.4-positive samples were collected from the same patient in different clinical phases following allogeneic hematopoietic stem cell transplantation, and had viral RNA concentrations of 2.46 × 10 6 , 1.47 × 10 6 , and 2.26 × 10 6 genome copies/mL. The non-synonymous (dN) and synonymous (dS) substitution ratio of the sequences in the partial P domain were >1, indicating strong positive selection in the patient. Both the number and the frequency of the single nucleotide variants increased over time in the patient. Also, the majority of capsid amino acid changes were located at blocking epitopes and histo-blood group antigen (HBGA)-binding sites, and 11 positive selection sites were found in the capsid region, of which 8 sites were presented in blocking epitopes or HBGA-binding sites. Homodimeric P-domain capsid models also suggested a structural change in the epitopes and HBGAbinding sites. The results suggested that novel variants of NV GII.4 with HBGA and antigenic site changes were produced in the immunocompromised patient. Further functional and epidemiological studies are needed to determine whether the new variants are a risk to public health.

Noroviruses—The State of the Art, Nearly Fifty Years after Their Initial Discovery

“…Noroviruses have been detected in previously unrecognised host species [18,19]; detection itself is facilitated by the novel analytical techniques that increasingly supplement established molecular methods [259,[261][262][263]265]. New potential HuNoV transmission routes and/or viral reservoirs have been postulated [223,230,233]. Recent in vivo and in vitro findings have added to the understanding of host immunity in response to norovirus infection [272][273][274].…”

“…Not only has the involvement of chronic shedders in hospital outbreaks indicated them to be a reservoir for nosocomial transmission of noroviruses [146], but persistently infected patients have also been suggested to contribute to HuNoV transmission as reservoirs for emerging strains. Intra-host evolution via point mutation accumulation [230,231] and the acquisition of superinfections over the protracted period of persistent infections [143] implicate persistently infected patient cohorts as potential reservoirs for novel HuNoV variants [213]. Multiple phylogenetic analyses have identified viral populations in persistently infected patients to be highly diverse and genetically distinct from viruses circulating in the general population [147,232].…”

“…Multiple phylogenetic analyses have identified viral populations in persistently infected patients to be highly diverse and genetically distinct from viruses circulating in the general population [147,232]. The within-host viral variation via the acquisition of point mutations in chronic shedders is typically not random but has been shown to be a result of positive selection, as evidenced both by nonsynonymous versus synonymous substitution ratios (>1) and the clustering of amino acid changes at VP1 blocking epitopes (hypervariable P2 domain) and HBGA binding sites on the capsid surface [139,230,231,233,234]. Indeed, the intra-host emergence of antigenically distinct strains comparable to the variation between chronologically predominant GII.4 strains has been observed, suggesting that in certain individuals the evolution during a persistent norovirus infection translates into relevant phenotypic variability, thus, potentially selecting for viruses able to escape herd immunity to earlier isolates [235].…”

Acceptance of coronavirus disease 2019 vaccine among health-care personnel in India: a cross-sectional survey during the initial phase of vaccination

“…The phase-III trials of coronavirus disease 2019 (Covid-19) vaccines had shown high preventive efficacy against symptomatic infection and acceptable safety profile in a record time, yet their public acceptance would be an essential deterrent to pandemic control [ 1 ]. The hesitancy to a safe and effective vaccine against a severe infection is a major global health threat and commonly referred to as the “pandemic public health paradox”, previously well-observed with influenza [ 2 , 3 ]. Healthcare personnel (HCP) are among the first to receive the Covid-19 vaccination.…”

Complete genome characterization of human noroviruses allows comparison of minor alleles during acute and chronic infections

“…The non-structural protein, p22, and structural protein VP2 are likely to influence the replication process with roles in antagonism of protein secretion [33] and host cell entry [34], respectively. It is notable that none of the non-synonymous minor variants observed during chronic infection were found in ORF2, given the breadth of literature reporting minor variants or amino acid fixations in epitopes or putative epitope sites in VP1 during chronic infection [24,29,35,36]; however, these studies sampled over a much longer period (76-1811 days). Distinct antigenic types of HuNoV have been reported to emerge over the course of chronic infection, leading to predictions that changes occurring in immunodominant epitopes could lead to evasion of population humoral immunity, and subsequent strain emergence [37,38].…”