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Viral intra-host evolution in immunocompetent children contributes to human norovirus diversification at the global scale.

ABSTRACT: Norovirus is a major cause of acute gastroenteritis. Human noroviruses present >30 different genotypes, with a single genotype (GII.4) predominating worldwide. Concurrent outbreaks of norovirus are often associated with the emergence of new viruses. While different hypotheses have been presented, the source of new mutations in noroviruses is still unknown. In this study, we applied high-resolution sequencing to determine the intra-host viral diversity presented by noroviruses during the acute and shedding phase of infection in children. Profiling viral intra-host diversification at nearly full genome level indicated that GII.4 viruses presented dynamic intra-host variation, while non-GII.4 viruses presented minimal variation throughout the infection. Notably, the intra-host genetic variation during the shedding phase recapitulates the genetic diversity observed at the global level, particularly those mapping at the VP1 antigenic sites. Thus the intra-host evolution in healthy children explains the source of norovirus mutations that results in diversification at the global scale.

SUBMITTER: Tohma K

PROVIDER: S-EPMC8425682 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Viral intra-host evolution in immunocompetent children contributes to human norovirus diversification at the global scale.

Tohma Kentaro K Saito Mayuko M Pajuelo Monica J MJ Mayta Holger H Zimic Mirko M Lepore Cara J CJ Ford-Siltz Lauren A LA Gilman Robert H RH Parra Gabriel I GI

Emerging microbes & infections 20211201 1

Norovirus is a major cause of acute gastroenteritis. Human noroviruses present >30 different genotypes, with a single genotype (GII.4) predominating worldwide. Concurrent outbreaks of norovirus are often associated with the emergence of new viruses. While different hypotheses have been presented, the source of new mutations in noroviruses is still unknown. In this study, we applied high-resolution sequencing to determine the intra-host viral diversity presented by noroviruses during the acute an ...[more]

PMID: 34376124

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Project description:Typically, human noroviruses cause symptoms of acute gastroenteritis for 2 to 4 days. Often, the virions are shed in stool for several days after the symptoms recede, which in turn can lead to further contamination and transmission. Moreover, a number of reports have considered that chronic norovirus infections, i.e., lasting months and years, might even function as reservoirs for the generation of novel strains that can escape the herd immunity or have modified binding interactions with histo-blood group antigens (HBGAs). In this study, we analyzed noroviruses isolated from a patient who has presented a chronic infection for more than 6 years. We found that the isolated capsid sequences clustered into two main genetic types (termed A and B), despite a plethora of capsid quasi-sequences. Furthermore, the two genetic types corresponded well with distinct antigenicities. On the other hand, we showed that numerous amino acid substitutions on the capsid surface of genetic types A and B did not alter the HBGA binding profiles. However, divergent binding profiles for types A and B were observed with human milk oligosaccharides (HMOs), which structurally mimic HBGAs and may act as natural antivirals. Importantly, the isolated capsid sequences only had approximately 90% amino acid identity with other known sequences, which suggested that transmission of these chronic noroviruses could be limited. IMPORTANCE The norovirus genogroup II genotype 4 (GII.4) variants have approximately 5% divergence in capsid amino acid identity and have dominated over the past decade. The precise reason(s) for the GII.4 emergence and persistence in the human population is still unknown, but some studies have suggested that chronically infected patients might generate novel variants that can cause new epidemics. We examined GII.4 noroviruses isolated from an immunocompromised patient with a long-term infection. Numerous norovirus capsid quasi-species were isolated during the 13-month study. The capsid quasi-species clustered into two genetic and antigenic types. However, the HBGA binding profiles were similar between the two antigenic clusters, indicating that the amino acid substitutions did not alter the HBGA binding interactions. The isolated sequences represented two new GII.4 variants, but similar sequences were not found in the database. These results indicated that chronically infected patients might not generate novel noroviruses that cause outbreaks.

Project description:Whether or not primary norovirus infections induce protective immunity has become a controversial issue, potentially confounded by the comparison of data from genetically distinct norovirus strains. Early human volunteer studies performed with a norovirus-positive inoculum initially led to the conclusion that primary infection does not generate long-term, protective immunity. More recently though, the epidemiological pattern of norovirus pandemics has led to the extrapolation that primary norovirus infection induces herd immunity. While these are seemingly discordant observations, they may in fact reflect virus strain-, cluster-, or genogroup-specific differences in protective immunity induction. Here, we report that highly genetically related intra-cluster murine norovirus strains differ dramatically in their ability to induce a protective immune response: Primary MNV-3 infection induced robust and cross-reactive protection, whereas primary MNV-1 infection induced modest homotypic and no heterotypic protection. In addition to this fundamental observation that intra-cluster norovirus strains display remarkable differences in protective immunity induction, we report three additional important observations relevant to norovirus:host interactions. First, antibody and CD4⁺ T cells are essential to controlling secondary norovirus infections. Second, the viral minor structural protein VP2 regulates the maturation of antigen presenting cells and protective immunity induction in a virus strain-specific manner, pointing to a mechanism by which MNV-1 may prevent the stimulation of memory immune responses. Third, VF1-mediated regulation of cytokine induction also correlates with protective immunity induction. Thus, two highly genetically-related norovirus strains displayed striking differences in induction of protective immune responses, strongly suggesting that the interpretation of norovirus immunity and vaccine studies must consider potential virus strain-specific effects. Moreover, we have identified immune (antibody and CD4⁺ T cells) and viral (VP2 and possibly VF1) correlates of norovirus protective immunity. These findings have significant implications for our understanding of norovirus immunity during primary infections as well as the development of new norovirus vaccines.

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Viral intra-host evolution in immunocompetent children contributes to human norovirus diversification at the global scale.

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Viral intra-host evolution in immunocompetent children contributes to human norovirus diversification at the global scale.

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