{"doi":"10.1101/2021.05.14.444272","title":"Human norovirus infection of primary B cells triggers immune activation <i>in vitro</i>","abstract":"Abstract Human norovirus (HNoV) is a global health and socio-economic burden, estimated to infect every individual at least five times during their lifetime. The underlying mechanism for the potential lack of long-term immune protection from HNoV infections is not understood and prompted us to investigate HNoV susceptibility of primary human B cells and its functional impact. Primary B cells isolated from whole-blood were infected with HNoV-positive stool samples and harvested 3 days post infection (dpi) to assess viral RNA yield by RT-qPCR. A 3-18 fold increase in HNoV RNA yield was observed in 50-60% donors. Infection was further confirmed in B cells derived from splenic and lymph node biopsies. Next, we characterized infection of whole-blood derived B cells by flow cytometry in specific functional B cell subsets (naïve CD27 - IgD + , memory switched CD27 + IgD - , memory unswitched CD27 + IgD + and double-negative CD27 - IgD - ). While susceptibility of subsets was similar, we observed changes in B cell subsets distribution upon infection that were recapitulated after treatment with HNoV virus-like particles and mRNA encoding for HNoV NS1-2 protein. Importantly, treatment of immortalized BJAB B cell lines with the predicted recombinant NS1 protein triggered cell proliferation, increased ATP production, and induced metabolic changes, as detected by means of CFSE/Ki67 staining, seahorse analysis and metabolomics, respectively. These data demonstrate the susceptibility of primary B cells to HNoV infection and suggest that the secreted NS1 protein affects B cell function, proliferation and metabolism in vitro , which could have implications for viral pathogenesis and immune response in vivo . Importance Human norovirus (HNoV) is the most prevalent causative agent of gastroenteritis worldwide. Infection results in a self-limiting disease that can become chronic and severe in the immunocompromised, elderly and infants. There are currently no approved therapeutic and preventative strategies to limit the health and socio-economic burden associated with HNoV infections. Moreover, HNoV does not elicit life-long immunity as repeat infections are common, presenting a challenge for vaccine development. Given the importance of B cells for humoral immunity, we investigated susceptibility and impact of HNoV infection on human B cells. We found that HNoV replicates in human primary B cells derived from blood, spleen and lymph nodes specimens and induces functional changes in B cells, mediated in part by the non-structural protein NS1. Because of the secreted nature of NS1, we put forward the hypothesis that HNoV infection can modulate bystander B cell function with potential implications in systemic immune response.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":224342,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9666,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":328719,"name":"Melissa K. Jones","orcid":"0000-0002-7093-2351","position":1,"is_corresponding":false},{"id":826353,"name":"Vivienne L. Young","orcid":"0000-0002-9216-5552","position":2,"is_corresponding":false},{"id":297999,"name":"Abimbola O. Kolawole","orcid":"0000-0001-8520-865X","position":3,"is_corresponding":false},{"id":581693,"name":"Irene A. Owusu","orcid":"0000-0002-4445-1220","position":4,"is_corresponding":false},{"id":620761,"name":"Mengrou Shan","orcid":"0000-0001-6385-9064","position":5,"is_corresponding":false},{"id":564236,"name":"Basel H. Abuaita","orcid":"0000-0001-6492-2707","position":6,"is_corresponding":false},{"id":301029,"name":"Irina Grigorova","orcid":"0000-0002-4963-7403","position":7,"is_corresponding":false},{"id":355135,"name":"Steven K. Lundy","orcid":"0000-0002-3655-2216","position":8,"is_corresponding":false},{"id":106351,"name":"Costas A. Lyssiotis","orcid":"0000-0001-9309-6141","position":9,"is_corresponding":false},{"id":826354,"name":"Vernon K. Ward","orcid":"0000-0001-8692-5116","position":10,"is_corresponding":false},{"id":486194,"name":"Stephanie M. Karst","orcid":"0000-0003-0406-4637","position":11,"is_corresponding":false},{"id":288650,"name":"Christiane E. Wobus","orcid":"0000-0001-5286-0924","position":12,"is_corresponding":false},{"id":93854,"name":"Carmen Mirabelli","orcid":"0000-0002-4785-5482","position":0,"is_corresponding":true}],"reference_count":26,"raw_metadata":null,"created_at":"2026-07-18T23:54:18.470602Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}