Experimental rhinovirus infection induces an antiviral response in circulating B cells which is dysregulated in patients with asthma

• Published in: Allergy (Copenhagen) Vol. 77; no. 1; pp. 130 - 142
• Main Authors: Wirz, Oliver F., Jansen, Kirstin, Satitsuksanoa, Pattraporn, Veen, Willem, Tan, Ge, Sokolowska, Milena, Mirer, David, Stanić, Barbara, Message, Simon D., Kebadze, Tatiana, Glanville, Nicholas, Mallia, Patrick, Gern, James E., Papadopoulos, Nikolaos, Akdis, Cezmi A., Johnston, Sebastian L., Nadeau, Kari, Akdis, Mübeccel
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01-01-2022; John Wiley and Sons Inc
• Subjects: allergic asthma; Antiviral Agents - therapeutic use; Antiviral drugs; Asthma; B lymphocytes; Cell differentiation; Cytokines - pharmacology; Gene expression; Humans; Humoral immunity; Infections; Inflammation; Interferon; Interferons; interferon‐stimulated genes (ISG); Lymphocytes B; Original; ORIGINAL ARTICLES; Picornaviridae Infections; pro‐inflammatory cytokines; Rhinovirus; rhinovirus infection; Ribonucleic acid; RNA; Viral infections; Viruses; allergic asthma; B lymphocytes; pro-inflammatory cytokines; interferon-stimulated genes (ISG); rhinovirus infection
• ISSN: 0105-4538; 1398-9995
• DOI: 10.1111/all.14985

Background
Rhinoviruses are the predominant cause of respiratory viral infections and are strongly associated with asthma exacerbations. While humoral immunity plays an important role during virus infections, cellular aspects of this response are less well understood. Here, we investigated the antiviral response of circulating B cells upon experimental rhinovirus infection in healthy individuals and asthma patients.
Methods
We purified B cells from experimentally infected healthy individuals and patients with asthma and subjected them to total RNA‐sequencing. Rhinovirus‐derived RNA was measured in isolated B cells using a highly sensitive PCR. B cells were stimulated with rhinovirus in vitro to further study gene expression, expression of antiviral proteins and B‐cell differentiation in response rhinovirus stimulation. Protein expression of pro‐inflammatory cytokines in response to rhinovirus was assessed using a proximity extension assay.
Results
B cells isolated from experimentally infected subjects exhibited an antiviral gene profile linked to IFN‐alpha, carried viral RNA in vivo and were transiently infected by rhinovirus in vitro. B cells rapidly differentiated into plasmablasts upon rhinovirus stimulation. While B cells lacked expression of interferons in response to rhinovirus exposure, co‐stimulation with rhinovirus and IFN‐alpha upregulated pro‐inflammatory cytokine expression suggesting a potential new function of B cells during virus infections. Asthma patients showed extensive upregulation and dysregulation of antiviral gene expression.
Conclusion
These findings add to the understanding of systemic effects of rhinovirus infections on B‐cell responses in the periphery, show potential dysregulation in patients with asthma and might also have implications during infection with other respiratory viruses.
Intranasal infection with rhinovirus‐A16 elicits antiviral response in peripheral B cells, characterized by upregulated antiviral response and cytokine genes. Peripheral B cells are dependent on external type‐I‐IFN to develop an antiviral activation state. Rhinovirus stimulation induces strong antiviral response in plasmablasts. Dysregulated expression of antiviral response and antibody genes in individuals with asthma is observed after rhinovirus infection. Abbreviations: IFI44L, interferon induced protein 44 like; IFIT, interferon induced protein with tetratricopeptide repeats; IGHA, immunoglobulin heavy constant alpha; IGHG, immunoglobulin heavy constant gamma; IFN‐ α, IFN‐alpha; MX, MX dynamin like GTPase; OASL, 2'‐5'‐oligoadenylate synthetase like; RV‐A16, rhinovirus‐A16; STAT1, signal transducer and activator of transcription 1