AbstractBackgroundRhinoviruses 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.MethodsWe 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.ResultsB 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.ConclusionThese 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.