Interferon-β treatment reverses the detrimental effect of B-cell depletion therapy on respiratory virus infection

Disease-modifying therapies (DMTs) are critical for managing autoimmunity such as multiple sclerosis (MS), yet concerns exist regarding their impact on viral infections. B-cell depletion (α-CD20) and IFN-β are 2 DMTs with seemingly opposing effects on viral infections. Pre-vaccine COVID-19 data linked B-cell depletion to worse outcomes, while IFN-β is believed to offer protection to viral infection. The mechanisms underlying the interactions between these DMTs and infection have yet to be fully elucidated. Our goal was to determine the modulatory effects of α-CD20 and IFN-β, administered individually or in combination, during acute respiratory viral infections in mice. In our study, B-cell depletion was achieved by administering α-CD20 antibodies 3 times every 5 days, starting 7 days before influenza A virus (IAV) infection. IFN-β was administered on days 1 and 2 p.i. α-CD20 administered alone exacerbated infection outcomes. At day 9 postinfection, mice treated with α-CD20 had elevated viral RNA, accompanied by greater weight loss, impaired viral clearance, heightened myeloid cell infiltration in the lungs, and elevated systemic inflammatory cytokines in the blood. Notably, T-cell responses to IAV were not inhibited by α-CD20. IFN-β monotherapy failed to confer significant protection against viral infection, but when combined with α-CD20, it reversed the exacerbated effects of B-cell depletion by reducing viral load, improving morbidity, limiting neutrophil infiltration, and restoring cytokine homeostasis. These findings suggest IFN-β's capacity to counteract the deleterious impacts of α-CD20 on respiratory viral infections, offering potential treatment strategies for autoimmune diseases during viral outbreaks.