A B1a–natural IgG–neutrophil axis is impaired in viral- and steroid-associated aspergillosis

The lung naturally resists Aspergillus fumigatus (Af) in healthy individuals, but multiple conditions can disrupt this resistance, leading to lethal invasive infections. Core processes of natural resistance and its breakdown are undefined. We investigated three distinct conditions predisposing to lethal aspergillosis—severe SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, influenza A viral pneumonia, and systemic corticosteroid use—in human patients and murine models. We found a conserved and essential coupling of innate B1a lymphocytes, Af-binding natural immunoglobulin G antibodies, and lung neutrophils. Failure of this axis concealed Af from neutrophils, allowing rapid fungal invasion and disease. Reconstituting the axis with immunoglobulin therapy reestablished resistance, thus representing a realistic pathway to repurpose currently available therapies. Together, we report a vital host resistance pathway that is responsible for protecting against life-threatening aspergillosis in the context of distinct susceptibilities. Description A B cell–neutrophil pathway maintains protection against Aspergillus fumigatus and its disruption underlies acquired aspergillosis. Avoiding acquired aspergillosis Avoiding acquired Aspergillosis Healthy humans are able to maintain protection against Aspergillus fumigatus (Af) infection despite frequent exposure to this fungus. However, in a subset of individuals, Af is able to establish infection in the lung. Here, Sarden et al. aimed to characterize the mechanism by which resistance to Af fails in some individuals. The authors found that an axis consisting of innate B1a cells, natural IgG antibodies, and neutrophils is essential for maintaining protection against Af infection in preclinical models. This axis can be disrupted by factors ranging from influenza A and SARS-CoV-2 infection to corticosteroid treatment. Importantly, the authors showed that re-establishing this axis, including by administration of Af¬-reactive antibodies, can protect mice, highlighting a potential treatment. -CM 