Human gut mycobiota tune immunity via CARD9-dependent induction of anti-fungal IgG antibodies

Antibodies mediate natural and vaccine-induced immunity against viral and bacterial pathogens, whereas fungi represent a widespread kingdom of pathogenic species for which neither vaccine nor neutralizing antibody therapies are clinically available. Here, using a multi-kingdom antibody profiling (multiKAP) approach, we explore the human antibody repertoires against gut commensal fungi (mycobiota). We identify species preferentially targeted by systemic antibodies in humans, with Candida albicans being the major inducer of antifungal immunoglobulin G (IgG). Fungal colonization of the gut induces germinal center (GC)-dependent B cell expansion in extraintestinal lymphoid tissues and generates systemic antibodies that confer protection against disseminated C. albicans or C. auris infection. Antifungal IgG production depends on the innate immunity regulator CARD9 and CARD9+CX3CR1+ macrophages. In individuals with invasive candidiasis, loss-of-function mutations in CARD9 are associated with impaired antifungal IgG responses. These results reveal an important role of gut commensal fungi in shaping the human antibody repertoire through CARD9-dependent induction of host-protective antifungal IgG. [Display omitted] •Multi-kingdom antibody profiling reveled systemic IgG repertoires against gut fungi•Candida albicans is the major inducer of antifungal IgG (αF-IgG) in mice and humans•Gut-induced anti-Candida IgG protects against systemic C. albicans and C. auris•CARD9+CX3CR1+ phagocytes mediate αF-IgG that is decreased in CARD9-deficient patients Doron et al. present evidence that commensal fungi in the human gut shape antibody responses in the blood to protect the host from systemic lethal fungal infections. The innate immunity regulator CARD9 and CARD9+CX3CR1+ macrophages play an important role in antifungal IgG production, which is decreased in CARD9-deficient patients.