STAT3 Gene Mutations Drive Susceptibility to Severe Fungal Infections by Impairing IL-17-Mediated Immunity

Signal transducer and activator of transcription 3 (STAT3) is a crucial transcription factor governing genes and signaling pathways essential for a robust antifungal immune response. Dysfunction in STAT3 is a known cause of susceptibility to severe and recurrent fungal infections, primarily by disrupting the interleukin-17 (IL-17)-mediated immune axis. Current standard-of-care for these infections often relies on broad-spectrum antifungals, which may not address the underlying immunological defect. This review addresses the mechanistic gap in understanding how STAT3 mutations compromise host defense, leading to chronic and disseminated fungal diseases.

This systematic review synthesized current mechanistic insights into STAT3 dysfunction, focusing on its role in impairing the differentiation and effector function of T helper 17 (Th17) cells. Researchers also performed a systematic review of 135 published cases linking STAT3 mutations to fungal infections. The aim was to further characterize the specific role of STAT3 gene defects in fungal susceptibility, integrating both molecular mechanisms and clinical observations from diverse settings.

The review elucidated that STAT3 dysfunction profoundly impairs Th17 cell differentiation and effector function, leading to a significant deficiency of IL-17 and IL-22. These cytokines are indispensable for orchestrating antifungal defense, particularly at mucosal barriers. The resulting immunopathological features include compromised epithelial barrier function, impaired neutrophil recruitment to fungal invasion sites, and a failure to effectively eradicate common pathogens such as Candida spp. and Aspergillus spp..

Individuals harboring STAT3 mutations face a substantially increased risk of disseminated and chronic fungal diseases, a finding supported by the systematic analysis of 135 published cases. This comprehensive analysis underscores the critical role of STAT3-dependent signaling in maintaining antifungal immunity.