Insights Into the Susceptibility of Fungal Infection and STAT3 Genetic Mutations.

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a key transcription factor that regulates a spectrum of genes and signalling pathways critical for the antifungal immune response. Mutations in the STAT3 gene confer susceptibility to severe and recurrent fungal infections, predominantly via disruption of interleukin-17 (IL-17)-mediated immunity. This review synthesises current mechanistic insights into STAT3 dysfunction, which impairs the differentiation and effector function of T helper 17 (Th17) cells. This defect results in a profound deficiency of IL-17 and IL-22, which are indispensable for orchestrating antifungal defence at mucosal barriers. The subsequent immunopathological features include impaired neutrophil recruitment to fungal invasion sites, compromised epithelial barrier function and failure to eradicate pathogens such as Candida spp. and Aspergillus spp. Consequently, individuals harbouring STAT3 mutations face a substantially increased risk of disseminated and chronic fungal diseases. Elucidating this STAT3-dependent signalling pathway is essential for deciphering the pathological basis of fungal susceptibility across diverse clinical settings and informing the development of targeted immunotherapies, including immunomodulatory and genetic therapeutic strategies. Additionally, we performed a systematic review of 135 published cases linking STAT3 mutations to fungal infections, aiming to further characterise the role of STAT3 gene defects in fungal susceptibility.