Host–Fungus Interactions Link Autoimmune and Immune-Mediated Inflammatory Diseases to Gastrointestinal Cancer: Lessons from KA/KA and Card9−/− Mouse Models

Authors:
Open Access
Publisher website
Google Scholar
Abstract
Autoimmune diseases, immune-mediated inflammatory diseases, and cancer are distinct pathological conditions that can intersect through immune dysregulation, chronic inflammation, impaired host defense, and altered host–microbe interactions. In selected settings, autoimmune and immune-mediated inflammatory diseases are associated with increased gastrointestinal cancer risk. Although bacterial and viral contributions to inflammation-associated cancer have been extensively studied, the role of fungi remains less investigated. This Opinion article discusses host–fungus interactions through two experimental mouse models that connect altered immune tolerance, innate antifungal responses, and gastrointestinal tumorigenesis. Kinase-dead IKKα K44A knock-in mice develop defective central immune tolerance, APECED-like autoimmune manifestations, mucosal fungal infection, epithelial EGFR signaling, and esophageal squamous cell carcinoma. By contrast, Card9−/− mice provide a distinct model in which impaired innate antifungal immunity alters intestinal fungal ecology and myeloid-cell responses in colitis-associated colorectal cancer. In the CARD9 setting, fungi may exert pathogenic or protective effects depending on host genotype, immune context, fungal species, and mycobiome structure. Together, these models provide useful tools for investigating how fungi may contribute to gastrointestinal tumorigenesis through cancer-promoting inflammation and immune suppression in a context-dependent manner. However, these findings do not yet validate clinical strategies and should not be interpreted as broadly representative of all autoimmune or immune-mediated inflammatory diseases. Further mechanistic and human studies are needed.
Funding Information
  • intramural research program of the National Institutes of Health (ZIA BC011212)
  • intramural research program of the National Institutes of Health (ZIA BC011391)

This publication has 63 references indexed in Scilit: