A study published in Nature Communications has identified a previously underappreciated role for eosinophils in defending against systemic Candida albicans infections. Long associated with allergic responses and parasitic infections, eosinophils are now shown to participate directly in antifungal immunity through a defined receptor-ligand interaction that influences fungal clearance and host survival.
Researchers from the Hebrew University of Jerusalem and collaborating institutions demonstrated that eosinophils can phagocytose C. albicans in its yeast form and release granule proteins that reduce fungal viability. During hyphal growth, however, C. albicans secretes the peptide toxin candidalysin, which compromises eosinophil membrane integrity and induces cell death. This cytolysis results in the release of major basic protein-1 (MBP-1), among other mediators, which significantly inhibit fungal growth in vitro.
The study also identified CD48, a glycosylphosphatidylinositol-anchored receptor expressed on eosinophils, as a critical component in fungal recognition. CD48 binds specifically to the fungal surface protein Als6, facilitating eosinophil activation. In CD48-deficient mice, researchers observed higher kidney fungal burdens and reduced survival compared to wild-type controls, indicating that CD48 contributes to protection in systemic candidiasis.
This CD48–Als6 interaction was further evaluated across a range of C. albicans clinical isolates. Of the 34 strains tested, 55 percent exhibited significant binding to CD48, suggesting that the interaction may be relevant in clinical contexts. In vivo experiments using eosinophil-deficient mice, generated either genetically (ΔdblGATA) or through anti–IL-5 antibody treatment, confirmed that absence of eosinophils led to increased fungal load and altered cytokine responses, including elevated interleukin-6 and reduced interferon-gamma levels.
Microscopy and flow cytometry analyses showed that eosinophils not only phagocytose C. albicans but also release extracellular traps and cytokines, including IFN-γ, in response to fungal stimulation. These findings suggest that eosinophils contribute to multiple aspects of antifungal immunity. Furthermore, the use of als6Δ/Δ mutant strains of C. albicans demonstrated that the absence of Als6 negates the protective effect associated with CD48, reinforcing the importance of the CD48–Als6 axis in eosinophil-mediated fungal inhibition.
The study also notes that eosinophil depletion through biologic therapies, such as those targeting IL-5 for the treatment of eosinophilic disorders, has been associated with increased infection risk in post-marketing surveillance reports. These findings may have implications for clinical decision-making in patients at risk for invasive fungal infections.
By characterizing the CD48–Als6 interaction and its impact on eosinophil function in systemic candidiasis, the study provides evidence for a broader immunological role of eosinophils beyond their traditional associations.