In the relentless battle between humans and fungal pathogens, the fungus Candida albicans stands out for its ability to cause systemic infections that can prove life-threatening, especially in immunocompromised individuals. Recent groundbreaking research sheds light on a crucial mechanism by which the immune system harnesses eosinophils—a type of white blood cell usually associated with allergies—to combat this pervasive fungal invader. Published in Nature Communications, the study conducted by Zaffran, Gaur, Ofori, and colleagues reveals the protective interaction between eosinophil CD48 receptors and the fungal adhesin Als6 protein, opening new avenues for understanding immune resilience against systemic candidiasis.
Candida albicans is known for its ability to switch between commensalism and pathogenicity, complicating treatment strategies. Its adhesion molecules, particularly the Als (agglutinin-like sequence) family, facilitate attachment to host tissues, a critical initial step in infection development. Although the immune system deploys multiple strategies to thwart fungal dissemination, the specific cellular and molecular players that achieve this control remain incompletely characterized. This study uncovers that eosinophil surface receptor CD48 binds directly to the fungal Als6 adhesin, an interaction that is pivotal in mounting an effective antifungal response.
Through a combination of sophisticated in vitro assays and rigorous in vivo mouse models, the researchers demonstrate that CD48-expressing eosinophils recognize and interact with Candida albicans via Als6. This binding event triggers a cascade of immune responses resulting in fungal killing, including the release of cytotoxic granules and pro-inflammatory mediators. Notably, mice deficient in eosinophils or specifically lacking CD48 expression exhibit heightened susceptibility to systemic candidiasis, underscoring the protective role of this receptor-ligand axis.
One of the most compelling aspects of this research lies in the characterization of the Als6 protein not merely as an adhesin but as a direct ligand for an immune receptor. Als6’s identification as a target of eosinophil CD48 challenges conventional paradigms focused solely on fungal virulence factors and highlights a sophisticated mechanism by which the immune system exploits fungal surface molecules to detect and eradicate pathogens. This finding suggests a dual role for Als6 in facilitating adhesion and inadvertently marking the fungus for immune attack.
Eosinophils have historically been relegated to a role in allergic inflammation and defense against parasitic helminths. However, mounting evidence positions these granulocytes as versatile players in antiviral, antibacterial, and antifungal immunity. The current study solidifies this perspective by providing molecular evidence positioning eosinophils as frontline defenders against Candida albicans, especially in systemic infection contexts where rapid containment is paramount for host survival.
Mechanistically, the interaction between CD48 and Als6 promotes eosinophil adhesion and activation. The engagement stimulates intracellular signaling pathways including those that mobilize reactive oxygen species and facilitate degranulation, releasing enzymes like major basic protein that are toxic to fungi. This immune assault not only impedes fungal proliferation but also helps in recruiting additional innate and adaptive immune cells to the site of infection, orchestrating a multifaceted defense strategy.
Importantly, the researchers employed knockout mouse models to dissect the contributions of eosinophil subsets and receptor specificity. Eosinophil depletion or genetic ablation of CD48 resulted in uncontrolled fungal growth and increased mortality in systemic candidiasis models. These findings provide direct causal links between eosinophil-CD48 interactions and host resistance, highlighting the therapeutic potential of augmenting this pathway to enhance antifungal immunity.
The study’s in vitro data complemented the in vivo observations, showing that purified eosinophils incubated with Candida albicans strains deficient in Als6 adhere less efficiently and exhibit impaired fungicidal activity. Restoration of Als6 expression rescues eosinophil binding and killing, confirming the specificity of the CD48-Als6 molecular interaction. This precise receptor-ligand pairing offers an attractive target for interventions aiming to boost immune recognition of fungal pathogens.
Beyond immunological insights, this research has significant clinical implications. Systemic candidiasis remains a major cause of morbidity and mortality in hospitalized patients, with limited therapeutic options and rising antifungal resistance. By defining a novel immune recognition mechanism, the authors provide a framework for designing new immunomodulatory therapies that harness or mimic the CD48-Als6 interaction to bolster host defenses and reduce fungal burden.
The discovery of eosinophil CD48 as a key mediator of antifungal defense calls for reevaluation of current antifungal strategies that largely ignore the contribution of granulocytes other than neutrophils. Therapeutic strategies that preserve eosinophils or enhance CD48 expression and signaling may improve outcomes in patients vulnerable to systemic candidiasis. Moreover, understanding how fungal pathogens like Candida albicans might evade or suppress this immune axis could reveal new mechanisms of pathogenicity and immune escape.
This research further emphasizes the complexity of the host-pathogen interface, where fungal surface proteins serve multiple roles beyond virulence factors—they also become critical ligands for immune receptors. Investigating whether other members of the Als family or fungal adhesins interact with immune cells similarly could broaden our understanding of fungal immunosurveillance and potentially identify other exploitable targets for therapy.
The work by Zaffran and colleagues is a testament to the power of interdisciplinary collaboration involving immunologists, microbiologists, and molecular biologists. Their integration of cellular assays, genetic mouse models, and fungal molecular biology not only elucidates a new dimension of eosinophil function but also paves the way for future studies aimed at harnessing granulocyte responses in combating systemic fungal infections.
As systemic candidiasis continues to pose global health challenges, particularly among immunocompromised populations including transplant recipients, cancer patients, and individuals with HIV/AIDS, novel insights such as these are invaluable. They inform both fundamental immunology and translational medicine, enhancing our armamentarium against fungal diseases that have eluded effective control for decades.
Looking ahead, clinical trials evaluating agents capable of upregulating CD48 or enhancing eosinophil function could test the relevance of this axis in human disease. Similarly, diagnostic approaches leveraging CD48-Als6 interactions might enable early detection or monitoring of fungal infections, improving patient management. Personalized medicine approaches could also emerge, tailoring treatments based on individual immune profiles including eosinophil abundance and function.
In conclusion, the identification of eosinophil CD48 interactions with Candida albicans Als6 as a protective mechanism against systemic candidiasis represents a breakthrough in fungal immunology. This work reframes eosinophils as vital antifungal effector cells and opens new therapeutic vistas. As the burden of fungal infections grows globally, such fundamental discoveries illuminate a path towards more effective and targeted interventions that leverage the nuanced interplay of immune recognition and fungal virulence.
Subject of Research: Eosinophil-CD48 receptor interactions with Candida albicans Als6 adhesin and their role in protection against systemic candidiasis.
Article Title: Eosinophil CD48 interactions with Candida albicans Als6 is protective in vitro and in mouse systemic candidiasis.
Article References:
Zaffran, I., Gaur, P., Ofori, P. et al. Eosinophil CD48 interactions with Candida albicans Als6 is protective in vitro and in mouse systemic candidiasis. Nat Commun 16, 9291 (2025). https://doi.org/10.1038/s41467-025-64276-3
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