Decoding Host-Fungal Interactions in the Skin

Candida auris, an emerging multidrug-resistant fungal pathogen that preferentially colonizes human skin, leading to nosocomial transmission and outbreaks of systemic fungal infections in humans. C. auris was recently classified within the critical priority fungal pathogens group by the World Health Organization (WHO) and categorized as an urgent threat by the US Centers for Disease Control and Prevention (CDC). Given that most C. auris isolates exhibit resistance to several FDA-approved antifungal drugs, developing novel host-directed therapeutic approaches is critical to prevent and treat this emerging skin-tropic fungal pathogen. Because skin colonization is a prerequisite for C. auris transmission and subsequent invasive disease, understanding the host immune factors, microbiota, and pathogen factors that regulate the colonization and persistence of C. auris in the skin is critical to understand the pathogenesis and to develop novel approaches to prevent and treat C. auris invasive infections in humans. Our lab utilizes various mouse models of skin infection, fungal mutant strains, single-cell RNA sequencing to analyze immune cells, CRISPR-Cas9, and molecular approaches to dissect the immune cell types, fungal factors, and signaling pathways that regulate the colonization and persistence of C. auris in the skin. Tharp et al. mSphere, 2023, Datta et al. Microbiology Spectrum, 2023, Carty et al. PLOS Pathogens, 2023, Balakumar et al. Trends in Microbiology, 2024, Bryak et al.;  mSphere 2024, Towns et al. Microbiology Spectrum, 2024, Balakumar et al., mSphere, 2024, 

Balakumar et al. PLOS Pathogens 2024,  Das et al. PLOS Pathogens 2025, Balakumar et al., mBio, 2026, 

Balakumar et al.,Trends in Microbiology, 2026,  Thangamani et al. PLOS Pathogens, 2026,

 To understand the innate immune responses during C. auris skin infection, we utilized unbiased single-cell transcriptomics. We identified that C. auris skin infection results in the accumulation of immune cells, including neutrophils, inflammatory monocytes, macrophages, dendritic cells, T cells, and NK cells, at the site of infection. We found that fibroblasts were a major non-immune cell type that accumulated in C. auris-infected skin tissue. Comprehensive single-cell profiling revealed transcriptomic signatures of cytokines, chemokines, host receptors (TLRs, C-type lectin receptors, NOD receptors), antimicrobial peptides, and immune signaling pathways in individual immune and non-immune cells during C. auris skin infection. Our analysis revealed that C. auris infection upregulates IL-1RN expression (encoding the IL-1R antagonist protein) across different cell types. We found IL-1Ra produced by macrophages during C. auris skin infection decreases neutrophil killing activity. Furthermore, C. auris uses a unique outer layer of cell wall mannan to evade IL-1R-mediated host defense. Collectively, our single-cell RNA-seq profiling identified transcriptomic signatures in immune and non-immune cells during C. auris skin infection. Our results demonstrate the IL-1Ra- and IL-1R-mediated immune evasion mechanisms C. auris employs to persist in the skin. Understanding the role of immune and non-immune cells involved during C. auris skin colonization will open the door to developing novel antifungal therapeutics. Balakumar et al. PLOS Pathogens 2024. Ganesh et al. Journal of Infectious Diseases, 2025.

 Unlike other Candida species, such as Candida albicans, which colonizes the intestinal tract, C. auris preferentially colonizes the human skin. However, the factors that contribute to C. auris skin persistence remain unclear. We identified that, unlike C. albicans, which induces IL-17-secreting protective effector Th17 cells, C. auris predominantly induces IFNγ-secreting pathogenic Th1 cells during reinfection. Surprisingly, we found that IFNγ enhances skin infection of C. auris but not C. albicans. IFNγ enhances skin infection of C. auris by dampening the protective IL-17 responses and increasing dermal damage. Furthermore, we identified that Th1 cell development occurs through IL-12 produced by C. auris-induced inflammatory macrophages and monocyte-derived dendritic cells. In addition, our findings reveal that C. auris' unique outer cell wall mannan layer induces IFNγ, thereby promoting fungal colonization of the skin. These findings help explain why C. auris but not C. albicans preferentially persist in the skin long-term. Identifying the factors that regulate pathogenic IFNγ response and protective IL-17 responses during C. auris skin infection is critical to develop novel vaccine strategies and antifungal therapeutics to prevent and treat this emerging fungal pathogen in humans. Datta et al. Microbiology Spectrum, 2023, 

Bryak et al.;  mSphere ,2024, Balakumar et al., mSphere, 2024, Das et al. PLOS Pathogens 2025.