A spatial transcriptomic atlas of the host response to oropharyngeal candidiasis.

Oropharyngeal candidiasis (OPC) caused by the fungus triggers a robust inflammatory response that rapidly eliminates the bulk of the fungal load in the oral mucosa. While pro-inflammatory responses to OPC have been extensively studied, little is known about the counterbalance of immunity in the infection milieu that mitigates inflammatory damage. We employed 10× Visium Spatial Transcriptomics, a next-generation technology that preserves the spatial integrity of infected tongue tissues, enabling high-resolution mapping of the host microenvironment during infection in a murine OPC model. This approach provided a view of cellular interactions and immune dynamics, revealing intricate crosstalk between distinct immune cell populations. Our findings highlight a previously underappreciated role of the type-2 immune response and M2 macrophages in maintaining tissue homeostasis, and the predicted role of platelet degranulation in facilitating disease resolution. Finally, we identified a novel family of small proline-rich antimicrobial proteins with potent antifungal activity. These molecules emerge as promising therapeutic candidates, offering a new avenue for combating OPC.IMPORTANCEOropharyngeal candidiasis (OPC), a fungal infection caused by , affects individuals with weakened immune systems. Our study used spatial transcriptomics, a cutting-edge technology that preserves tissue architecture while mapping immune interactions at high resolution. This approach allowed us to uncover previously unrecognized cellular crosstalk and regulatory pathways that shape the host response to OPC. We discovered that platelets, beyond their role in clotting, play a key role in antifungal defense. Additionally, M2 macrophages are important for resistance to OPC. Most notably, we identified a new family of antimicrobial proteins with strong antifungal properties, presenting promising therapeutic potential. By uncovering these overlooked immune mechanisms, our research findings may lead to better treatments for OPC, particularly in immunocompromised individuals.