F SCHÖNHERR ¹, C FRAGOSO-CORTI ², O PETRINI ³, S LEIBUNDGUT-LANDMANN <sup>1

1</sup>Section of Immunology, Vetsuisse Faculty, University of Zürich, Winterthurerstrasse 266a, 8057 Zürich, Switzerland , ²Laboratory of Applied Microbiology, DACD, SUPSI, Via Mirasole 22A, 6500 Bellinzona, Switzerland , ³POLE Pharma consulting, Breganzona, Switzerland

Candida albicans is a member of the normal human microbiota, but as an opportunistic pathogen it can also cause severe infections in immunocompromised individuals. It is generally believed that the host immune status alone determines the outcome of the interaction between the commensal fungus and the host, resulting in either health or disease. Interleukin 17 (IL-17)-mediated immunity has emerged as a critical mechanism of the host to regulate the antimicrobial response, thereby limiting fungal overgrowth at the epithelial barriers. Complementarily, neutrophils contribute to host defense by preventing systemic dissemination of the fungus. Whether in addition to host factors, differences in C. albicans that exist between individuals may also contribute to disease development remains unclear. We used the well-established mouse model of oropharyngeal candidiasis (OPC) to probe the host response to diverse natural isolates of C. albicans in a uniform and Candida-naïve host environment. The isolates displayed no gross differences in growth, hyphenation, drug resistance or cell wall composition in vitro, but they triggered highly variable degrees of inflammation in vivo. The weak and delayed induction of IL-17 and antimicrobial peptides by some isolates correlated with their persistence in the mucosal epithelium. Importantly, however, the requirement of IL-17 for preventing fungal outgrowth was conserved with all isolates tested, highlighting the key role of this cytokine in host protection from C. albicans. Differences in the host response induced by the diverse isolates in vivo was reflected by their capacity to induce the release of ‘alarmins’ such as IL-1α from keratinocytes. This supports the notion that the epithelium can sense variations in the fungus and translate them into host signals that mediate fungal clearance or persistence. This study demonstrates the relevance of the natural diversity of C. albicans for determining the fine balance between commensalism and pathogenicity in vivo.