Cathelicidin modulates the host response during fungal sepsis.

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PROJECT SUMMARY Sepsis is the most common cause of hospital-associated death in the world. The fungal pathogen Candida is the major cause of invasive fungal infections, and leads to sepsis in about 30% of cases, which is associated with an unacceptably high rate of mortality (60%). Despite the prevalence and severity of fungal sepsis, our understanding of the host factors that dictate Candida sepsis risk and outcome remain limited. Preliminary data generated by the candidate, Dr. Alison Coady, demonstrates that loss of the host defense peptide cathelicidin in mice (CRAMP KO) is unexpectedly beneficial to host survival in a systemic C. albicans infection model of fungal sepsis. Enhanced survival is associated with a significant increase in the inflammatory cytokine IL-1β. Despite the known role of IL-1β in controlling fungal growth in the host, CRAMP KO mice display no changes in fungal burden during infection compared to wildtype animals. Collectively, the proposed studies seek to 1) delineate the role of cathelicidin in driving detrimental host responses during fungal sepsis, 2) define the impact of cathelicidin on IL-1β activity, and 3) determine how diabetes, a risk factor for severe disease in patients, influences cathelicidin-dependent responses. These studies will increase our fundamental understanding of how dysregulated immune responses modulate host outcomes during invasive fungal infection and inform the rational development of therapeutics to treat sepsis and other inflammatory diseases. Dr. Coady’s background in fungal pathogenesis and immunology, supplemented by the expertise in neutrophil biology and host inflammatory responses of the Nizet lab, make her uniquely poised to make significant contributions in the fields of fungal immunology, host-pathogen interactions, and sepsis. A K22 award would support this important research, as well as generate the preliminary data for future R01 grant applications that further examine the molecular mechanisms underlying host responses during fungal sepsis and their contributions to patient morbidity and mortality.