Cathelicidin modulates the host response during fungal sepsis.

项目总结 脓毒症是世界上最常见的医院相关死亡原因。真菌病原体念珠菌是 侵袭性真菌感染的主要原因，并在约30%的病例中导致败血症，这与 死亡率高得令人无法接受(60%)。尽管真菌败血症的流行和严重程度，我们的 对决定念珠菌败血症风险和结果的宿主因素的了解仍然有限。初步数据 由候选人艾莉森·科迪博士产生的研究表明，宿主防御素在 在系统性白念珠菌感染真菌模型中，小鼠(抽筋KO)出人意料地有利于宿主存活 败血症。生存率的提高与炎性细胞因子IL-1β的显著增加有关。尽管 已知的IL-1β在控制宿主真菌生长中的作用，痉挛KO小鼠在真菌方面没有变化 与野生型动物相比，感染期间的负担。总而言之，拟议的研究试图1)划定 在真菌败血症期间，长春花碱在驱动有害宿主反应中的作用，2)确定 泻药对IL-1β活性的影响，以及3)如何确定糖尿病，糖尿病是患者严重疾病的风险因素， 影响泻药依赖的反应。这些研究将增加我们对如何 在侵袭性真菌感染期间，失调的免疫反应调节宿主的结局，并向理性的 治疗败血症和其他炎症性疾病的治疗药物的发展。科迪博士的真菌专业背景 发病机制和免疫学，辅以中性粒细胞生物学和宿主炎症方面的专业知识 Nizet实验室的反应，使她独特地准备在真菌领域做出重大贡献 免疫学、宿主-病原体相互作用和败血症。K22奖将支持这项重要的研究，因为 并为将来的R01拨款申请生成初步数据，这些申请将进一步研究分子 真菌败血症时宿主反应的潜在机制及其对患者发病率和 死亡率。

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.