Candida albicans oral infection shapes innate immunity and recruitment of myeloid-derived suppressor cells

白色念珠菌口腔感染塑造先天免疫和骨髓源性抑制细胞的招募

• 批准号: 10665797
• 负责人: Mira Edgerton
• 金额: $ 38.12万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-14 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665797
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Aspartic Endopeptidases; Bacterial Infections; Benign; Cancer Etiology; Candida albicans; Cells; Complex; Cues; Disease; Enzymes; Epithelial Attachment; Epithelial Cells; Epithelium; Equilibrium; Future; Goals; Human; Hyphae; IL17 gene; Image; Immune; Immune response; Immunity; Immunologic Factors; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response; Integration Host Factors; Interleukin-1; Intestines; Invaded; Kininogenase; LTB4R gene; Leukotriene B4; Macrophage-1 Antigen; Measures; Mediating; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Mycoses; Myeloid-derived suppressor cells; Natural Immunity; Neutrophil Infiltration; Nutrient; Oral; Oral candidiasis; Oral cavity; Organism; Outcome; Pathogenesis; Peptide Hydrolases; Persons; Production; Proliferating; Proteins; Role; Shapes; Signal Transduction; Symptoms; T-Lymphocyte; Thick; Tissues; Tongue; Tumor Escape; Virulence; arginase; arm; chronic infection; cytokine; fungicide; fungus; granulocyte; gut microbiome; immune activation; in vivo; in vivo evaluation; mouse model; mucosal site; mutant; neutrophil; novel; oral cavity epithelium; oral infection; oropharyngeal thrush; overexpression; pathogen; pathogenic fungus; recruit

Project Summary Candida albicans is a fungal commensal organism that causes oropharyngeal candidiasis (OPC) and may disseminate systemically in immune compromised people. However, most healthy people have oral levels of C. albicans and it is a beneficial organism in the human gut microbiome. Mice infected with C. albicans also have low numbers of oral fungi but have much higher numbers of C. albicans in the gut so that they are a good model to study what factors permit fungal tolerance at human mucosal sites. C. albicans hyphae secrete the aspartyl protease Sap6 that mediates virulence in OPC, induces cytokine release from oral epithelial cells, and initiates neutrophil recruitment. Oral infection by C. albicans in mice caused recruitment of neutrophil “swarms” surrounding invading hyphae, as well as localized Arginase1 positive (Arg1+) granulocytic cells. These Arg1+ cells showed suppression of T cells thus identifying them as myeloid-derived suppressor cells (MDSC). MDSCs have a well-known immunosuppressive role in cancer causing tumor immune evasion, but also have a major role in host immune responses to bacterial and fungal infections by favoring pathogen persistence and chronic infection. We are the first to identify MDSC recruitment upon C. albicans oral infection but we do not know their role here. C. albicans infection resulted in changes the oral epithelium (Ep) including expression of kallikrein (KLK5) proteases accompanying increased Ep desquamation, and increased levels of tissue Arginase 1 (Arg1). The Aims of this project are to 1) Identify in what manner Arg1 and KLK5 expression in oral Ep alters C. albicans infection by examining the effect of Arg1 and KLK5 depletion; 2) Determine how C. albicans induces neutrophil swarming and recruitment of MDSCs in vitro by using live imaging of neutrophil swarming induced by C. albicans and Sap6 and to measure fungicidal activity of MDSCs; and 3) Ascertain the contribution of MDSCs in oral and gut Ca infection in vivo by comparing C. albicans infection in tongue and intestine following MDSC depletion or adoptive transfer of MDSCs. The goal of this proposal is to determine the function of MDSCs in mucosal immunity as well as how Arginase metabolites and KLK5 expression control the final outcome of fungal infection. It is proposed that MDSCs are a novel and unexplored arm of oral epithelial immunity that contribute to oral or gut tolerance of fungal pathogens. The long-range goal of this project is to understand host response to C. albicans and that will guide future strategies to reduce the immune escape of C. albicans and add to our understanding of host tolerance.

项目摘要 白色念珠菌是一种引起口咽念珠菌病(OPC)和 可能会在免疫系统受损的人群中传播。然而，大多数健康人都有 口头的 白色念珠菌的水平，它是人体肠道微生物群中的一种有益微生物。感染C. 白色念珠菌的口腔真菌数量也很少，但口腔真菌的数量要多得多。 肠道中的白色念珠菌所以 它们是研究哪些因素允许人类粘膜部位的真菌耐受性的一个很好的模型。 白念珠菌菌丝分泌天冬氨酸蛋白酶Sap6，介导OPC毒力，诱导细胞因子 从口腔上皮细胞释放，并启动中性粒细胞募集。小鼠口腔感染白色念珠菌的实验研究 导致入侵菌丝周围的中性粒细胞“蜂拥而至”以及局部的精氨酸酶1 阳性(Arg1+)粒细胞。这些Arg1+细胞表现出对T细胞的抑制，从而识别它们 作为髓系来源的抑制细胞(MDSC)。MDSCs具有众所周知的免疫抑制作用 癌症引起的肿瘤免疫逃避，也在宿主对细菌的免疫反应中起着主要作用 和真菌感染，有利于病原体的持久性和慢性感染。我们是第一个发现 MDSC招募对白色念珠菌口腔感染，但我们不知道他们在这里的作用。白色念珠菌感染 引起口腔上皮(EP)的改变，包括激肽释放酶(KLK5)的表达 伴随EP脱屑增加，组织精氨酸酶1(Arg1)水平增加。目标 该项目的目的是1)确定口腔EP中Arg1和KLK5的表达如何改变白色念珠菌 通过检测Arg1和KLK5枯竭的影响感染；2)确定白色念珠菌是如何诱导 中性粒细胞聚集的实时成像在MDSCs体外聚集和募集中的应用 用白念珠菌和Sap6诱导，并测定MDSCs的杀菌活性； 口腔和肠道内白念珠菌体内感染与MDSCs感染的比较 骨髓间充质干细胞耗尽或过继移植后的肠道。这项提议的目标是 确定MDSCs在粘膜免疫中的作用以及精氨酸酶代谢产物和KLK5 表达控制着真菌感染的最终结果。有人认为MDSCs是一种新颖的 口腔上皮免疫的未知分支，有助于口腔或肠道对真菌病原体的耐受。 这个项目的长期目标是了解宿主对白色念珠菌的反应，这将指导未来 减少白念珠菌免疫逃逸的策略，增加我们对宿主耐受性的理解。