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募集

• 批准号: 10501899
• 负责人: Mira Edgerton
• 金额: $ 38万
• 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/10501899
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Aspartic Endopeptidases; Bacterial Infections; Benign; Cancer Etiology; Candida albicans; Cells; Complex; Cues; Disease; Enzymes; Epithelial; Epithelial Attachment; Epithelial Cells; Equilibrium; Future; Goals; Human; Hyphae; Image; Immune; Immune response; Immunity; Immunologic Factors; In Vitro; Individual; Industrial fungicide; Infection; Inflammatory; Inflammatory Response; Integration Host Factors; Interleukin-1; Interleukin-17; Intestines; Invaded; Kininogenase; LTB4R gene; Lead; 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; Proteins; Role; Shapes; Signal Transduction; Symptoms; T-Lymphocyte; Thick; Tissues; Tongue; Tumor Escape; Virulence; arginase; arm; chronic infection; cytokine; 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）的真菌性口腔微生物， 可能会在免疫力低下的人群中全身传播。然而，大多数健康的人 口服 水平C。白色念珠菌，并且它是人类肠道微生物组中的有益生物体。感染C. 白色念珠菌也有少量的口腔真菌，但有更多的 C.肠道里有白色念珠菌 他们是一个很好的模型，研究什么因素允许真菌耐受性在人类粘膜网站。 C.白念珠菌菌丝分泌乙酰基蛋白酶Sap6，其介导OPC的毒力，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。口腔感染C.小鼠白色念珠菌 引起侵入菌丝周围的中性粒细胞"群"的募集，以及局部精氨酸酶1 （Arg1+）粒细胞。这些Arg1+细胞显示出对T细胞的抑制，从而将它们鉴定为 作为骨髓来源的抑制细胞（MDSC）。MDSC具有众所周知的免疫抑制作用， 癌症导致肿瘤免疫逃避，但在宿主对细菌的免疫反应中也发挥重要作用 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C。白色念珠菌口腔感染，但我们不知道他们在这里的作用。C.白色念珠菌感染 导致口腔上皮（Ep）的变化，包括激肽释放酶（KLK 5）蛋白酶的表达 伴随Ep脱屑增加和组织精氨酸酶1（Arg1）水平增加。目标 本研究的主要目的是：1）确定口腔Ep中Arg1和KLK 5的表达是如何改变C.白色 通过检测Arg1和KLK5缺失的影响来检测感染; 2）确定C.白色念珠菌诱导 通过使用中性粒细胞群集的活体成像体外进行中性粒细胞群集和MDSC募集 诱导的C.白色念珠菌和Sap 6，并测量MDSC的杀真菌活性;以及3）确定MDSC的抗真菌活性。 MDSC在体内口腔和肠道Ca感染中的贡献，通过比较C.舌白色念珠菌感染 以及在MDSC耗竭或MDSC过继转移后的肠。本提案的目的是 确定MDSC在粘膜免疫中的功能以及精氨酸酶代谢物和KLK 5 表达控制真菌感染的最终结果。提出MDSC是一种新的， 口腔上皮免疫的一个未探索的分支，有助于口腔或肠道对真菌病原体的耐受。 本研究的长期目标是了解宿主对C.白色念珠菌，这将指导未来 减少C.并增加了我们对宿主耐受性的理解。