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 白色念珠菌是一种真菌共生生物，会引起口咽念珠菌病（OPC）和 可以在免疫受损的人中全身传播。但是，大多数健康的人都有 口服 白色念珠菌的水平，它是人类肠道微生物组中的一种有益的生物。感染C的小鼠。 白色唱片人的口服真菌数量也很少 肠道中的白色念珠菌 它们是研究哪些因素允许在人粘膜部位进行真菌耐受性的好模型。 白色念珠菌菌丝分泌介导OPC病毒的Aspartyl蛋白酶SAP6诱导细胞因子 从口服上皮细胞释放，并引发中性粒细胞募集。白色念珠菌在小鼠中的口服感染 引起围绕入侵菌丝的嗜中性粒细胞“蜂群”以及局部精氨酸酶1 阳性（arg1+）粒细胞细胞。这些Arg1+细胞显示了T细胞的抑制作用，从而识别它们 作为髓样衍生的抑制细胞（MDSC）。 MDSC在 导致肿瘤免疫进化的癌症，但在宿主免疫反应中也具有重要作用 和真菌感染通过偏爱病原体持久性和慢性感染。我们是第一个识别的人 MDSC招募白色念珠菌口腔感染，但我们在这里不知道它们的作用。白色念珠菌感染 导致口服上皮（EP）的变化，包括Kallikrein（KLK5）蛋白酶的表达 采用EP脱离的增加，并增加组织精氨酸酶1（ARG1）。目的 该项目的内容是1）识别口服EP中的Arg1和Klk5表达的方式变化了白色念珠菌 通过检查ARG1和KLK5耗竭的作用来感染； 2）确定白色念珠菌如何影响 通过使用嗜中性粒细胞的活成像，中性粒细胞在体外蜂拥而至和募集MDSC 由白色念珠菌和SAP6诱导，并测量MDSC的真菌活性； 3）确定 通过比较白色念珠菌感染的舌 MDSC耗竭或MDSC的自适应转移后的肠道和肠道。该提议的目的是 确定MDSC在粘膜免疫中的功能以及精氨酸酶代谢物和KLK5的功能 表达控制真菌感染的最终结果。有人提出MDSC是一部小说， 口服上皮免疫的未开发臂，导致真菌病原体的口服或肠道耐受性。 该项目的远程目标是了解主机对白色念珠菌的反应，这将指导未来 减少白色念珠菌免疫镜的策略并增加了我们对宿主耐受性的理解。