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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要白色念珠菌是一种真菌共生生物，可引起口咽念珠菌病 (OPC) 和可能会在免疫功能低下的人群中进行系统性传播，但是大多数健康人都会出现这种情况。口服白色念珠菌水平，它是感染念珠菌的小鼠肠道微生物组中的有益生物。白色念珠菌的口腔真菌数量也较少，但口腔真菌数量却要高得多肠道中的白色念珠菌它们是研究哪些因素允许人类粘膜部位真菌耐受的良好模型。白色念珠菌菌丝分泌天冬氨酰蛋白酶 Sap6，介导 OPC 毒力，诱导细胞因子从口腔上皮细胞中释放，并引发小鼠白色念珠菌口腔感染。引起入侵菌丝周围中性粒细胞“群”的募集，以及局部精氨酸酶1 阳性 (Arg1+) 粒细胞。这些 Arg1+ 细胞表现出 T 细胞抑制，从而识别它们。众所周知，骨髓源性抑制细胞 (MDSC) 具有免疫抑制作用。癌症导致肿瘤免疫逃避，但也在宿主对细菌的免疫反应中发挥重要作用和真菌感染，通过促进病原体持久性和慢性感染，我们是第一个发现的。 MDSC 在白色念珠菌口腔感染时招募，但我们不知道它们在白色念珠菌感染中的作用。导致口腔上皮 (Ep) 发生变化，包括激肽释放酶 (KLK5) 蛋白酶的表达伴随着 Ep 脱屑的增加和组织精氨酸酶 1 (Arg1) 水平的增加。该项目的目标是 1) 确定口腔 Ep 中 Arg1 和 KLK5 的表达以何种方式改变白色念珠菌通过检查 Arg1 和 KLK5 消耗的影响来确定感染；2) 确定白色念珠菌如何诱导；使用中性粒细胞群实时成像进行体外中性粒细胞群和 MDSC 募集由白色念珠菌和 Sap6 诱导并测量 MDSC 的杀菌活性；3) 确定通过比较舌中白色念珠菌感染，了解 MDSC 在口腔和肠道 Ca 感染中的作用 MDSC 耗尽或 MDSC 过继转移后的肠道和肠道本提案的目标是确定 MDSC 在粘膜免疫中的功能以及精氨酸酶代谢物和 KLK5 的作用 MDSCs 的表达控制着真菌感染的最终结果。口腔上皮免疫中尚未探索的部分，有助于口腔或肠道对真菌病原体的耐受性。该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色念珠菌免疫逃逸并增加我们对宿主耐受性的理解的策略。