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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

基本信息

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
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/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

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.

项目总结