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The Functional Role of the Tetraspanin CD82/Kai1 in Fungal Innate Immunity

四跨膜蛋白 CD82/Kai1 在真菌先天免疫中的功能作用

基本信息

批准号：
10090557
负责人：
Jatin M Vyas
金额：
$ 52.94万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-11 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090557
关键词：
Adhesions Affect Antibodies Aspergillus Autophagocytosis Bacteria Biochemical Biological Assay Biological Process Biotin C Type Lectin Receptors CD47 gene CD81 gene Candida Candida albicans Candidiasis Carbohydrates Cell Wall Cell membrane Cell physiology Cells Cholesterol Complex Confocal Microscopy Critical Illness DNA Binding Defect Dendritic Cells Enzyme Activation Event Family Generations Glucans Hepatitis C virus Host Defense Human Immune Immune response Immune system Immunity Immunocompromised Host Infection Innate Immune Response Internet Intracellular Membranes KAI1 gene Kinetics Knockout Mice Label Life Ligands Lipid Bilayers Lipids Listeria monocytogenes MHC Class II Genes Malignant Neoplasms Membrane Membrane Lipids Membrane Microdomains Membrane Proteins Methods Microscopy Modification Molecular Molecular Conformation Morbidity - disease rate Mus Mycoses Myeloid Cells Names Natural Immunity Nematoda Neoplasm Metastasis PTPRC gene PTPRJ gene Parasites Pathway interactions Phagocytes Phagocytosis Phagosomes Phosphorylation Plasmodium Play Protein Family Proteins Reaction Receptor Signaling Resolution Role Second Messenger Systems Sepsis Signal Transduction Sphingolipids Structure Surface System T-Lymphocyte TLR2 gene TLR4 gene Time Tissues Tumor Immunity Tumor Suppressor Proteins Ubiquitination Virus base cell motility cell type cytokine dectin 1 exosome extracellular fungus in vivo Model live cell imaging macrophage member migration monocyte mortality particle pathogen pathogenic fungus receptor receptor binding recruit response trafficking tumor tumor progression

项目摘要

Project Summary: Invasive fungal infections (IFIs) represent a major threat to critically ill and immunocompromised patients and are associated with significant morbidity and mortality. Aspergillus and Candida are opportunistic fungi that cause the majority of these life-threatening infections. In order to exert their deleterious effects, pathogens including viruses, bacteria, parasites, and fungi can hijack tetraspanins for cell invasion or intracellular trafficking. Tetraspanins comprise a family of proteins that are expressed on the plasma membrane, intracellular membranes, and exosomes from nearly all cell types. As their name implies, tetraspanins span the membrane four times and have short intracellular amino and carboxyl-termini and two extracellular loops. Tetraspanins regulate diverse biological processes including cell migration, adhesion, and signaling events by serving as organizers of multimolecular complexes; they form promiscuous associations with one another and other membrane proteins and lipids to generate tetraspanin-enriched microdomains. Elucidating the precise function of tetraspanins has been difficult due to molecular redundancy, a lack of catalytic activity, and insufficient specific antibodies. Despite these challenges, several tetraspanins have been implicated as key regulators of cancer progression and immunity. In particular, CD82 acts as a potent suppressor of tumor metastasis. Tetraspanins including CD82 are also widely expressed in immune cells, but their exact role in undefined. We have made several key observations that begin to define the role of CD82 in fungal immunity. Following phagocytosis by macrophages, CD82 is specifically recruited to phagosomes containing fungal pathogens prior to lysosomal fusion. Remarkably, LysM-Cre CD82 knockout mice infected with Candida albicans have significantly reduced survival compared to wild-type controls, indicating that CD82 plays an important functional role in myeloid cells in response to systemic fungal infection. We developed fungal-like particles to probe directly the immune response to carbohydrates expressed on the fungal cell wall, such as β- 1,3 glucan which is recognized by the pathogen recognition receptor, Dectin-1. We demonstrated that Dectin-1 is critical for phagolysosomal maturation and controls recruitment of the autophagy-related protein, LC3, to fungal containing phagosomes through Syk activation. We also found that CD82 associates with Dectin-1 in macrophages and is important for downstream signaling events in response to fungal infection including Syk activation and ROS generation. To determine the molecular mechanism of CD82 in fungal innate immunity in macrophages, we propose the following two specific aims: (1) Determine the role of CD82 in Dectin-1 signaling by macrophages stimulated with β-1,3 glucan, and (2) Define the role of CD82 in LC3 associated phagocytosis in macrophages challenged by C. albicans.

项目总结: