The role of CD38 in immunity to tuberculosis

CD38在结核免疫中的作用

• 批准号: 10727585
• 负责人: SAMUEL M BEHAR
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727585
• 关键词: ATP binding cassette transporter 1; Address; Affect; Agonist; Alveolar Macrophages; Anti-Bacterial Agents; Antimycobacterial Agents; Autophagocytosis; Bacteria; Biological Markers; Biological Process; Biology; CD14 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Compartmentation; Cell Nucleus; Cell surface; Cells; Collaborations; Communicable Diseases; Containment; Cyclic ADP-Ribose; Data; Dendritic Cells; Disease; Endocytic Vesicle; Environment; Event; Foundations; Goals; Growth; Host Defense; Human; ITGAX gene; Immunity; Immunodeficient Mouse; In Vitro; Infection; Infection Control; Inflammatory; Inflammatory Response; Interferon Type II; Investigation; Knockout Mice; Lung; Lysosomes; Macrophage; Mediator; Modeling; Molecular; Monitor; Mus; Mycobacterium tuberculosis; NAADP; Nitric Oxide; Pathway interactions; Persons; Phagocytosis; Phagolysosome; Population; Production; Pulmonary Tuberculosis; Research Proposals; Resistance; Role; Scheme; Second Messenger Systems; Signal Transduction; T-Cell Activation; T-Lymphocyte; Tuberculosis; antagonist; cell type; effector T cell; global health; improved; in vivo; interest; interstitial; monocyte; novel; peripheral blood; podoplanin; programs; recruit; therapeutic target; tuberculosis immunity

Abstract. The WHO estimates that 25% of the world’s population has been infected with Mycobacterium tuberculosis (Mtb), the bacterium that causes the disease tuberculosis (TB). Despite major advances in the field, how T cells and macrophages collaborate to control intracellular infection is incompletely defined. Alveolar macrophages are the first cell that Mtb infects but ultimately, CD11c+ monocyte-derived macrophages (MDM) become the major infected cell type. Our studies show that Mtb-infected CD11c+ MDM cells can be distinguished from uninfected bystander macrophages by their expression of cell surface CD38, CD14, ABCA1. CD38 is also expressed by activated T cells. Peripheral blood and lung CD4 T cells from people with TB also express CD38, which has been proposed as a biomarker to distinguish active TB from latent TB, and to monitor treatment. While these data establish CD38 as an interesting cellular marker, its known biological functions suggested that it could have an important role in immunity to TB. CD38 is a multifunctional ectoenzyme that converts NAD+ to NAADP or cADPR. These second messengers trigger intracellular Ca2+ release, which promotes phagocytosis and phagolysosome formation in macrophages. Our preliminary studies show that CD38 knockout (CD38KO) mice have higher Mtb burdens in the lung and significantly reduced survival, compared to CD38-sufficient mice. How CD38 promotes resistance to Mtb is unknown. This proposal will identify the cellular and molecular mechanism(s) by which CD38 contributes to protection against Mtb. We propose three aims: 1) Determine the cellular basis for how CD38 contributes to anti-Mtb immunity in vivo; 2) Investigate how CD38 affects intracellular survival of Mtb within macrophages; and 3) Assess how CD38 signaling affects control of intracellular Mtb in human macrophages. Our goal is to define the basic cellular and molecular mechanisms by which CD38 promotes antimycobacterial immunity. We suggest that CD38 converts T cell signals into a macrophage antibacterial defense program. Our proposed in vivo studies using the murine TB model, and in vitro studies using murine and human macrophages, will establish how CD38 functions to enhance immunity to TB and provide a strong foundation for further investigations. As well-defined agonists and antagonists exist for CD38, and it is already a therapeutic target for other diseases, an improved understanding of how CD38 modulates immunity against Mtb infection could identify it as a novel HDT target for TB and other infectious diseases.

摘要。世界卫生组织估计，世界上25%的人口感染了分枝杆菌