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.

抽象的。世卫组织估计世界上有25％的人口感染了分枝杆菌 结核病（MTB），导致疾病结核病的细菌（TB）。尽管在 领域，未完全定义了T细胞和巨噬细胞如何协作控制细胞内感染。 肺泡巨噬细胞是MTB感染但最终是CD11C+单核细胞衍生的巨噬细胞的第一个细胞 （MDM）成为主要感染细胞类型。我们的研究表明，MTB感染的CD11C+ MDM细胞可以是 通过未感染的旁观者巨噬细胞的表达CD38，CD14， ABCA1。 CD38也通过活化的T细胞表达。来自患有患者的外周血和肺CD4 T细胞 TB还表达CD38，该CD38被认为是将活性结核与潜在结核区分开的生物标志物，并且 监测治疗。尽管这些数据将CD38作为有趣的细胞标记，但已知的生物学 功能表明，它可能在对结核病的免疫中起重要作用。 CD38是多功能的 将NAD+转换为NAADP或CADPR的外侧酶。这些第二个使者触发细胞内CA2+ 释放，促进巨噬细胞中的吞噬作用和吞噬溶血体形成。我们的初步研究 证明CD38敲除（CD38KO）小鼠在肺中具有较高的MTB Burnens，并且显着降低了 与CD38充足的小鼠相比，生存率。 CD38如何促进对MTB的抵抗力尚不清楚。这个建议 将确定CD38有助于保护MTB的细胞和分子机制。我们 提案三个目的：1）确定CD38如何对体内抗MTB免疫的贡献的细胞基础； 2） 研究CD38如何影响巨噬细胞中MTB的细胞内存活； 3）评估CD38的方式 信号会影响人类巨噬细胞中细胞内MTB的控制。我们的目标是定义基本的细胞和 CD38促进抗菌免疫史的分子机制。我们建议CD38转换 T细胞信号进入巨噬细胞抗菌防御计划。我们建议使用鼠的体内研究 结核病模型以及使用鼠和人类巨噬细胞的体外研究将确定CD38如何发挥作用 增强对结核病的免疫力，并为进一步研究提供了坚实的基础。以及定义明确的激动剂 和CD38存在拮抗剂，并且已经是其他疾病的治疗靶标 了解CD38如何调节对MTB感染的免疫力可以将其识别为新的HDT靶标 用于结核病和其他传染病。