The role of CD38 in immunity to tuberculosis

抽象的。世卫组织估计，全球有25%的人口感染过分枝杆菌 结核病（Mtb）是导致结核病（TB）的细菌。尽管取得了重大进展， 在该领域，T细胞和巨噬细胞如何协作以控制细胞内感染尚未完全确定。 肺泡巨噬细胞是Mtb感染的第一个细胞，但最终是CD 11 c+单核细胞衍生的巨噬细胞 (MDM)成为主要的感染细胞类型。我们的研究表明，Mtb感染的CD 11 c + MDM细胞可以被 与未感染的旁观者巨噬细胞的区别在于它们表达细胞表面CD 38，CD 14， ABCA 1. CD 38也由活化的T细胞表达。外周血和肺CD 4 T细胞从人与 TB还表达CD 38，其已被提议作为区分活动性TB与潜伏性TB的生物标志物，并且 监测治疗情况。虽然这些数据确立了CD 38作为一种令人感兴趣的细胞标志物，但其已知的生物学特性 功能表明它可能在结核病免疫中发挥重要作用。CD 38是一种多功能 将NAD+转化为NAADP或cADPR的胞外酶。这些第二信使触发细胞内Ca 2 + 释放，其促进巨噬细胞中的吞噬作用和吞噬溶酶体形成。我们的初步研究 显示CD 38敲除（CD 38 KO）小鼠在肺中具有较高Mtb负荷， 与CD 38充足的小鼠相比。CD 38如何促进对Mtb的耐药性尚不清楚。这项建议 将确定CD 38有助于保护免受Mtb的细胞和分子机制。我们 提出三个目标：1）确定CD 38如何在体内促进抗Mtb免疫的细胞基础; 2） 研究CD 38如何影响巨噬细胞内Mtb的细胞内存活;以及3）评估CD 38如何影响巨噬细胞内Mtb的细胞内存活。 信号传导影响人巨噬细胞中细胞内Mtb的控制。我们的目标是定义基本的细胞和 CD 38促进抗分枝杆菌免疫的分子机制。我们认为，CD 38转化为 T细胞信号进入巨噬细胞抗菌防御程序。我们提出的使用小鼠的体内研究 TB模型以及使用鼠和人巨噬细胞的体外研究将确定CD 38如何发挥作用， 增强对结核病的免疫力，并为进一步调查提供坚实的基础。作为明确的激动剂 CD 38的拮抗剂已经存在，它已经是其他疾病的治疗靶点， 了解CD 38如何调节抗Mtb感染的免疫力可以将其确定为新的HDT靶点 肺结核和其他传染病的治疗方法。

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.