Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA 70433.
Department of Microbiology & Immunology, Tulane University School of Medicine, New Orleans, LA 70112.
Proc Natl Acad Sci U S A. 2018 Jan 2;115(1):E62-E71. doi: 10.1073/pnas.1711373114. Epub 2017 Dec 18.
continues to cause devastating levels of mortality due to tuberculosis (TB). The failure to control TB stems from an incomplete understanding of the highly specialized strategies that utilizes to modulate host immunity and thereby persist in host lungs. Here, we show that induced the expression of indoleamine 2,3-dioxygenase (IDO), an enzyme involved in tryptophan catabolism, in macrophages and in the lungs of animals (mice and macaque) with active disease. In a macaque model of inhalation TB, suppression of IDO activity reduced bacterial burden, pathology, and clinical signs of TB disease, leading to increased host survival. This increased protection was accompanied by increased lung T cell proliferation, induction of inducible bronchus-associated lymphoid tissue and correlates of bacterial killing, reduced checkpoint signaling, and the relocation of effector T cells to the center of the granulomata. The enhanced killing of in macrophages in vivo by CD4 T cells was also replicated in vitro, in cocultures of macaque macrophages and CD4 T cells. Collectively, these results suggest that there exists a potential for using IDO inhibition as an effective and clinically relevant host-directed therapy for TB.
继续导致结核病（TB）的死亡率达到毁灭性水平。未能控制结核病源于对其利用高度专业化策略来调节宿主免疫从而在宿主肺部持续存在的不完全理解。在这里，我们表明，在患有活动性疾病的动物（小鼠和猕猴）的巨噬细胞和肺部中诱导了色氨酸分解代谢相关酶吲哚胺 2,3-双加氧酶（IDO）的表达。在猕猴吸入性结核病模型中，抑制 IDO 活性可降低细菌负荷、病理学和结核病临床症状，从而提高宿主生存率。这种增强的保护作用伴随着肺 T 细胞增殖增加、诱导诱导性支气管相关淋巴组织和与杀菌相关的标志物、减少检查点信号以及效应 T 细胞向肉芽肿中心的重新定位。在体外，在猕猴巨噬细胞和 CD4 T 细胞的共培养物中，CD4 T 细胞在体内对巨噬细胞中 进行的增强杀伤作用也得到了复制。总的来说，这些结果表明，使用 IDO 抑制作为一种有效且具有临床相关性的宿主定向治疗结核病具有潜力。
