Host-directed therapy of tuberculosis: Rescuing macrophages and enhancing their activation

结核分枝杆菌(Mtb)是一种引起结核病(TB)的细菌，是导致结核病的唯一主要原因 当今世界死于传染病的人数最多。巨噬细胞是最常感染的宿主细胞。 并最终负责确定接触结核分枝杆菌的结果是否为无感染、潜伏 感染或活动性疾病。我们正在测试两种改善宿主对结核病控制的方法，这两种方法都涉及 抑制靶标在巨噬细胞中，而不是在细菌中，期望这种宿主指导 治疗(HDT)可与传统的抗分枝杆菌治疗(AMT)相结合，以缩短病程 根治疗法。我们将检验以下假设。(1)Mtb的主机控制将被屏蔽 MTB诱导的巨噬细胞死亡。我们的初步证据支持以下具体假设：结核分枝杆菌- I型干扰素的自分泌作用加剧了巨噬细胞的死亡。(2)主机控制 与干扰素-(干扰素)相比，通过增强巨噬细胞的激活，结核分枝杆菌也将受到青睐 独自一人。我们的初步证据支持这样一种特定的假设，即这种增强是由一种小说所支持的， 我们已经鉴定了一种类药物化合物，其作用导致抑制机制靶点 雷帕霉素(MTOR)，导致某些转录因子的激活，包括TFEB，促进 溶酶体生物发生和自噬。(3)提高巨噬细胞的存活率与其 加强激活在改善结核分枝杆菌控制方面将是相加的或协同的，并且不会加剧 免疫病理学如果由此导致的细菌负荷和抗原负荷的减少足够大的话。因此， 我们将在感染结核分枝杆菌的小鼠身上单独和一起测试这两种HDTS，无论是否使用AMT。最后，我们 假设宿主导向疗法(HDT)与抗分枝杆菌疗法(AMT)相结合将允许 结核分枝杆菌感染小鼠无复发治愈的缩短治疗。目标1的重点是延长 结核分枝杆菌感染的巨噬细胞处于健康状态，并确定阻断I型干扰素的机制 信令会这样做。目标2的重点是增强存活的巨噬细胞的激活，并定义 MTOR和TFEB家族转录因子在此过程中的作用。目标3的作用是测试这两个 相互结合以及与AMT相结合的干预措施。

Mycobacterium tuberculosis (Mtb) is a bacterium that causes tuberculosis (TB), the single leading cause of death in the world from infectious disease today. The macrophage is the host cell most commonly infected by Mtb and ultimately responsible for determining whether the outcome of exposure to Mtb is no infection, latent infection or active disease. We are testing two ways to improve the host's control of TB, both of which involve inhibiting targets in the macrophage, rather than in the bacterium, with the expectation that such host-directed therapies (HDT) can be combined with conventional anti-mycobacterial therapy (AMT) to shorten the course of curative treatment. We will test the following hypotheses. (1) Host control of Mtb will be favored by blocking Mtb-induced death of macrophages. Our preliminary evidence supports the specific hypothesis that Mtb- induced death of macrophages is exacerbated by the autocrine action of type I interferon. (2) Host control of Mtb will also be favored by enhancing macrophage activation over the level achieved with interferon- (IFN) alone. Our preliminary evidence supports the specific hypothesis that such enhancement is favored by a novel, drug-like chemical compound we have identified whose action leads to inhibition of mechanistic target of rapamycin (mTOR), resulting in the activation of certain transcription factors, including TFEB, that promote lysosomal biogenesis and autophagy. (3) The combination of enhanced survival of macrophages and their enhanced activation will be additive or synergistic in improving the control of Mtb and will not exacerbate immunopathology if the resulting reduction in bacterial burden and antigenic load is great enough. Accordingly, we will test the two HDTs alone and together in Mtb-infected mice, with and without AMT. Finally, we hypothesize that host-directed therapy (HDT) combined with anti-mycobacterial therapy (AMT) will allow treatment-shortening for relapse-free cure of Mtb-infected mice. The focus of Aim 1 is to prolong the survival of Mtb-infected macrophages in a healthy state and to define the mechanisms by which blockade of type I IFN signaling does so. The focus of Aim 2 is to enhance the activation of surviving macrophages and to define the role of mTOR and TFEB family transcription factors in doing so. The role of Aim 3 is to test these two interventions in combination with each other and with AMT.