Integrating cAMP- and nitric oxide- signalling in Mycobacterium tuberculosis: novel regulatory networks that challenge established paradigms

结核病（TB）通常被认为是一种过去的疾病，但它仍然是许多发展中国家的地方病。世界人口的三分之一--大约20亿人--感染了结核病的病原体，即结核分枝杆菌。大多数感染者没有症状，细菌以休眠状态驻留在他们的体内。然而，在他们一生中的某个时候，这些感染者中约有10%会发展为活动性结核病，在这种情况下，损害他们的免疫系统的条件允许细菌“醒来”并开始生长和繁殖。因此，每年约有180万人死于结核病，使其成为单一传染性病原体导致的最大死亡原因。尽管有有效的药物治疗。然而，治疗方案延长，需要至少6个月，并受到多重耐药菌株出现的威胁。此外，BCG疫苗虽然非常安全，但效力不同。因此，结核病是一个主要的全球性卫生保健问题，寻求新的和更好的药物和疫苗是一个紧迫的研究目标。为了为控制结核病的干预措施开辟新的机会，我们需要更详细地了解M。结核很明显，它能够在受感染个体的肺部以休眠、非复制状态存在数十年，后来才出现并引起活动性结核病（再活化结核病），这是该疾病的一个核心特征。如果我们能更好地了解细菌是如何进入休眠状态和从休眠状态退出的，这将为确定新的药物靶点和疫苗成分提供前景。我们以前的工作已经确定，两个基因调节剂在控制结核病发病机制的这一中心特征中发挥关键作用。一种称为CRPMT的蛋白质是M.它调节一系列基因，以响应小信号分子cAMP浓度的变化，细菌产生cAMP以通过损害宿主信号通路来促进生长。CRPMT调控的基因中有whiB 1。WhiB 1是一种对一氧化氮有反应的基因调节剂。一氧化氮是由宿主肺巨噬细胞产生的，以杀死M。结核病，但低水平的一氧化氮推动细菌进入休眠状态。CRPMT和WhiB 1共同调节细菌蛋白分泌系统的功能，该系统将特定的细菌蛋白释放到宿主细胞中以促进细菌生长。因此，我们认为CRPMT和WhiB 1是决定M是否存在的关键因素。结核病是否会生长并引起活动性结核病或是否会进入休眠的非复制状态（潜伏性结核病）。我们的目标是获得CRPMT（和相关蛋白质Cmr）和WhiB 1如何共同优化基因表达以控制M的中心特征的详细机制理解。结核病毒力在这样做的过程中，我们将提供科学基础，以帮助寻求确定和开发新的药物靶点和疫苗成分。

Tuberculosis (TB) is often considered as a disease of the past, but it remains an endemic disease in many developing countries. One third of the world's population some 2 billion people are infected with the causative agent of TB, the bacterium Mycobacterium tuberculosis. Most infected individuals are asymptomatic and the bacterium resides within their bodies in a dormant state. However, at some point during their lifetimes about 10% of these infected individuals will develop active TB in which conditions that compromise their immune systems allow the bacteria to 'wake up' and begin to grow and multiply. Consequently about 1.8 million deaths are caused by TB every year, making it the greatest cause of death due to a single infectious agent. This is despite the availability of an effective drug treatment. However, the treatment regimen is prolonged, taking at least 6 months, and is threatened by the emergence of multi-drug resistant strains. Moreover, the BCG vaccine, although very safe, is of variable efficacy. Thus, TB is a major worldwide healthcare problem and the quest for new and better drugs and vaccines is a pressing research goal. To open up new opportunities for interventions to control TB we need a more detailed understanding of the fundamental biology of M. tuberculosis. It is clear that its ability to exist for decades in the lungs of infected individuals in a dormant, non-replicating state only to emerge later and cause active TB (reactivation TB) is a central feature of the disease. If we had a better understanding of how the bacterium enters and exits from the dormant state this could offer the prospect of identifying new drug targets and vaccine components. Our previous work has established that two gene regulators play key roles in controlling this central feature of TB pathogenesis. A protein known as CRPMT is required for M. tuberculosis virulence and it regulates a suite of genes in response to changes in the concentration of a small signalling molecule cAMP, which the bacterium produces to promote growth by compromising host signalling pathways. Amongst the genes regulated by CRPMT is whiB1. WhiB1 is a gene regulator that responds to nitric oxide. Nitric oxide is produced by host lung macrophages to kill M. tuberculosis, but low levels of nitric oxide push the bacterium into the dormant state. CRPMT and WhiB1 together regulate the function of a bacterial protein secretion system that releases specific bacterial proteins into host cells to promote bacterial growth. Hence, we believe that CRPMT and WhiB1 are key players in determining whether M. tuberculosis will grow and cause active TB or whether it will enter the dormant non-replicating state (latent TB). Our goal is to obtain a detailed mechanistic understanding of how CRPMT (and a related protein Cmr) and WhiB1 work together to optimize gene expression to control central features of M. tuberculosis virulence. In doing so we will provide the scientific underpinning to aid the quest to identify and develop new drug targets and vaccine components.