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

结核病通常被认为是一种过去的疾病，但它在许多发展中国家仍然是一种地方病。世界人口的三分之一，约20亿人感染了结核病的病原体结核分枝杆菌。大多数受感染的人是无症状的，细菌在他们体内处于休眠状态。然而，在这些感染者一生中的某个时候，大约10%的人将发展为活动性结核病，在这种情况下，损害其免疫系统的条件使细菌“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造成的最大死亡原因。尽管有一种有效的药物治疗方法。然而，治疗方案延长，至少需要6个月，并受到多重耐药菌株出现的威胁。此外，卡介苗虽然非常安全，但疗效不一。因此，结核病是一个主要的全球卫生保健问题，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结核分枝杆菌的基本生物学。很明显，它能够在感染者的肺部以休眠、非复制状态存在数十年，之后才出现并引起活动性结核病（再激活结核病），这是该疾病的一个核心特征。如果我们对细菌如何进入和退出休眠状态有了更好的了解，这将为确定新的药物靶点和疫苗成分提供前景。我们之前的工作已经确定，两个基因调节因子在控制结核病发病机制的这一核心特征中起关键作用。一种被称为CRPMT的蛋白质是结核分枝杆菌毒力所必需的，它调节一组基因，以响应一种小信号分子cAMP的浓度变化，这种小信号分子是细菌产生的，通过破坏宿主信号通路来促进生长。受CRPMT调控的基因之一是whiB1。WhiB1是一种对一氧化氮有反应的基因调节因子。一氧化氮是由宿主肺巨噬细胞产生的，用来杀死结核分枝杆菌，但低水平的一氧化氮会使细菌进入休眠状态。CRPMT和WhiB1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WhiB1是决定结核分枝杆菌是否生长并引起活动性结核或是否进入休眠非复制状态（潜伏性结核）的关键因素。我们的目标是获得CRPMT（和相关蛋白Cmr）和WhiB1如何共同优化基因表达以控制结核分枝杆菌毒力的核心特征的详细机制理解。在这样做的过程中，我们将提供科学基础，以帮助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.