Macrophage-induced drug tolerant persisters in tuberculosis

全球每年有超过180万人死于结核病，使其成为单一细菌感染造成的最大死亡原因。这相当于每天有超过10架满载的波音747‘S的乘客死于这种疾病。这是尽管有针对结核分枝杆菌(结核分枝杆菌)病原体的抗生素可用。任何疾病的抗生素治疗都是一个漫长的过程；然而，在结核病中，根除感染细菌需要6-9个月，需要至少3种剧毒药物。这主要是因为存在一小群或亚群的细菌，它们可以抵抗抗生素治疗并存活下来。这些细菌被称为耐药持久性细菌，最早于1942年被发现，但我们距离了解这些难以捉摸的细菌还有很长的路要走。其中一个原因是它们的存在数量如此之少(大约每10,000个中就有1个持久细菌)，以至于很难研究它们。我们实验室的初步结果表明，与我们宿主用来杀死入侵病原体的细胞相互作用，可以诱导出更多数量的持续型杆菌。一旦感染结核分枝杆菌或许多其他入侵病原体，我们的免疫系统就会部署白细胞来杀死入侵者，其中一种被称为巨噬细胞。从我们的结果来看，结核分枝杆菌似乎使用我们自己的巨噬细胞作为特洛伊木马，当进入这个宿主细胞时，它就变成了一个几乎无法治愈的耐药持久细胞。我们称之为巨噬细胞诱导的持续体或MIP。耐药持续体形成的触发因素(S)目前尚不清楚，但可能是未来药物开发的理想靶点1)我们的目标是识别形成MIP所需的细菌触发基因。发现对形成耐药持久者至关重要的细菌基因将有助于我们了解结核分枝杆菌是如何逃避杀灭的，并可能代表未来的药物靶点。2)确定导致MIP形成的巨噬细胞条件。众所周知，持久细胞很难治疗，因为它们在人群中很罕见。通过确定细菌正在感应哪些因素或条件来诱导MIP的形成，我们将能够产生足够的持久菌来进行进一步的研究。我们还打算开发一个新的药物测试平台，以便我们能够识别能够杀死这些MIP的药物，即在我们体内形成的持久性药物。针对耐药持久性药物的潜在应用和好处是抗击结核病的关键。了解这一细菌亚群的性质将使我们能够开发新的治疗策略，要么攻击细菌本身，要么推动宿主免疫反应朝着正确的方向发展。这可以改善患者对治疗的耐受性，并提高治疗成功率。目前的抗药性威胁与艾滋病毒流行相结合，使得制定新的结核病治疗战略变得至关重要。

More than 1.8 million people die worldwide each year from Tuberculosis (TB), making it the biggest cause of mortality due to a single bacterial infection. This equates to the passengers of more than 10 full Boeing 747's succumbing to the disease every single day. This is despite the availability of antibiotics against the causative agent of the disease Mycobacterium tuberculosis (Mtb). Antibiotic treatment for any disease is a lengthy process; however, in TB, eradication of the infecting bacilli takes 6-9 months and requires at least 3 highly toxic drugs. This is primarily due to the presence of a small group or sub-population of bacteria that can resist and survive antibiotic treatment. Termed drug-tolerant persisters, these bacilli were first discovered in 1942 and yet we are still a long way from understanding these elusive bacteria. One of the reasons for this is that they are present at such low numbers (approximately 1 persistent bacilli in 10, 000) that they are difficult to study. Preliminary results from our laboratory have shown that interacting with the very cell that we, the host, deploy to kill invading pathogens can induce much higher numbers of these persister bacilli. Upon infection with Mtb or many other invading pathogens, our immune system deploys white blood cells to kill the invader, one of which is called the macrophage. From our results it appears that Mtb uses our own macrophages as a Trojan Horse and when inside this host cell changes into a virtually untreatable drug-tolerant persister cell. We have called these macrophage-induced persisters or MIPs. The trigger(s) for the formation of drug-tolerant persisters is currently unknown but could represent an ideal target for future drug developmentOur aims1) To identify the bacterial trigger genes required for the formation of MIPs. Discovering the bacterial genes vital to the formation of drug-tolerant persisters would add to our understanding of how Mtb is able to evade killing and could represent future drug targets.2) To determine the macrophage conditions responsible for MIP formation. Persister cells are notoriously difficult to treat due to their rarity in a population. By identifying what factors or conditions the bacterium is sensing to induce the formation of MIPs, we will be able to generate enough persisters to enable further study. We also intend to develop a novel drug testing platform so we can identify drugs capable of killing these MIPs, i.e. persisters formed whilst within our own bodies.Potential applications and benefits Targeting drug-tolerant persisters is key to combatting TB. Understanding the nature of this sub-population of bacteria will enable us to develop new treatment strategies that either attack the bacteria themselves or push the host immune response in the right direction. This could improve treatment tolerance among patients, and improve treatment success rates. The current threat of drug resistance combined with the HIV epidemic makes the development of new TB treatment strategies of the upmost importance.