Klebsiella pneumonaie anti-immunology: exploiting mTORC1 to control cell-intrinsic immunity.

控制细菌感染也许是现代医学最重要的成就。然而，我们未能跟上微生物对现有治疗方法越来越耐药的步伐。多重耐药肺炎克雷伯氏菌对所有主要的一线抗生素化合物都有耐药性，就是这种威胁的例证。事实上，对“最后手段”抗菌药物耐药的菌株越来越多地被分离出来，这大大缩小了治疗选择，或者在某些情况下完全消除了治疗选择。这在低收入和中等收入国家尤其令人担忧。特别令人关切的是社区中耐药性感染的增加，这可能使更多的人处于危险之中。例如，过去五年，英国的侵袭性克雷伯菌感染增加了12%。不幸的是，新的药物类别没有被发明出来，抗药性继续无情地蔓延。风险很高，我们可能正在进入一个前抗生素时代。据英国公共卫生部计算，缺乏有效的抗生素将使超过300万例手术和癌症治疗危及生命，预计在未来30年内，英国将有超过9万人死于抗生素耐药性感染。开发新的抗微生物疗法的一个有吸引力的方法是增强保护性免疫反应，事实上，这可以保护大多数人。然而，在克雷伯氏菌感染的情况下，这是特别困难的，因为我们仍然不知道这些反应中哪些是保护性的，哪些可能有益于微生物。此外，我们对克雷伯氏菌为避免我们的防御系统受到攻击而采取的策略缺乏全面的了解。像克雷伯氏菌这样的微生物是迷人的，因为它们已经进化到在我们的身体中蓬勃发展，尽管我们的免疫系统受到攻击。通过了解它们是如何做到这一点的，我们可以识别我们防御的脆弱热点，同时发现我们的身体和微生物之间相互作用的复杂性。在这项研究中，我们将揭示一个迄今为止未知的克雷伯氏菌逃避策略，旨在抵消巨噬细胞的杀微生物功能。这些细胞对我们抵御克雷伯氏菌至关重要。为了扭转克雷伯氏菌感染的趋势，我们将研究阻断这种逃避策略是否有助于我们的防御系统清除感染。干扰微生物为了自身利益而劫持的信号通路是治疗多药感染的一种特别引人注目的方法。据认为，这种策略对耐药性的发展施加的选择性压力比传统的抗菌药物治疗要小，传统的抗菌药物治疗旨在杀死微生物或防止其生长。在我们的工作中，我们将使用一种已经批准用于人类的药物，靶向克雷伯氏菌操纵的蛋白质，但用于与抗菌活性无关的目的。从药物发现的角度来看，这大大缩短了药物开发过程，从而允许从基础研究到临床开发的潜在快速过渡。我们设想，我们的研究结果将鼓励其他学者和制药公司遵循这一研究途径，以解决对抗生素耐药的微生物缺乏治疗方法的问题。

The control of bacterial infections is perhaps the most important achievement of modern medicine. However, we have failed to keep pace with microbes becoming increasingly resistant to available treatments. This threat is exemplified by multidrug resistant Klebsiella pneumoniae, resistant to all major front line antibiotic compounds. In fact, the increasing isolation of strains resistant to "last resort" antimicrobials has significantly narrowed, or in some settings completely removed, the therapeutic options. This is particularly alarming in low and middle income countries. Of particular concern is the rise of resistant infections in the community, which can put more people at risk. For example, invasive Klebsiella infections have increased 12% in the UK in the last five years. Unfortunately, new classes of drugs are not being invented and resistance continues to spread inexorably. The stakes are high and we might be entering into a pre-antibiotic era. Public Health England has calculated that the lack of effective antibiotics will render more than the three million operations and cancer treatments life threatening, and more than 90,000 people are estimated to die in the UK over the next 30 years due to antibiotic resistant infections.An attractive appraoch to develop new antimicrobial therapeutics is to boost protective immune responses that, in fact, protect most people. However this is particularly difficult in the case of Klebsiella infections because still we do not know which of such responses are protective and which ones may benefit the microbe. Moreover, we lack a complete understanding of the strategies deployed by Klebsiella to avoid the attack of our defenses. Microbes such as Klebsiella are fascinating because they have evolved to flourish in our body despite the attack of our immune system. By learning how they do it, we can identify the vulnerable hot spots of our defenses while discovering the intricacies of the interaction between our body and a microbe. In this research, we will expose a hitherto unknown Klebsiella evasion strategy directed to counteract the microbicidal function of macrophages. These cells are crucial in our protection against Klebsiella. To turn the tide on Klebsiella infections, we will investigate whether blocking this evasion strategy will help our defenses to clear the infection. Interference with the signalling pathways hijacked by microbes for their own benefit is an especially compelling approach to treat multidrug infections. It is thought that this strategy apply less selective pressure for the development of resistance than traditional antimicrobial therapeutics, which are aimed at killing microbes or preventing their growth. In our work we will use a drug already approved for use in humans targeting the proteins manipulated by Klebsiella but used for purposes unrelated to antimicrobial activity. From the drug discovery point of view, this significantly short cuts the drug development process hence allowing a potential fast-track transition from the basic research to clinical development. We envision that our results will encourage other academics as well as pharmaceutical companies to follow this avenue of research to tackle the problem of lack of therapies for microbes resistant to antibiotics.