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

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.