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.

Pneumonias due to multiple-drug resistant pathogens are an important public health problem and are major causes of morbidity and mortality worldwide. Of particular concern are the infections caused by Klebsiella pneumoniae. The isolation of Klebsiella strains resistant to "last resort" antimicrobials has significantly narrowed, or in some settings completely removed, the therapeutic options for the treatment of Klebsiella infections. Not surprisingly, K. pneumoniae has been singled out by the World Health Organization as an "urgent threat to human health" due to multidrug resistant strains. Less obvious, but central to pathogenesis, are the adaptations to the human immune system. However, our knowledge of the interface between Klebsiella and these pathways is still elementary, as it is our understanding of which of such responses benefit the host versus the pathogen. In this project, we will expose a Klebsiella immune evasion strategy based on hijacking the immunomodulatory functions of the cell master regulator mTORC1. We will use a multidisciplinary approach leveraging the power of biochemistry, cellular microbiology, proteomics and in vivo models. We will detail the signalling pathway exploited by Klebsiella to activate mTORC1, uncover how Klebsiella manipulates the localization of mTORC1 to the Klebsiella containing vacuole, identify the Klebsiella factors involved in mTORC1 activation, and dissect the effect of mTORC1 on Klebsiella infection biology. Finally, we also set out to provide compelling experimental pre-clinical evidence for host-directed therapeutics targeting this "covert" Klebsiella strategy. Altogether, this project will uncover a new angle of Klebsiella adaptations to survive in what should be a hostile environment. The findings of this project shall be the foundation for novel therapeutics based on enhancing innate host resistance to infection, and ameliorating pathophysiological tissue destruction.