Bilateral BBSRC-SFI Innate immune signalling underpinning Klebsiella-host interactions

点击翻译按钮获取中文摘要

Our struggle against infectious diseases is far from over. Globalisation has increased the risk of pandemics, and the rise of antibiotic-resistant microbes threatens to render existing drugs useless. Of particular concern is the health burden of respiratory infections being the UK in the top 25 countries for deaths from acute respiratory infections, above most other European countries. It is therefore urgent and necessary to develop new therapeutics based on new concepts and approaches. This is particularly important in the case of Klebsiella infections showing a 12% increased incidence over the last five years within the UK alone. In fact, the increasing isolation of strains resistant to "last resort" antimicrobials has significantly narrowed, or in some settings completely removed, the therapeutic options for the treatment of Klebsiella infections. Unfortunately, at present, we cannot identify candidate compounds in late-stage development for treatment of multidrug Klebsiella infections; this pathogen is exemplary of the mismatch between unmet medical needs and the current antimicrobial research and development pipeline. Alarmingly, recent studies have recognized that several Klebsiella virulent and multidrug resistant isolates have access to a mobile pool of virulence and antimicrobial resistance genes; hence making possible the emergence of a multidrug resistant, hypervirulent K. pneumoniae isolate capable of causing untreatable infections in healthy individuals. However, our understanding of Klebsiella pathogenesis still contains considerable gaps thereby making a compelling case to better understand Klebsiella infection biology in the context of the complex interactions between bacterial pathogens and their hosts.In this proposal, by combining the distinct but synergistic expertise and experience across the disciplines of molecular and cellular microbiology, biochemistry, and immunology, of the Bengoechea (UK) and Bowie (Ireland) laboratories we will better understand the various Achilles heels of host defense, and thereby more precisely shore-up these vulnerable hot spots while deconstructing the strategies used by Klebsiella to survive within the infected tissue. Our efforts will expose a Klebsiella anti-immune strategy based on co-opting functions (receptors and immune signals) implicated in antimicrobial defense. This remarkable strategy is radically different to those employ by other well studied bacterial pathogens which disrupt host defenses instead of hijacking them like Klebsiella. Harnessing the host-pathogen interface opens the avenue for new antimicrobial therapeutics. Interference with pathogen virulence and/or signalling pathways hijacked by pathogens for their own benefit is an especially compelling approach, as it is thought to apply less selective pressure for the development of resistance than traditional strategies, which are aimed at killing pathogens or preventing their growth. There is extensive research on the pathways targeted by Klebsiella, and new drugs are currently under development. We anticipate that the outcomes of this proposal would lead to test these drugs in pre-clinical models of klebsiella disease hence allowing a potential fast-track transition from the basic research to clinical development.