Klebsiella anti-immunology: exploiting proteins with a eukaryotic SEFIR domain

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Our struggle against infectious diseases is far from over. Globalization has increased the risk of pandemics, and the rise of antibiotic-resistant microbes threatens to render existing drugs useless. 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. Of particular concern is the mounting prevalence of respiratory infections caused by Gram-negative bacteria, in particular Klebsiella pneumoniae (the focus of this project), with a 12% increased in incidence in the last five years only in the UK.This is particularly alarming given the high rates of resistance to empirical antibiotics commonly recommended for Klebsiella treatment. 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. Not surprisingly, this pathogen has been singled out as an "urgent threat to human health" by the UK Government, the U.S. Centers for Disease Control and Prevention, and the World Health Organization due to extremely drug resistant strains. 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. Worryingly, recent studies have alerted 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 across the disciplines of molecular and cellular microbiology, immunology and biochemsitry of the Bengoechea, Moynagh and Schroeder laboratories, we will uncover a hitherto unknown Klebsiella immune evasion strategy directed to blunt IL17-governed host defenses, which have been shown to be essential for the clearance of Klebsiella infections. Our research will reveal that this immune evasion strategy also attenuates host defense signalling launched upon activation of the receptors implicated in sensing infections. Collectively, this proposal will shed new light into the sophisticated means exploited by pathogens to overcome host defenses while opening new opportunities to develop 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.