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

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.

Successful elimination of infections by the innate immune system is crucially dependent on the activation of germline-encoded pattern-recognition receptors (PRRs) that survey both the extracellular and intracellular space for signatures of infection. This proposal will expose a remarkable immune evasion strategy by a human pathogen based on co-opting cellular functions dedicated to control immune balance. By exploiting the power of cellular microbiology with in vivo models, we will embark on harnessing fundamental knowledge about how Klebsiella pneumoniae avoids immune control by exploiting PRR regulators and the immunosuppressive effects of type I IFN. K. pneumoniae has been recently 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. Despite its clinical relevance, our understanding of K. pneumoniae pathogenesis contains considerable gaps thereby making a compelling case to better understand its infection biology to design new strategies to treat Klebsiella infections.This proposal capitalizes on a decade of studies on K. pneumoniae infection biology and innate immune signaling by Bengoechea and Bowie laboratories' and will provide novel mechanistic insights into (i) inflammasome activation, (ii) DNA sensing in bacterial infections, and (iii) immunosupressive properties of type I IFN promoting virulence (reprogramming of epigenome, avoiding cell-autonomous immunity). Altogether, our research will place Klebsiella as a true cell biologist manipulating all aspects of cell function to overcome immune responses. The findings of this proposal may serve as the foundation for novel therapeutic and prevention strategies based on enhancing innate host resistance to infection, and ameliorating pathophysiological tissue destruction.

Who will benefit from this research? Academics will be the main short to medium term beneficiary, as the research will provide knowledge to understand how pathogens counteract the activation of host defenses. This is one of the most competitive areas of research in the field of microbial pathogenesis and immunology. The main collaborative interactions will be with Prof Philippe J. Sansonetti (Institut Pasteur) on Klebsiella infection biology; and Prof Kate Fitzgerald (UMass Medical School) on innate immune signalling. However we anticipate exciting new collaborations with groups focusing on type I IFN. The research will enhance the career development of the requested PDRAs. They will receive training in some of the most novel aspects of host-pathogen interactions with emphasis on innate immune signaling. Industry: The growing number of organisms resistant to available antibiotics has become a public health threat worldwide, being Klebsiella a paradigm of an emerging pathogen. There is a need to develop effective therapeutics based on new targets and approaches. There are already drugs under development targeting the signalling pathways manipulated by Klebsiella which can be tested in our pre-clinical infection models. This will allow a fast-track transition from the basic research to clinical development. Public bodies: The UK Government is committed to taking an integrated approach to tackle the antimicrobial resistance challenge as part of the one health agenda at a national and international level. This proposal is aligned with the strategic action "supporting the development of new antimicrobials and alternative treatments" outline in the UK antimicrobial resistance strategy 2013- 2018. General public: Infections are one of the major global threats that are unfortunately very likely to become more urgent in the near future. It is not appropriate to generate an atmosphere of fear since medical care in UK is at a very high level. However, it is advisable to increase public awareness about the potential threats and to provide the UK national regulatory bodies, with a top-class knowledge platform to maintain the unique position of UK as an area of research excellence on infection biology.
How will they benefit from this research?: Knowledge of value to the academic sector will be communicated by publication in peer-reviewed journals, oral and poster presentations at conferences and via invited lectures. Exchange of staff and students will promote knowledge transfer between collaborative groups. Staff working on the project will receive training on complementary skills (group management, know-how transfer, and entrepreneurship) which together with the cutting-edge research training received will give the PDRAs all options for either an excellent career in academia, industry, or to develop a business plan for their own start-up enterprise. Knowledge transfer to industry on new therapeutics to treat infections might have economic potential since royalty payments can reach numbers in the magnitude of several millions or tens of millions. This new treatment(s) will benefit the UK health system. The grant will have impact on the wider public sector by continuing our program of scientific communication. Bengoechea and Bowie laboratories host undergraduates (summer students) to engage them in the fundamentals of scientific research. Social media will be targeted via Twitter (@josebengoechea). Queen's University Belfast, Trinity College Dublin, and the Bengoechea and Bowie web pages will be additional channels to promote this BBSRC-SFI-funded research. Queen's and Trinity produce regularly videos (Bowie, https://www.tcd.ie/Biochemistry/assets/mp4/ABowie.mp4; Bengoechea https://www.youtube.com/watch?v=H2kaBs9IPzg) to showcase the impact of the research done.