Macrophage sabotage: undermining macrophage signalling by Klebsiella pneumoniae

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Respiratory infections are the leading cause of infectious disease mortality and morbidity in UK, affecting roughly 1% of the adult population per year. This health burden is increasing due to ageing of the population, growing numbers of immunosuppressed patients and multidrug-resistant microorganisms. 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. 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. Furthermore, there is still scant evidence on K. pneumoniae pathogenesis at the molecular and cellular level. The development of new therapeutic strategies requires a better understanding of K. pneumoniae pathophysiology in the context of the complex interactions between bacterial pathogens and their hosts.Macrophages have been at the heart of immune research for over a century and are an integral component of innate immunity. Not surprisingly, macrophages also play a critical role in the clearance of K. pneumoniae in vivo. However, in a landmark contribution of the laboratory we have discovered that K. pneumoniae survives inside macrophages hence suggesting that Klebsiella may exploit macrophages to enhance its survival while avoiding immune control. In this project, by bridging cellular microbiology and immunology, we will gain holistic understanding of the strategies used by K. pneumoniae to manipulate macrophages to survive during pneumonia. Furthermore, and by building up upon this knowledge platform, we also set out to provide evidence demonstrating that antagonism of this virulence strategy will favour pathogen clearance. 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 are already drugs approved for use in humans which may target this Klebsiella virulence strategy. From the drug discovery point of view, this significantly circumvents the drug development process hence allowing a potential fast-track transition from the basic research to clinical development. Altogether, 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.