Klebsiella pneumoniae type VI secretion system: a weapon for innate immunity warfare

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The global problem of antimicrobial resistance (AMR) is fast becoming one of the major scientific and health issues of modern times. No surprisingly, AMR is included in the recently release UK government "National Risk Register of Civil Emergencies" that may directly affect the UK over the next 5 years. More than 80,000 deaths are estimated if there is a widespread outbreak of a resistant microbe. The development of new antibiotics is slow and difficult work but bacterial resistance is decreasing our arsenal of existing drugs. A post-antibiotic era - in which common infections and minor injuries can kill - far from being an apocalyptic fantasy, is a very real possibility for the 21st Century. The recent O'Neill review on AMR sets out the global threat by highliting that "drug-resistant infections already kill hundreds of thousands a year globally, and by 2050 that figure could be more than 10 million". Of particular concern is the mounting prevalence of infections caused by multidrug resistant Gram-negative bacteria, in particular Klebsiella pneumoniae. 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. However, there is scant evidence on K. pneumoniae pathogenesis at the molecular and cellular level. Therefore, it is both urgent and necessary to better understand its pathophysiology to be able to design new strategies to treat Klebsiella infections.Previous studies from the laboratory support the notion that Klebsiella subverts the activation of host defence mechanisms to survive in the lung. While we have progressed on understanding the cellular pathways manipulated by the pathogen to block inflammation, there is a major gap on decoding the anti-immune factors employed by Klebsiella. By applying a multidisciplinar approach encompassing cellular and molecular microbiology, innate immunity, structural bioinformatics; and exploiting Saccharomyces cerevisiae to express heterologous proteins, we will embark on harnessing basic knowledge about how Klebsiella pneumoniae type VI secretion system (T6SS)-delivered effectors block the activation of cell intrinsic immunity. T6SS is a recently discovered nanomachinery that bacteria use to deliver proteins to a recipient cell (either a competitor bacteria and/or an eukaryotic cell). We will characterize Klebsiella T6SS at the molecular level. We will dissect how T66S-delivered proteins antagonize the activation of the signalling pathway controlling the majority of host defense responses upon infection. And, finally, we will illuminate a hithertho unknown Klebsiella virulence strategy based on targeting mitochondrial dynamics.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. It is therefore believed that such targets - if found and validated during the research - will meet big interest at pharmaceutical companies.