Klebsiella pneumoniae T6SS: a weapon for trans kingdom warfare

12 September 2019

Quadram Institute

Speaker: Professor Jose Bengoechea

Hosted by: Prof. Mark Pallen

Abstract: Klebsiella pneumoniae is recognized as an urgent threat to human health due to the increasing isolation of multidrug resistant strains. Hypervirulent strains are a major concern due to their ability to cause life-threating infections in healthy hosts. The type VI secretion system (T6SS) is widely implicated in microbial antagonism, and it mediates interactions with host eukaryotic cells in some cases. In this talk I will summarize our recent efforts to characterize the contribution of the T6SS to Klebsiella infection biology. In silico search for genes orthologous to T6SS component genes and T6SS effector genes across 700 K. pneumoniae genomes shows extensive diversity in T6SS genes across the K. pneumoniae  species. Temperature, oxygen tension, pH, osmolarity, iron levels, and NaCl regulate the expression of the T6SS encoded by a hypervirulent K. pneumoniae strain.  Polymyxins and human defensin 3 also increase the activity of the T6SS. A screen for regulators governing T6SS uncover the correlation between the transcription of the T6SS and the ability to kill E. coli prey. Whereas HN-S represses the T6SS, PhoPQ, PmrAB, Hfq, Fur, RpoS and RpoN positively regulate the T6SS. K. pneumoniae T6SS mediates intra and inter species bacterial competition. This antagonism is only evident when the prey possess an active T6SS. The PhoPQ two component system governs the activation of K. pneumoniae T6SS in bacterial competitions. Mechanistically, PhoQ periplasmic domain, and the acid patch within, is essential to activate K. pneumoniae T6SS. Klebsiella T6SS also mediates anti-fungal competition. We have delineated the contribution of each of the individual VgrGs in microbial competition, and identified VgrG4 as a T6SS effector. Structurally, domain DUF2345 of VgrG4 is sufficient to intoxicate bacteria and yeast. ROS generation mediates the antibacterial effects of VgrG4, and the antitoxin Sel1E protects against the toxic activity of VgrG4. Our findings provide a better understanding of the regulation of the T6SS in bacterial competitions, and place ROS as an early event in microbial competition.

Biography:  Prof Bengoechea completed his degree in Biology and acquired further specialisation in Microbiology in the University of Navarra (Pamplona, Spain) during his PhD. In 1998, he took a postdoc position in the laboratory of Prof Mikael Skurnik (Turku, Finland) to receive advanced training on molecular microbiology. In 2002, after obtaining a “Miguel Servet” tenure-track contract, funded by the Spanish Ministry of Health, Prof Bengoechea started his independent research career at University Hospital Son Dureta (Palma de Mallorca, Spain) focusing on respiratory infections caused by Klebsiella. In 2007, he earned a tenure position in the Spanish Research Council (CSIC). Prof Bengoechea joined Queen’s University Belfast in July 2013, as Professor of Molecular Microbiology and he is currently the Director of the Wellcome-Wolfson Institute for Experimental Medicine. This flagship £32 m research Institute of Queen’s is a multidisciplinary centre housing  44 principal investigators to deliver excellent discovery science bridging clinical and fundamental research to tackle major global health problems (diabetic complications –eye and cardiovascular disease-, lung inflammatory diseases –asthma, COPD, CF, acute respiratory distress syndrome-, antibiotic resistance).

Prof Bengoechea research programme is strongly supported by UK national agencies (BBSRc and MRC), and the EU. He has recently been awarded an MRC research grant to run the first-in-kind host-directed therapeutics approach agiainst Klebsiella infections. Prof Bengoechea has also provided leadership and strategic direction to large multidisciplinary EU consortia aiming to identify new antimicrobials using “omics” approaches, which have been recognized by the EU as successful research projects due to the translational outcomes.