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• genetics, genomics and molecular biology
• infectious disease and the immune system

• Medicine

• Infectious diseases
• Immunology
• Respiratory Medicine

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. This is particularly important in the case of Klebsiella pneumoniae 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 Therefore, it is an urgent priority to develop effective therapeutics based on new targets and concepts. Amazingly, and despite its clinical relevance, our understanding of K. pneumoniae infection biology contains considerable gaps. Rising to this challenge, the focus of the Bengoechea laboratory is to improve the understanding of the Klebsiella-host interface and use this knowledge to develop new therapeutics which enhance innate host resistance to infection and ameliorate pathophysiological tissue destruction. The Bengoechea laboratory has established a unique reputation in the study of K. pneumoniae infection biology and have made seminal contributions to the understanding of its pathogenesis. The field currently accepts that the virulence strategy of Klebsiella is to evade many components of the immune system. This paradigm is in no small part due to research outputs from the laboratory. Our research endevours are leading to the development of antimicrobial therapies based on the modulation of the host-pathogen interface by targeting host factors manipulated by the pathogen for its own benefit (host directed therapeutics).

Klebsiella pneumoniae has been singled out as an "urgent threat to human health" due to drug resistant strains. New effective therapeutics based on new targets/concepts are urgently needed. This clinical PhD project rises to this challenge by improving our understanding of Klebsiella infection biology in the context of the interactions between bacterial pathogens and the immune system. A better understanding of the host-pathogen interactions offers the potential for pharmacological intervention by targeting the strategies employed by pathogens to manipulate for their own benefit early innate immune responses. Host targeted drugs are less likely to engender resistance compared to conventional antibiotics and may decrease the development of resistance against co-administered drugs. This project aims to demonstrate that therapeutic antagonism of the host factors targeted by K. pneumoniae to prevent the activation of host defence responses will favour pathogen clearance. The Bengoechea laboratory has demonstrated that Klebsiella
targets EGF receptor to control host defence responses. These findings also support the therapeutic potential of blocking EGFR to limit pathogen survival. This proposal will pursue ambitious questions at the forefront of research in infection biology: (i) to characterize EGFR activation by K. pneumoniae; (ii) to determine the role of EGFR in Klebsiella avoidance of cell-autonomous immunity; and (iii) to provide preclinical rationale for EGFR inhibitors as therapy for K. pneumoniae infections. There are already drugs approved for use in humans targeting EGFR but used for purposes unrelated to antimicrobial activity. From the drug discovery point of view, this significantly short cuts the drug-development process hence allowing a potential fast-track transition from the basic research to clinical development.