Subversion of pathogen recognition receptors (PRRs) spactial-temporal localization by microbila proteins to moderate innate immune signalling cascades

Outline, including interdisciplinary dimension

Respiratory infections are the leading cause of infectious disease mortality and morbidity in world wide. 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). This is particularly alarming given the high rates of resistance to empirical antibiotics commonly recommended for Klebsiella treatment. 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.

A better understanding of Klebsiella-host interface will provide opportunities to perturbate this interaction in order to enhance innate host resistance to infection, ameliorate pathophysiological tissue destruction, and reduce the development of antibiotic resistance. However, there is scant evidence on K. pneumoniae pathogenesis at the molecular and cellular levels. Therefore, it is both urgent and necessary to better understand its pathophysiology to be able to design new strategies to treat Klebsiella infections.

Over the last decade, the Bengoechea laboratory has made significant contributions to the understanding of Klebsiella pathogenesis. This proposal builds up upon a landmark study of the Bengoechea laboratory demonstrating that K. pneumoniae persists intracellularly in human and mouse macrophages within a unique compartment. In this PhD project, we will exploit this expertise to address what we believe is among the most fundamental questions in K. pneumoniae biology, namely how the pathogen undermines macrophage signalling to enhance its own survival whilst avoiding immune control. By bridging cellular and molecular microbiology, and immunology and by using state-of-the-art single cell imagining analysis and transcriptomics we will pursue the following objectives:

1-. To detail how K. pneumoniae subverts macrophage signalling toward and anti-inflammatory phenotype

2-. To identify K. pneumoniae factors required for manipulating macrophage signalling.

Altogether, the study of Klebsiella infection biology offers unique opportunities to gain fundamental knowledge about mechanisms by which a pathogen overcomes innate immune mechanisms. The studies proposed in this PhD project may serve as the foundation for novel therapeutic and prevention strategies targeting the host-pathogen interface.

Key words/descriptors

receptors sensing infections, bacterial effector proteins

First supervisor

Professor Jose Bengoechea - School of Medicine, Dentistry and Biomedical Sciences