Functional antimicrobial resistance during complex interactions of microbial cells with the human host (Complex Diseases: Cells to Systems)

Aims: This project builds on our complimentary expertise on the three main bacterial pathogens involved in antimicrobial drug resistance (AMR) and the infections of otitis media (the most common reason for antibiotic prescription in children), meningitis and sepsis (pathologies with the highest mortality in children). The main aim of the project is to create a strong training program for a PhD student interlinking MRC projects on phase variation in Streptococcus and Neisseria in Leicester to on-going work at MRC Harwell on non-typeable Haemophilus influenzae; an ideal setup to investigate common underlying mechanisms that drive key events in multiple disease processes. The scientific aims would be to target common patterns in the infection models leading to functional antimicrobial resistance, a topic highlighted in the e IMPACT strategy document and also flagged up as a key involvement of the UK government in its effort to slow the growth of AMR (HMGovernment_2014).

Background: AMR is a world-wide health challenge and has been recently identified as one of the four Priority Challenges of the MRC. Across our groups we have generated detailed information on specific events during the pathogenesis of infection such as population bottlenecks, phase variation, biofilm formation and host immune responses. Not only do all of these processes impact the dynamics of infection but also on the development of functional resistance to antimicrobial therapy. AMR is a highly complex phenotype including host components and multiple aspects of microbial life including phase variation (Alamro_2014; Manso_2014; Oldfield_2013), population dynamics of selection (Gerlini_2014) and growth related phenotypes such as biofilm or intracellular growth (Trappetti_2015). All these aspects are largely ignored by normal in vitro testing but are reflected in the treatment failures associated with many bacterial infections. We now have models that give detailed insight into specific steps of the pathogenesis of infection and thus allow testing of specific hypotheses linked to potential treatment failures such as intracellular stages preceding sepsis or biofilm formation. The identification of the underlying mechanisms in the complexity in cause and consequences in infectious disease are predicted to give the project a strong case for producing innovation in treatment strategies.

Hypothesis: The central hypothesis of this proposal is that we will overcome functional AMR associated to treatment failure by targeting precise events in pathogenesis.

Experimental Methods: The student will test the hypothesis using experimental infection models of otitis media at Harwell (Jenkins_2010) and sepsis at Leicester (Gerlini_2014) and a large panel of complementary in vitro studies. Improved treatment strategies with antibiotics, peptides and bacteriophages will be investigated. Biofilms (Trappetti_2015) and intracellular replication (Gerlini_2014) will be the specific aspects addressed to solve functional AMR. The student will use multiple methodologies to complement the experimental infection work including; drug-susceptibility-testing, confocal microscopy and gene expression profiling (Oggioni_2015; Trappetti_2015; Manso_2014). The student will receive training in bioinformatics and programming to analyse high throughput sequencing data. The student will undertake interdisciplinary work as part of our on-going collaboration with the Leicester Mathematics department which aims to develop theoretical models of how the complex host-pathogen interactions may impact AMR (Manso_2014; Palmer_2013). Given the expertise, the details of the experimental plan and the precise nature of events to be tested, we envisage that the project will have a real impact on treatment strategies, potentially saving life and reducing health care costs.
The variety of cutting edge technologies ranging from phenotypes to genomics make this interdisciplinary project on the edge between