Establishing the role of pathogenetic mechanisms in the evolution of epidemic K. pneumoniae lineages.

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Phylogenomic-Analyses of Epidemic lineages of KP. Using existing genome sequences, we will undertake a population level genomic and phylogenetic analyses of RamR mutations in different epidemic and ST15 lineages with temporal and geographic data to identify (i) additional mutational events (ii) emerging epidemic sub-lineages with advantageous mutations and (iii) map the potential drivers of mutational events. Undertake comparative genomics of the RamA regulon in ST15 and non-ST15 epidemic lineages. Using data derived from the bioinformatic analyses, we will identify the relevant strains to undertake established transcriptomic and ChIP-seq based analyses, to ascertain the DTP Precision Medicine Project Call 21/22 Page 3 of 4 regulatory cascade and binding interactions of RamA. This data will be critical in defining the regulatory impact of RamA and facilitate mechanistic analyses of how these changes host-pathogen interactions in the ST15 epidemic lineage. Establish the infection dynamics of ST15 (RamA overexpressed) and ST15R (RamA overexpression is repaired using genetic manipulation) in specific murine models which mimic systemic infection. Using the murine model of infection, in addition to assessing the viability of these strains in the presence of antibiotics, we will establish the immune checkpoints which are relevant to counter the infection of ST15 and ST15R variants. These data will be utilized in collaboration with Prof. David Dockrell in existing SHIELD consortium screens to establish innate immune responses as tools for diagnosis or treatment of KPN infection.