Impact of hypermutable sequences on microbial elicitation and evasion of host immune responses

Non-typeable Haemophilus influenzae (NTHi) cause multiple human diseases including otitis media, the commonest bacterial infection in children. This disease involves influxes of host immune modulators into the middle ear in response to bacterial infection1. Infections are often chronic due to poor antibiotic efficacy and ineffective immune responses. Multiple genes of NTHi undergo phase variation (PV) mediated by mutations in repetitive simple sequence DNA tracts. PV changes the expression of virulence determinants, such as lipopolysaccharide epitopes and iron-binding proteins, and allows the bacteria to evade or manipulate host immune responses2.
This project aims to determine how PV controls elicitation of host immune responses, survival of killing by immune effectors and induction of disease symptoms. The project will involve PCR-based analysis of repetitive DNA to monitor PV; engineering of mutant strains; assaying disease phenotypes in infection models such as interaction of bacteria with immune and epithelial cells and infections in mouse models of otitis media.

Cross-institutional supervision will provide a comprehensive training opportunity across multiple institutions; bacterial genetic research undertaken with Dr. Chris Bayliss at the University of Leicester; experimental models of infection with Dr. Derek Hood at MRC Harwell; and immunological assays with Dr. Luisa Martinez-Pomares at the University of Nottingham.