The individualised innate immune response in CF infection: increasing fundamental understanding and identification of bacterial biomarkers of inflammation.

A 3 year fully funded PhD studentship starting October 2018 as part of a new Cystic Fibrosis Trust- funded Strategic Research Centre at Imperial.

PhD with Dr Huw Williams (Life Sciences) and Prof Jane Davies (Medicine) Imperial College London. ([Email Address Removed] ).

The individualised innate immune response in CF infection: increasing fundamental understanding and identification of bacterial biomarkers of inflammation.

Hypochlorous acid (HOCL) produced by neutrophil myeloperoxidase (MPO) and hypothiocyanous acid (HOSCN) by the DUOX/LPO system of the airway epithelium are potent antibacterial products of the innate immune system (Odobasic et al., 2016). However, in Cystic Fibrosis prolonged neutrophil recruitment fails to resolve infection leading to a damaging inflammatory cycle and progressive lung damage, in part due to the action of these thiol reactive oxidants (Williams & Davies, 2012, Winterbourn et al., 2016).

Inflammatory biomarkers could play a critical role in the development of anti-inflammatory therapies and reflect downstream improvements in CF-lung disease for individualised disease-modifying treatments (Muhlebach et al., 2016), but recent interventional trials fail to show significant changes in sputum inflammatory markers (Muhlebach et al., 2016, Horsley et al., 2013). We hypothesise that infecting bacteria, such as P. aeruginosa, will produce bacterial biomarkers that will be indicators of the innate immune activity encountered in the CF lung.

Building on preliminary work, this PhD will: (i) identify and validate redox-specific bacterial biomarkers based on gene expression and/or redox-proteomics-based analyses of the response of P. aeruginosa to HOCL and HOSCN, (ii) use redox biomarkers to address key questions in Cystic Fibrosis infection biology, and (iii) elucidate HOCl and HOSCN- specific protection and repair mechanisms in this opportunistic pathogen.

Experimental approaches: The project will involve some/all of the following experimental approaches: gene expression studies using qRT-PCR and RNA-seq, quantitative mass spectrometry-based proteomics, cell biology work with neutrophils, air- liquid interface cultures and patient samples, bacterial molecular genetics and biochemistry.

Who should apply: This PhD will suit a student with a BSc degree at 2:1 level or better and a Masters degree, at Merit level or better, in Biochemistry, Biological Sciences or related discipline with interests in studying oxidative stress damage and protection mechanisms in a clinically important context. Exceptional applicants without a Masters degree might be considered.

The deadline for applications is 4th June 2018 and candidates should submit a full CV and the names and contact details of 2 academic referees to Dr Huw Williams ([Email Address Removed]) by the deadline.