TrIFIC: Targeting Immunotherapy for Fungal Infections in Cystic Fibrosis, Medical Sciences – PhD (Funded)
The Strategic Research Centre TrIFIC is funded by the UK Cystic Fibrosis Trust and encompasses a multicentre collaboration between Imperial College London, University of Manchester, University of Massachusetts Medical School (USA), Radboud University Medical Center Nijmegen (NL), and the University of Exeter.
The University of Exeter’s College of Medicine and Health, in partnership with the Cystic Fibrosis Trust, is inviting applications for a fully-funded PhD studentship to commence in October 2019 or as soon as possible thereafter. For eligible students the studentship will cover UK/EU tuition fees plus an annual tax-free stipend of at least £15,009 pa for 3 years full-time, or pro rata for part-time study. The student will be based in the Geoffrey Pope building in the College of Medicine and Health at the Streatham Campus in Exeter.
The mould Aspergillus fumigatus colonises the airways of 50% of adult cystic fibrosis (CF) patients, with 30% developing Aspergillus bronchitis (AB) and 15% allergic broncho-pulmonary aspergillosis (ABPA). This leads to severe airway inflammation, accelerated lung function decline, and invasive infection risk. Currently available anti-fungal drugs are poorly effective, and drug resistance is rapidly emerging, therefore new treatments are urgently required. Immunotherapies are currently revolutionizing clinical medicine and have great potential for re-purposing to treat severe inflammation in CF AB and ABPA. We will undertake the pre-clinical and clinical studies required to identify the key inflammatory pathways that can be safely targeted by immunotherapies in CF AB and ABPA. In parallel, we will develop the required immuno-diagnostic tools required to enable a precision medicine approach that allows the right individual to receive the right immunotherapy for their infection.
The focus of the PhD project is how to target neutrophilic inflammation in Aspergillus bronchitis. Whilst CF is inherently associated with airway neutrophilic inflammation, comparative studies of bacterial and fungal infection in the CF airway have demonstrated that A. fumigatus is associated with a ten-fold increase in neutrophils compared to un-infected CF controls. This was associated with marked airway inflammation characterized by increased neutrophil elastase and IL-8. We have recently shown that increased production of ROS against A. fumigatus by CF neutrophils was associated with an increased number of clinical exacerbations in the previous year and reduced lung function. We will therefore seek to assess the utility of existing neutrophil targeting anti-inflammatories (including acebilustat and an inhaled neutrophil elastase inhibitor) for repurposing in CF AB. We will characterize sputum neutrophil counts, elastase activity, extracellular trap formation and ROS production in our cohort of CF AB patients, in comparison to control patients with Aspergillus colonization or non-fungal disease controls. Sputum levels of acebilustat and neutrophil ROS will be analyzed. In parallel, ROS production from isolated peripheral blood neutrophils will be measured in response to Aspergillus challenge using a newly developed CF neutrophil trans-epithelial migration ex-vivo model.
This award provides annual funding to cover UK/EU tuition fees and a tax-free stipend. For students who pay UK/EU tuition fees the award will cover the tuition fees in full, plus at least £15,009 per year tax-free stipend. Students who pay international tuition fees are eligible to apply, but should note that the award will only provide payment for part of the international tuition fee and no stipend.
The studentship will be awarded on the basis of merit for 3 years of full-time study to commence in October 2019. The collaboration with the named project partner is subject to contract. Please note full details of the project partner’s contribution and involvement with the project is still to be confirmed and may change during the course of contract negotiations. Full details will be confirmed at offer stage.