The burden of influenza infection lies disproportionately with over-65s, who may develop serious complications and even die of infection. This issue is compounded by traditionally poor vaccine efficacy in this age group. In addition, due to rapid influenza virus evolution, vaccines need to be re-formulated and re-administered most years at significant cost. This provides a significant challenge to getting the right vaccine to the right age-group. Antivirals are available, but resistance is emerging. An attractive alternative is to target the host innate immune response, either to reduce morbidity associated with inflammatory tissue damage, or to enhance the adaptive immune response to vaccines. This project seeks to understand how innate immune mechanisms modulate influenza virus infection and how these may be harnessed to develop novel therapeutic interventions.
The host protein, glycoprotein nonmetastatic melanoma protein B (GPNMB), is expressed in macrophages and negatively regulates their pro-inflammatory functions. Based on preliminary data generated in the supervisors’ laboratories, this project will test the hypothesise that, in the absence of GPNMB, a robust macrophage response leads to rapid clearance of the virus, but also rapid contraction of the T cell response, compromising development of immunological memory. This will be achieved through the following specific objectives:
(1) Assess age-related changes in GPNMB expression and function in macrophages. This will allow us to determine if age-related alterations to the GPNMB pathway underlie susceptibility to influenza infection.
(2) Assess the influence of GPNMB on morbidity, tissue damage, and tissue repair following influenza virus infection.
(3) Assess how GPNMB influences the generation of adaptive immune responses to influenza virus infection, and whether it has adjuvant effects that could be used to improve the efficacy of influenza vaccination.
The student will receive extensive training in in vivo infection models, multi-parameter flow cytometry, two-photon imaging, and functional analysis of immune cell populations.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website: http://www.dimen.org.uk/
Coombes JL, Han SJ, van Rooijen N, Raulet DH, Robey EA (2012). Infection- induced regulation of natural killer cells by macrophages and collagen at the lymph node subcapsular sinus. Cell Rep. 2(1):124-35.
Akram KM, Moyo NA, Leeming GH, Bingle L, Jasim S, Hussain S, Schorlemmer A, Kipar A, Digard P, Tripp RA, Shohet RV, Bingle CD and Stewart JP (2018). An innate defense peptide BPIFA1/SPLUNC1 restricts influenza A virus infection. Mucosal Immunology. 11:71-81.
Ripoll VM, Irvine KM, Ravasi T, Sweet MJ and Hume DA (2007). Gpnmb Is Induced in Macrophages by IFN-γ and Lipopolysaccharide and Acts as a Feedback Regulator of Proinflammatory Responses. J Immunol. 178 (10):6557-6566.