PhD Research Project: How does antibody increase the severity of bacterial infections?

Chronic and recurrent infections represent a failure of the immune system to protect against the infecting organism. Recent work in our laboratory focused on patients with the respiratory disease Bronchiectasis. Many of these patients become infected with Pseudomonas aeruginosa, leading to increased morbidity and mortality. We identified that ~20% of patients with bronchiectasis and chronic P. aeruginosa infection had excess IgG2 specific to the bacterium. This antibody recognised the O-antigen of LPS. In contrast to the serum bactericidal effects normally associated with antibody, this IgG2 inhibited killing of the infecting strain. Importantly, patients with inhibitory antibodies had worse lung disease. Subsequently, we used plasmapheresis to treat two critically ill patients with chronic P. aeruginosa infections; plasmapheresis removes antibodies from the circulatory system. Both patients had severe bronchiectasis with significant morbidity, did not respond to antibiotics, were hospitalised and were unsuitable for lung transplant. After treatment both patients reported greater independence and mobility than at any point in the previous 2 years, required fewer days in hospital and had a much reduced dependency on antibiotics. This is the first description of antibody-mediated exacerbation of bacterial infections.

Several other studies have hinted at a role for antibody in chronic and recurrent bacterial infections. We have several projects exploring the role of antibody in exacerbating infections e.g. Burkholderia, E. coli, Haemophilus, Mycobacterium and Neisseria gonorrhoeae.
At the University of Birmingham, Institute of Microbiology and Infection, you will be part of a vibrant and lively postgraduate community and one of the world-leading institutes for microbiological and infectious disease research.

Person Specification
If you are an enthusiastic scientist with an interest in host-pathogen interactions, looking for a PhD position, we would be happy to hear from you. A background in immunology, microbiology or molecular genetics would be helpful. An enthusiastic approach to science, together with the ability to take ownership of your own project within a young, dynamic research team, is essential. You should have a commitment to academic research and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

How to apply
Informal enquiries should be directed to Prof. Ian Henderson
Applications should be directed to Ian Henderson (email i.r.henderson@bham.ac.uk). To apply, please send:
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable;
• All applicants should indicate in their applications how they intend to fund their studies.

Funding notes:
We have a thriving community of international PhD students and encourage applications at any time from students able to find their own funding or who wish to apply for their own funding (e.g. Commonwealth Scholarship, Islamic Development Bank).

The Institute of Microbiology and Infection offers a number of UK Research Council (http://www2.warwick.ac.uk/fac/cross_fac/mibtp/; http://www.birmingham.ac.uk/schools/mds-graduate-school/scholarships/mrc-impact/index.aspx) PhD studentships each year and studentships funded by Wellcome (http://www.birmingham.ac.uk/schools/mds-graduate-school/wellcome-aamr/index.aspx; http://www.birmingham.ac.uk/schools/mds-graduate-school/scholarships/wellcome.aspx). Fully-funded research council studentships are normally only available to UK nationals (or EU nationals resident in the UK) but part-funded studentships may be available to EU applicants resident outside of the UK. The deadline for applications for research council and Wellcome studentships is in January each year.

Each year we also have a number of fully funded Darwin Trust Scholarships (http://www.birmingham.ac.uk/postgraduate/funding/darwin-studentships.aspx). These are provided by the Darwin Trust of Edinburgh and are for non-UK students wishing to undertake a PhD in the general area of Molecular Microbiology. The deadline for this scheme is also in January each year.

Please note the only funding available for this PhD is via the Scholarships mentioned.

Funding Notes

Please see three funding options in the project description above.

References

Timothy J. Wells, John Davison, Emma Sheehan, Suren Kanagasundaram, Calman A. MacLennan, Robert A. Stockley, Adam F. Cunningham, Ian R. Henderson, Anthony De Soyza. The use of plasmapheresis in patients with bronchiectasis with Pseudomonas infection and inhibitory antibodies. AJRCCM. 2017.

Timothy J. Wells, Deborah Whitters, Yanina R. Sevastsyanovich, Jennifer N. Heath, John Pravin, Margaret Goodall, Douglas F. Browning, Matthew K. O’Shea, Amy Cranston, Anthony De Soyza, Adam F. Cunningham, Calman A. MacLennan, Ian R. Henderson, Robert A. Stockley. Increased severity of respiratory infections associated with elevated anti-LPS IgG2 which inhibits serum bactericidal killing. J Exp Med. 2014 211: 1893–1904.

Calman A. MacLennan, James J. Gilchrist, Melita A. Gordon, Adam F. Cunningham, Mark Cobbold, Margaret Goodall, Robert A. Kingsley, Joep J. G. van Oosterhout, Chisomo L. Msefula, Wilson L. Mandala, Denisse L. Leyton, Jennifer L. Marshall, Esther N. Gondwe, Saeeda Bobat, Constantino López-Macías, Rainer Doffinger, Ian R. Henderson, Eduard E. Zijlstra, Gordon Dougan, Mark T. Drayson, Ian C. M. MacLennan, Malcolm E. Molyneux. Dysregulated humoral immunity to nontyphoidal Salmonella in HIV-infected African adults. Science. 2010 328: 508–512.