Kennedy Trust Prize Studentships
Regional humoral immunity in the lung; exploring the function and biology of resident memory B cells in resistance against influenza virus
Influenza virus is a common airborne pathogen that continues to present a significant medical challenge causing over 3 million cases of critical illness and up to 500,000 deaths per annum. Efforts to develop vaccines against influenza have been hampered by the rapid generation of new escape variants each year. To avoid this problem, vaccines aim to induce broadly neutralizing antibodies that target stable epitopes shared by multiple strains. In recent years it has become clear that such antibodies can be induced in many individuals. However, the serum titers measured for such antibodies is too low, likely below the threshold necessary to reach sufficient concentrations at the site of infection to promptly block viral spread. It is therefor tempting to speculate that promoting the production of antibodies directly at the site of viral entry may help to increase the local concentration of neutralizing antibodies and enhance protection. However, the mechanisms that regulate such local B cell responses are poorly understood.
Several studies have shown that during influenza infection local B cell responses can develop and persist in the infected lung itself for prolonged periods of time. The nature of these tissue resident memory B cells and the factors that contribute to their development have been difficult to study, largely due to challenges associated with accurate identification of this rare and elusive cell population. To overcome this limitation, we have recently developed new mouse models allowing permanent fluorescent labeling and monitoring of memory B cells in the lung. Combined with hemagglutinin probes we were able to selectively identify and cell sort influenza-specific B cell subsets from spleen and lung allowing analysis of the unique expression profiles of these cells. Using 2-photon and confocal microscopy, we were also able to visualize memory B cells in live tissues and to study their dynamic behavior before and after re-challenge (unpublished). Together, these approaches provide an excellent platform to explore the function and biology of memory B cells in peripheral tissues. The current project will build on our newly established mouse models, imaging system and RNAseq data to investigate mechanisms that regulate the development and maintenance of long-term humoral immunity in the lung. Findings from these studies will not only help to improve our basic understanding of B cell biology, but may also help in the development of novel vaccines and treatments to chronic diseases that are mediated by locally produced pathogenic antibodies.
Environment and Training
In this project we focus is on mechanisms that regulate the development and function of local memory humoral responses in the lung of influenza-infected mice. However, the broader implications of this work go beyond the specific response to influenza; it aims to understand the unique and understudied biology of resident memory B cells in peripheral sites. It is therefore suitable for a student that has keen interest in basic immunology and is excited about testing conceptual biological questions in vivo using mouse models. The project will involve a variety of methods with a combination of advance imaging techniques and functional genomic approaches (such as RNA-Seq, ATAC-Seq, ChIP-Seq). This is a highly creative and innovative project, so a suitable student must be the kind that is motivated by challenges and cutting edge science. Interested candidates are encouraged to contact Dr. Tal Arnon by email directly.
- Reboldi A, Arnon TI, Rodda LB, Atakilit A, Sheppard D and Cyster JG. B cell interaction with subepithelial dendritic cells in Peyer's patches is critical for IgA production. (2016) Science352(6287).
- Arnon TI, Horton BM, Grigorova IL and Cyster JG. Visualization of splenic marginal zone B cell shuttling and follicular B cell egress. (2013) Nature493(7434):684-8.
- Byrne AJ, Weiss M, Mathie SA, Walker SA, Eames HL, Saliba D, Lloyd CM, Udalova IA. A critical role for IRF5 in regulating allergic airway inflammation.(2017)Mucosal Immunol.10(3):716-726.
HOW TO APPLY
The department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or the Directors of Graduate Studies who will be able to advise you of the essential requirements.
Interested applicants should have or expect to obtain a first or upper second class BSc degree or equivalent, and will also need to provide evidence of English language competence. The University requires candidates to formally apply online and for their referees to submit online references via the online application system.
The application guide and form is found online and the DPhil or MSc by research will commence in October 2019.
When completing the online application, please read the University Guide.