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Resolving the spatiotemporal events controlling effector T cell responses during malaria (Manchester-Melbourne Dual Award)


Project Description

Malaria remains one of the most important diseases in the world, responsible for hundreds of thousands of deaths and significant morbidity and suffering in many millions of people, each year. CD4+ T cells are essential for control of malaria, through helping macrophages kill parasites and promoting antibody production. However, it is well known that CD4+ T cell effector responses become suppressed during blood-stage malaria (a phenomenon called T cell exhaustion) and this directly impairs parasite control, contributes to chronicity of infection, and promotes susceptibility to reinfection. At present the pathways that promote T cell exhaustion during malaria are poorly understood.

In this PhD project, the successful student will dissect the processes that provoke T cell exhaustion during malaria. In the labs of Dr Kevin Couper and Prof. Andrew MacDonald at the University of Manchester, the student will reveal, using cutting-edge imaging mass cytometry (which allows the multiplex and concurrent detection of 40 molecules in a tissue section), the complex spatiotemporal cellular choreography that occurs within the spleen during the course of malaria. This will define, for the first time, the T cellular phenotypic, positional and interactional events that combine to regulate T cell function during malaria. Utilising complementary two-photon imaging approaches (a modality that allows us to look deep within intact tissues in live animals), the student will also assess the changing dynamic behaviour of antigen-specific CD4+ T cells, and their interactions with dendritic cells and tissue components, during the course of malaria, associated with alterations in T cell function. In the lab of Prof. Bill Heath at the Peter Doherty Institute at the University of Melbourne, the student will employ in vivo murine models of malaria and use novel approaches to perturb the activity of specific dendritic cell populations and immune and tissue factors (such as stromal cells), identified during experiments in Manchester. The student will examine how these targeted manipulations influence CD4+ T cell effector function and establishment of cellular exhaustion during malaria. Combined, the results from this collaborative project will transform our understanding of the pathways and cellular events that promote T cell exhaustion within a physiological tissue environment during malaria. This will directly lead to new strategies to therapeutically reinvigorate CD4+ T cells during malaria, and other human diseases characterised by T cell exhaustion, such as cancer.

The successful candidate will spend the first 15-18 months of the project at the University of Manchester followed by a 12-18 months placement at the Peter Doherty Institute in Melbourne. The student will then return to the University Manchester to complete their PhD and submit their thesis. The successful candidate will receive training in various cutting-edge immunological techniques including imaging mass cytometry, two-photon microscopy and multi-parameter flow cytometry, combined with in vivo training in host-pathogen infection models, utisiling a number of novel transgenic murine strains. Thus, the successful candidate will obtain essential interdisciplinary and quantitative in vivo skills to support their future career.

See https://www.manchester.ac.uk/study/postgraduate-research/golden/melbourne/

Funding Notes

This project is available to UK/EU candidates. Funding covers fees and stipend for 3.5 years. Candidates will be required to split their time between Manchester and Melbourne.

Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Perivascular Arrest of CD8+ T Cells Is a Signature of Experimental Cerebral Malaria.
Shaw TN, Stewart-Hutchinson PJ, Strangward P, Dandamudi DB, Coles JA, Villegas-Mendez A, Gallego-Delgado J, van Rooijen N, Zindy E, Rodriguez A, Brewer JM, Couper KN, Dustin ML.

PLoS Pathog. 2015 Nov 12;11(11):e1005210. doi: 10.1371/journal.ppat.1005210. eCollection 2015.


Parasite-Specific CD4+ IFN-γ+ IL-10+ T Cells Distribute within Both Lymphoid and Nonlymphoid Compartments and Are Controlled Systemically by Interleukin-27 and ICOS during Blood-Stage Malaria Infection.
Villegas-Mendez A, Shaw TN, Inkson CA, Strangward P, de Souza JB, Couper KN.
Infect Immun. 2015 Oct 12;84(1):34-46. doi: 10.1128/IAI.01100-15. Print 2016 Jan.


IL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals.
Villegas-Mendez A, de Souza JB, Lavelle SW, Gwyer Findlay E, Shaw TN, van Rooijen N, Saris CJ, Hunter CA, Riley EM, Couper KN.
PLoS Pathog. 2013;9(4):e1003293. doi: 10.1371/journal.ppat.1003293. Epub 2013 Apr 11.

Type I interferon is required for T helper (Th) 2 induction by dendritic cells.
Webb LM, Lundie RJ, Borger JG, Brown SL, Connor LM, Cartwright AN, Dougall AM, Wilbers RH, Cook PC, Jackson-Jones LH, Phythian-Adams AT, Johansson C, Davis DM, Dewals BG, Ronchese F, MacDonald AS.
EMBO J. 2017 Aug 15;36(16):2404-2418. doi: 10.15252/embj.201695345. Epub 2017 Jul 17.

Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria.
Fernandez-Ruiz D, Lau LS, Ghazanfari N, Jones CM, Ng WY, Davey GM, Berthold D, Holz L, Kato Y, Enders MH, Bayarsaikhan G, Hendriks SH, Lansink LIM, Engel JA, Soon MSF, James KR, Cozijnsen A, Mollard V, Uboldi AD, Tonkin CJ, de Koning-Ward TF, Gilson PR, Kaisho T, Haque A, Crabb BS, Carbone FR, McFadden GI, Heath WR.
J Immunol. 2017 Dec 15;199(12):4165-4179. doi: 10.4049/jimmunol.1700186. Epub 2017 Oct 30.

Spatiotemporally Distinct Interactions with Dendritic Cell Subsets Facilitates CD4+ and CD8+ T Cell Activation to Localized Viral Infection.
Hor JL, Whitney PG, Zaid A, Brooks AG, Heath WR, Mueller SN.
Immunity. 2015 Sep 15;43(3):554-65. doi: 10.1016/j.immuni.2015.07.020. Epub 2015 Aug 18. Erratum in: Immunity. 2015 Sep 15;43(3):615.

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