Cowan, Graeme

Gray, David

Smith, Natasha Louise

2022-04-11T10:10:41Z

2022-04-11T10:10:41Z

2022-04-04

Malaria continues to be a serious public health problem in many parts of the world, and progress in reducing the global malaria burden has stalled in recent years. Despite decades of research, current vaccine candidates have low efficacy, and major challenges in achieving long-lasting immune-mediated elimination of malaria remain. This is in part due to a lack of knowledge regarding how both clinical and anti-parasite immunity develops during a malaria infection. Epidemiologically, immunity to severe clinical disease develops after only a limited number of infections, whilst anti-parasite immunity requires years of repeat exposure. T-cells are known key functional mediators of the developing immune response during a first Plasmodium infection, undergoing extensive activation and splenic expansion during the acute phase. However aberrant T-cell responses have also been implicated in the pathogenesis of severe disease. The clonality and clonal composition of the T-cell response during a first malaria infection, and how this varies following repeat exposure, has not previously been described. Here, I have used T-cell receptor repertoire sequencing as a novel tool to address this knowledge gap. Firstly, I sequenced the splenic CD4+ T-cell receptor repertoires generated over the time-course of a murine P. chabaudi infection. Profiling the response using bulk TCRb repertoire sequencing, single-cell RNA-seq, and analyses of independent RNA-seq data, I determined that following a first infection - within a highly polyclonal expansion - murine T-effector repertoires are consistently dominated by a specific TCRb signature. This conserved T-cell response was consistently a hallmark of a first infection, but not expanded upon re-challenge. Determining the host or parasite factors driving this conserved response may uncover novel immune targets for malaria therapeutic purposes. Secondly, to resolve if similar dynamics occur in human P. falciparum infections, I sequenced the peripheral TCRb repertoires generated longitudinally over the time-course of a controlled human malaria infection model, including following re-challenge. No clonally expanded or conserved populations were evident in response to either a first or second P. falciparum infection. However, non-specific recruitment of established T-cell clones from the peripheral circulation was evident, a dynamic repeated in homologous re-challenge infections. Understanding the consequences of this non-specific trafficking, and whether or not it shapes an individual’s response to a Plasmodium infection, warrants further investigation. Overall, the results presented here demonstrate the utility of TCR repertoire sequencing when applied to antigenically complex infections and provide novel insights that deepen our understanding of the multifaceted immune response elicited by the parasite. Findings also set up a myriad of future research directions to address the question of how immune-mediated protection against malaria is achieved.

https://hdl.handle.net/1842/38850

http://dx.doi.org/10.7488/era/2104

en

The University of Edinburgh

Smith, N. L. et al. (2020) ‘A Conserved TCRβ signature dominates a highly polyclonal T-cell expansion during the acute phase of a murine malaria infection’, Frontiers in Immunology, 11(November), p. 2020.07.27.222570. doi: 10.3389/fimmu.2020.587756.

malaria

T-cell responses

T-cell receptors

CD4+ T-cell receptor

TCRb signature

TCR repertoire sequencing

Decoding malaria T-cell responses using adaptive immune receptor repertoire sequencing

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy