Decoding malaria T-cell responses using adaptive immune receptor repertoire sequencing
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Date
04/04/2022Author
Smith, Natasha Louise
Metadata
Abstract
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.