Spatiotemporal evaluation of splenic immune responses to blood-stage malaria

Abstract

Plasmodium falciparum malaria remains one of the leading causes of death by infectious disease worldwide. Immune responses to blood stage malaria are generated primarily in the spleen, which forms the interface between peripheral blood and the immune system. Effective immune responses to malaria are believed to involve a complex interplay of innate and adaptive immune cells, the various roles of which have been extensively investigated in murine models. It has also been suggested that disease severity may detrimentally impact the generation of specific aspects of anti-malarial immunity, which compromise host protection. However, we lack an integrated picture of how these individual cellular responses are coordinated in space and time, with respect to each other and the extensive remodelling of the broader splenic landscape. Despite the recognised importance of the spleen to immunity, we have relatively little understanding of the cellular composition and organisation of the human spleen in health or during malaria, and even less knowledge of how malarial disease severity might alter this. Here, we apply single-cell resolution spatial proteomics to the murine and human spleen during experimental and natural infection, respectively. We show how the murine spleen is remodelled on a histological and cellular level during the course of a non-lethal malaria infection and how different arms of anti-malarial immunity are coordinated in space and time to achieve a protective response. We also model how an antigen-specific CD4+ T-cell response evolves within the spleen against the backdrop of a rapidly changing splenic microenvironment. Our analysis of post-mortem spleens of children infected with P. falciparum reveals the cellular composition and organisation of the human spleen during malaria in detail for the first time. Remarkably, malarial disease severity appeared to only subtly impact the human splenic immune landscape in cell subset quantity and organisation, implying that, even in severe malaria, the overall anti-Plasmodium immune response remains comparatively intact. Together, these studies provide evidence that splenic immune responses to blood stage malaria in both mice and humans are highly organised processes, both in space and time.

Date of Award	14 May 2025
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Kevin Couper (Main Supervisor) & Andrew MacDonald (Co Supervisor)