A systematic analysis of the human immune response to Plasmodium vivax
Florian A. Bach, … , Simon J. Draper, Philip J. Spence
Florian A. Bach, … , Simon J. Draper, Philip J. Spence
Published August 24, 2023
Citation Information: J Clin Invest. 2023;133(20):e152463. https://doi.org/10.1172/JCI152463.
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A systematic analysis of the human immune response to Plasmodium vivax

Abstract

BACKGROUND The biology of Plasmodium vivax is markedly different from that of P. falciparum; how this shapes the immune response to infection remains unclear. To address this shortfall, we inoculated human volunteers with a clonal field isolate of P. vivax and tracked their response through infection and convalescence.METHODS Participants were injected intravenously with blood-stage parasites and infection dynamics were tracked in real time by quantitative PCR. Whole blood samples were used for high dimensional protein analysis, RNA sequencing, and cytometry by time of flight, and temporal changes in the host response to P. vivax were quantified by linear regression. Comparative analyses with P. falciparum were then undertaken using analogous data sets derived from prior controlled human malaria infection studies.RESULTS P. vivax rapidly induced a type I inflammatory response that coincided with hallmark features of clinical malaria. This acute-phase response shared remarkable overlap with that induced by P. falciparum but was significantly elevated (at RNA and protein levels), leading to an increased incidence of pyrexia. In contrast, T cell activation and terminal differentiation were significantly increased in volunteers infected with P. falciparum. Heterogeneous CD4+ T cells were found to dominate this adaptive response and phenotypic analysis revealed unexpected features normally associated with cytotoxicity and autoinflammatory disease.CONCLUSION P. vivax triggers increased systemic interferon signaling (cf P. falciparum), which likely explains its reduced pyrogenic threshold. In contrast, P. falciparum drives T cell activation far in excess of P. vivax, which may partially explain why falciparum malaria more frequently causes severe disease.TRIAL REGISTRATION ClinicalTrials.gov NCT03797989.FUNDING The European Union’s Horizon 2020 Research and Innovation programme, the Wellcome Trust, and the Royal Society.

Authors

Florian A. Bach, Diana Muñoz Sandoval, Michalina Mazurczyk, Yrene Themistocleous, Thomas A. Rawlinson, Adam C. Harding, Alison Kemp, Sarah E. Silk, Jordan R. Barrett, Nick J. Edwards, Alasdair Ivens, Julian C. Rayner, Angela M. Minassian, Giorgio Napolitani, Simon J. Draper, Philip J. Spence

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Figure 5

Activated T cells are functionally heterogeneous.

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Activated T cells are functionally heterogeneous. (A) Heatmap showing no...
(A) Heatmap showing normalized median expression values of all markers used for clustering in each of the 9 T cell clusters that were differentially abundant at T6. The horizontal bar chart shows the average frequency of each cluster across all volunteers. (B) Pie chart showing the relative size of each differentially abundant T cell cluster at T6. (C) Stacked bar chart showing the sum of activated CD4+ T cells at T6; each bar represents 1 volunteer. Data are shown as a proportion of the total non-naive CD45RO+CD4+ T cell pool. (D) UMAP plot showing the expression of activation, proliferation, and differentiation markers across each of the CD4+ T cell clusters that were differentially abundant at T6; each marker is independently scaled using arcsine-transformed signal intensity. The expression of these markers is shown across the entire UMAP plot in Supplemental Figure 5. In A–D, n = 6 and T cell clusters are color-coded according to the legend in B. EM, effector memory; CM, central memory.