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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Clinical Research and Public Health Immunology Infectious disease

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 2

Inflammation is followed by a transcriptional signature of proliferation.

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Inflammation is followed by a transcriptional signature of proliferation...
(A) Proportion of lymphocytes, monocytes, neutrophils, and eosinophils in whole blood at baseline, diagnosis, T6, and 90 days after challenge (memory). The mean frequency is shown for each time point (n = 6). Note that the relative increase in abundance of myeloid cells between baseline and diagnosis is 13.6%. (B and C) Genes that were differentially expressed in whole blood at diagnosis (B) and T6 (C) (relative to baseline, Padj < 0.05 and fold-change > 1.5) were used to create a gene ontology (GO) network in ClueGO. Each node represents a GO term and node size is determined by enrichment-adjusted P value. GO terms that share more than 40% of genes are connected by a line and organized into discrete functional groups (each given a unique color). The major functional groups are highlighted and labeled with a representative GO term. (D) The log2(fold-change) (log2FC) of signature genes associated with IFN signaling, type I inflammation, and proliferation are shown in whole blood at diagnosis and T6 (relative to baseline). Genes are ordered by unsupervised hierarchical clustering (denoted by the dendrogram) and those that were not differentially expressed (Padj > 0.05) are shown with a fold-change of zero. Asterisks indicate that common gene names have been used. In B–D, n = 6 per time point.