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 1

Plasmodium vivax triggers IFN-stimulated inflammation.

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Plasmodium vivax triggers IFN-stimulated inflammation. (A) Study design...
(A) Study design and sampling time points. (B) Circulating parasite density was determined twice daily by qPCR. Pretreatment measurements are shown as solid lines, posttreatment measurements as dotted lines. The limit of quantification (20 genome copies/mL) is shown by a black line. (C and D) Full blood counts and blood chemistry measured (C) lymphocyte frequencies and (D) the concentration of alanine aminotransferase (ALT) throughout infection and convalescence. In B–D, each line represents 1 volunteer (n = 6). (E) Multiplexed plasma analytes were measured using a custom Legendplex assay. Each row in the heatmap is an analyte and each column a plasma sample. Samples from v09 were excluded after failing QC (n = 5). Linear regression was used to identify analytes that varied across the volunteer cohort at each time point (compared with baseline) and these are ordered by FDR. FDR < 0.05 was considered significant after adjusting for multiple testing (Benjamini-Hochberg). Only 17 of the 39 analytes measured are shown (those with the lowest FDR) and the color of each tile corresponds to the row-wise z score–transformed concentrations. In C and D, the memory time point is 90 days after challenge and in E, memory is 45 days after challenge.