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 7

The host response is shaped by parasite species.

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The host response is shaped by parasite species. (A) The maximum circula...
(A) The maximum circulating parasite density in each volunteer during the VAC063/VAC063C CHMI trials (Plasmodium falciparum) and the VAC069A study (Plasmodium vivax). Significance between parasite species was assessed by 2-tailed Wilcoxon’s rank-sum exact test. (B) The total number of circulating lymphocytes through infection and convalescence; the memory time point is 90 days after challenge. In A and B, box (median and IQR) and whisker (1.5× upper or lower IQR) plots are shown with outliers as dots; n = 13 for P. falciparum and n = 6 for P. vivax (except at T6, where n = 3 for P. falciparum). (C–F) Whole blood RNA sequencing was performed identically during the VAC063/VAC063C and VAC069A studies and lists of differentially expressed genes (Padj < 0.05 and fold-change > 1.5) were combined for GO analysis at diagnosis and T6. Importantly, for every GO term the fraction of associated genes derived from each volunteer cohort was retained. (C and E) Each GO term is represented by a single point and these are positioned according to the proportion of genes that were differentially expressed in volunteers infected with P. falciparum or P. vivax. The gray circle represents a 65% threshold that needed to be crossed to call a GO term as predominantly derived from 1 volunteer cohort; beyond this threshold GO terms are colored by enrichment as shown in A. (D and F) ClueGO networks reveal the functional organization of GO terms at diagnosis (D) and T6 (F); nodes are color-coded by enrichment (shared GO terms are shown in gray) and each of the major functional groups is labeled with a representative GO term. In C and D, n = 13 for P. falciparum and n = 6 for P. vivax and in E and F, n = 3 and 6, respectively.