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ObjectivesTo dissect the transcriptional networks underpinning immune cells responses during primary Plasmodium vivax infection of healthy human adults.MethodsWe conducted network co-expression analysis of next-generation RNA sequencing data from whole blood from P. vivax and P. falciparum controlled human malaria infection (CHMI) of healthy naïve and malaria-exposed volunteers. Single cell transcription signatures were used to deconvolute the bulk RNA-Seq data into cell-specific signals.ResultsInitial exposure to P. vivax induced activation of innate immunity, including efficient antigen presentation and complement activation. However, this effect was accompanied by strong immunosuppression mediated by dendritic cells via the induction of Indoleamine 2,3-Dioxygenase 1(IDO1) and Lymphocyte Activation Gene 3 (LAG3). Additionally, P. vivax induced depletion of neutrophil populations associated with down regulation of 3G-protein coupled receptors, CRXCR1, CXCR2 and CSF3R. Accordingly, in malaria-exposed volunteers the inflammatory response was attenuated, with a decreased class II antigen presentation in dendritic cells. While the immunosuppressive signalling was maintained between plasmodium species, response to P. falciparum was significantly more immunogenic.ConclusionsIn silico analyses suggest that primary infection with P. vivax induces potent immunosuppression mediated by dendritic cells, conditioning subsequent anti-malarial immune responses. Targeting immune evasion mechanisms could be an effective alternative for improving vaccine efficacy.

Original publication

DOI

10.1016/j.jinf.2018.09.005

Type

Journal article

Journal

The Journal of infection

Publication Date

11/2018

Volume

77

Pages

440 - 447

Addresses

Clinical and Experimental Sciences and NIHR Southampton Biomedical Research Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, LE59, MP813, SO16 6YD, Southampton, UK.

Keywords

Dendritic Cells, Neutrophils, Humans, Plasmodium falciparum, Plasmodium vivax, Malaria, Falciparum, Malaria, Vivax, Gene Expression Profiling, Lymphocyte Activation, Immune Tolerance, Immunity, Cellular, Antigen Presentation, Down-Regulation, Indoleamine-Pyrrole 2,3,-Dioxygenase, High-Throughput Nucleotide Sequencing