Abstract
To dissect the transcriptional networks underpinning immune cells responses during primary Plasmodium vivax infection of healthy human adults. We 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. Initial 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. In 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.
Highlights
Malaria remains an important public health problem worldwide, with more than 216 million cases per year 445,000 deaths.[1]
controlled human malaria infection (CHMI) system is a well-controlled system allowing investigations of immune responses to infection with malaria parasites as they develop in a human host, offering the opportunity to capture the initial programming of systemic immune responses
Applying novel systems immunology approaches to the whole transcriptome data from a unique CHMI study has allowed us, for the first time, to describe molecular and cellular mechanisms potentially involved in malaria-induced immunosuppression
Summary
Malaria remains an important public health problem worldwide, with more than 216 million cases per year 445,000 deaths.[1] The cyclical fever and pro-inflammatory state associated with malaria has been postulated to inhibit establishment and maintenance of immunological memory[2]; humoral and cellular responses to Plasmodium antigens are inefficiently generated and rapidly lost in the absence of ongoing exposure. A.F. Vallejo et al / Journal of Infection 77 (2018) 440–447 genic substances such as indoleamine 2,3-dioxygenase (IDO1). It has been shown that DC uptake of infected red blood cells (iRBC) impairs the immune responses during blood stage malaria by interfering with the priming and elicitation of liver-stage immunity.[5,6] During the chronic phase of the infection, the inhibitory molecule IDO1 is up-regulated in DC, inducing PD1 and LAG-3 expression in CD4 T cells, interfering with the memory acquisition.[7,8,9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
