Blood Profile of Lymphocyte Lineage Determining Transcription Factor Gata3 May Influence Malaria Disease Outcome of Children in the South of Benin (original) (raw)
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eLife
Background:In a phase 3 trial in African infants and children, the RTS,S/AS01 vaccine (GSK) showed moderate efficacy against clinical malaria. We sought to further understand RTS,S/AS01-induced immune responses associated with vaccine protection.Methods:Applying the blood transcriptional module (BTM) framework, we characterized the transcriptomic response to RTS,S/AS01 vaccination in antigen-stimulated (and vehicle control) peripheral blood mononuclear cells sampled from a subset of trial participants at baseline and month 3 (1-month post-third dose). Using a matched case–control study design, we evaluated which of these ‘RTS,S/AS01 signature BTMs’ associated with malaria case status in RTS,S/AS01 vaccinees. Antigen-specific T-cell responses were analyzed by flow cytometry. We also performed a cross-study correlates analysis where we assessed the generalizability of our findings across three controlled human malaria infection studies of healthy, malaria-naive adult RTS,S/AS01 recipi...
2021
In a phase 3 trial in African infants/children, the RTS,S/AS01 (GSK) vaccine showed moderate efficacy against clinical malaria. We aimed to identify RTS,S/AS01-induced signatures associated with clinical malaria by analyzing antigen-stimulated peripheral blood mononuclear cells sampled from a subset of trial participants at baseline and month 3 (one month post-third dose). RTS,S/AS01 vaccination was associated with downregulation of B-cell and monocyte-related blood transcriptional modules (BTMs) and upregulation of T-cell related BTMs, as well as higher month 3 (vs baseline) circumsporozoite protein (CSP)-specific CD4+T-cell responses. There were few RTS,S/AS01-associated BTMs whose month 3 levels correlated with malaria risk. In contrast, baseline levels of BTMs associated with dendritic cells and with monocytes (among others) correlated with malaria risk. A cross-study analysis supported generalizability of the baseline dendritic cell- and monocyte-related BTM correlations with m...
Proceedings of the National Academy of Sciences, 2008
Previous interethnic comparative studies on the susceptibility to malaria performed in West Africa showed that Fulani are more resistant to Plasmodium falciparum malaria than are sympatric ethnic groups. This lower susceptibility is not associated to classic malaria-resistance genes, and the analysis of the immune response to P. falciparum sporozoite and blood stage antigens, as well as non-malaria antigens, revealed higher immune reactivity in Fulani.
BMC Research Notes, 2012
Background: Fulani ethnic group individuals are less susceptible than sympatric Mossi ethnic group, in term of malaria infection severity, and differ in antibody production against malaria antigens. The differences in susceptibility to malaria between Fulani and Mossi ethnic groups are thought to be regulated by different genetic backgrounds and offer the opportunity to compare haematological parameters, Tregs and γδT cell profiles in seasonal and stable malaria transmission settings in Burkina Faso. The study was conducted at two different time points i.e. during the high and low malaria transmission period. Results: Two cross-sectional surveys were undertaken in adults above 20 years belonging either to the Fulani or the Mossi ethnic groups 1) at the peak of the malaria transmission season and 2) during the middle of the low malaria transmission season. Full blood counts, proportions of Tregs and γδ T cells were measured at both timepoints. As previously shown the Fulani and Mossi ethnic groups showed a consistent difference in P. falciparum infection rates and parasite load. Differential white blood cell counts showed that the absolute lymphocyte counts were higher in the Mossi than in the Fulani ethnic group at both time points. While the proportion of CD4+CD25 high was higher in the Fulani ethnic group at the peak of malaria transmission season (p = 0.03), no clear pattern emerged for T regulatory cells expressing FoxP3 + and CD127 low. However CD3 + γδ + subpopulations were found to be higher in the Fulani compared to the Mossi ethnic group, and this difference was statistically significant at both time-points (p = 0.004 at low transmission season and p = 0.04 at peak of transmission). Conclusion: Our findings on regulatory T cell phenotypes suggest an interesting role for immune regulatory mechanisms in response to malaria. The study also suggests that TCRγδ + cells might contribute to the protection against malaria in the Fulani ethnic group involving their reported parasite inhibitory activities.
Major transcriptional changes observed in the Fulani, an ethnic group less susceptible to malaria
eLife, 2017
The Fulani ethnic group has relatively better protection from Plasmodium falciparum malaria, as reflected by fewer symptomatic cases of malaria, lower infection rates, and lower parasite densities compared to sympatric ethnic groups<strong>.</strong> However, the basis for this lower susceptibility to malaria by the Fulani is unknown. We have performed a pilot study to examine global transcription and DNA methylation patterns in specific immune cell populations in the Fulani to elucidate the mechanisms that confer the lower susceptibility to P.falciparum malaria. When we compared uninfected and infected Fulani individuals, in contrast to uninfected and infected individuals from the sympatric ethnic group Mossi, we observed a key difference: a strong transcriptional response was only detected in the monocyte fraction of the Fulani, where over 1000 genes were significantly differentially expressed upon P.falciparum infection.
Scientific reports, 2018
The immune response of malaria patients is a main factor influencing the clinical severity of malaria. A tight regulation of the CD4 T cell response or the induction of tolerance have been proposed to contribute to protection from severe or clinical disease. We therefore compared the CD4 T cell phenotypes of Ghanaian children with complicated malaria, uncomplicated malaria, asymptomatic Plasmodium falciparum (Pf) infection or no infection. Using flow cytometric analysis and automated multivariate clustering, we characterized the expression of the co-inhibitory molecules CTLA-4, PD-1, Tim-3, and LAG-3 and other molecules implicated in regulatory function on CD4 T cells. Children with complicated malaria had higher frequencies of CTLA-4 or PD-1 CD4 T cells than children with uncomplicated malaria. Conversely, children with uncomplicated malaria showed a higher proportion of CD4 T cells expressing CD39 and Granzyme B, compared to children with complicated malaria. In contrast, asymptom...
Immunogenomic profile at baseline predicts host susceptibility to clinical malaria
Frontiers in Immunology, 2023
Introduction: Host gene and protein expression impact susceptibility to clinical malaria, but the balance of immune cell populations, cytokines and genes that contributes to protection, remains incompletely understood. Little is known about the determinants of host susceptibility to clinical malaria at a time when acquired immunity is developing. Methods: We analyzed peripheral blood mononuclear cells (PBMCs) collected from children who differed in susceptibility to clinical malaria, all from a small town in Mali. PBMCs were collected from children aged 4-6 years at the start, peak and end of the malaria season. We characterized the immune cell composition and cytokine secretion for a subset of 20 children per timepoint (10 children with no symptomatic malaria age-matched to 10 children with >2 symptomatic malarial illnesses), and gene expression patterns for six children (three per cohort) per timepoint. Results: We observed differences between the two groups of children in the expression of genes related to cell death and inflammation; in particular, inflammatory genes such as CXCL10 and STAT1 and apoptotic genes such as XAF1 were upregulated in susceptible children before the transmission season began. We also noted higher frequency of HLA-DR+ CD4 T cells in protected children during the peak of the malaria season and comparable levels cytokine secretion after stimulation with malaria schizonts across all three time points.
Frontiers in Immunology, 2022
Effector capabilities of γδ T cells are evident in Plasmodium infection in young and adult individuals, while children are the most vulnerable groups affected by malaria. Here, we aimed to investigate the age-dependent phenotypic composition of Vδ1+, Vδ2+, and Vδ3+ T cells in children living in endemic malaria areas and how this differs between children that will develop symptomatic and asymptomatic Plasmodium falciparum infections. Flow cytometric profiling of naïve and effector peripheral blood γδ T cells was performed in 6 neonates, 10 adults, and 52 children. The study population of young children, living in the same malaria endemic region of Ghana, was monitored for symptomatic vs asymptomatic malaria development for up to 42 weeks after peripheral blood sampling at baseline. For the Vδ2+ T cell population, there was evidence for an established type 1 effector phenotype, characterized by CD94 and CD16 expression, as early as 1 year of life. This was similar among children diagn...