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Malawian children with uncomplicated and cerebral malaria have decreased activated V?9V?2 ?? T cells which increase in convalescence.

ABSTRACT: Malaria is responsible for almost half a million deaths annually. The role of V?9V?2 ?? T cells in malaria is still unclear. Studies have reported an association between this cell subset and malaria symptoms and severity. Profiles of V?9V?2 ?? T cells in bigger cohorts with different levels of clinical severity have not been described. Proportion, numbers, and activation status of V?9V?2 ?? T cells were measured by flow cytometry in 59 healthy controls (HCs), 58 children with uncomplicated malaria (UM) and 67 with cerebral malaria (CM,) during acute malaria and in convalescence 28 days later. V?9V?2 ?? T cell were lower in children presenting with UM and CM than in HCs. Cell counts did not vary with malaria severity (CM median counts 40 x 103 cells/?L, IQR [23-103]; UM median counts 30 x 103 cells/?L [10-90], P = 0.224). V?9V?2 ?? T cell counts increased during convalescence for UM (70 [40-60] x 103 cells/?L and CM (90 [60-140] x 103 cells/?L), to levels similar to those in HCs (70 [50-140] x 103 cells/?L), p = 0.70 and p = 0.40 respectively. Expression of the activation markers CD69 and HLA-DR on V?9V?2 ?? T cells was higher in malaria cases than in controls (HCs vs UM or CM, p < 0.0001) but was similar between UM and CM. HLA-DR expression remained elevated at 28 days, suggesting sustained activation of V?9V?2 ?? T cells during recovery. V?9V?2 ?? T cell proportions and cells counts were suppressed in acute disease and normalized in convalescence, a phenomenon previously hypothesized to be due to transient migration of the cells to secondary lymphoid tissue. The presence of highly activated V?9V?2 ?? T cells suggests that this T cell subset plays a specific role in response to malaria infection.

SUBMITTER: Harawa V

PROVIDER: S-EPMC6786631 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Malawian children with uncomplicated and cerebral malaria have decreased activated Vγ9Vδ2 γδ T cells which increase in convalescence.

Harawa Visopo V Njie Madi M Keller Thomas T Kim Kami K Jaworowski Anthony A Seydel Karl K Rogerson Stephen J SJ Mandala Wilson W

PloS one 20191010 10

Malaria is responsible for almost half a million deaths annually. The role of Vγ9Vδ2 γδ T cells in malaria is still unclear. Studies have reported an association between this cell subset and malaria symptoms and severity. Profiles of Vγ9Vδ2 γδ T cells in bigger cohorts with different levels of clinical severity have not been described. Proportion, numbers, and activation status of Vγ9Vδ2 γδ T cells were measured by flow cytometry in 59 healthy controls (HCs), 58 children with uncomplicated malar ...[more]

PMID: 31600250

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Project description:UnlabelledMost patients with cerebral malaria (CM) sustain cerebral microvascular sequestration of Plasmodium falciparum-infected red blood cells (iRBCs). Although many young children are infected with P. falciparum, CM remains a rare outcome; thus, we hypothesized that specific host conditions facilitate iRBC cerebral sequestration. To identify these host factors, we compared the peripheral whole-blood transcriptomes of Malawian children with iRBC cerebral sequestration, identified as malarial-retinopathy-positive CM (Ret+CM), to the transcriptomes of children with CM and no cerebral iRBC sequestration, defined as malarial-retinopathy-negative CM (Ret-CM). Ret+CM was associated with upregulation of 103 gene set pathways, including cytokine, blood coagulation, and extracellular matrix (ECM) pathways (P < 0.01; false-discovery rate [FDR] of <0.05). Neutrophil transcripts were the most highly upregulated individual transcripts in Ret+CM patients. Activated neutrophils can modulate diverse host processes, including the ECM, inflammation, and platelet biology to potentially facilitate parasite sequestration. Therefore, we compared plasma neutrophil proteins and neutrophil chemotaxis between Ret+CM and Ret-CM patients. Plasma levels of human neutrophil elastase, myeloperoxidase, and proteinase 3, but not lactoferrin or lipocalin, were elevated in Ret+CM patients, and neutrophil chemotaxis was impaired, possibly related to increased plasma heme. Neutrophils were rarely seen in CM brain microvasculature autopsy samples, and no neutrophil extracellular traps were found, suggesting that a putative neutrophil effect on endothelial cell biology results from neutrophil soluble factors rather than direct neutrophil cellular tissue effects. Meanwhile, children with Ret-CM had lower levels of inflammation, higher levels of alpha interferon, and upregulation of Toll-like receptor pathways and other host transcriptional pathways, which may represent responses that do not favor cerebral iRBC sequestration.ImportanceThere were approximately 198 million cases of malaria worldwide in 2013, with an estimated 584,000 deaths occurring mostly in sub-Saharan African children. CM is a severe and rare form of Plasmodium falciparum infection and is associated with high rates of mortality and neurological morbidity, despite antimalarial treatment. A greater understanding of the pathophysiology of CM would allow the development of adjunctive therapies to improve clinical outcomes. A hallmark of CM is cerebral microvasculature sequestration of P. falciparum-infected red blood cells (iRBCs), which results in vasculopathy in some patients. Our data provide a global analysis of the host pathways associated with CM and newly identify an association of activated neutrophils with brain iRBC sequestration. Products of activated neutrophils could alter endothelial cell receptors and coagulation to facilitate iRBC adherence. Future studies can now examine the role of neutrophils in CM pathogenesis to improve health outcomes.

Dataset Information

Malawian children with uncomplicated and cerebral malaria have decreased activated V?9V?2 ?? T cells which increase in convalescence.

Publications

Malawian children with uncomplicated and cerebral malaria have decreased activated Vγ9Vδ2 γδ T cells which increase in convalescence.

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