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Transcribed var genes associated with placental malaria in Malawian women.

ABSTRACT: Determining the diversity of PfEMP1 sequences expressed by Plasmodium falciparum-infected erythrocytes isolated from placentas is important for attempts to develop a pregnancy-specific malaria vaccine. The DBLgamma and var2csa DBL3x domains of PfEMP1 molecules are believed to mediate placental sequestration of infected erythrocytes, so the sequences encoding these domains were amplified from the cDNAs of placental parasites by using degenerate oligonucleotides. The levels of specific var cDNAs were then determined by quantitative reverse transcription-PCR. Homologues of var2csa DBL3x were the predominant sequences amplified from the cDNAs of most placental but not most children's parasites. There was 56% identity between all placental var2csa sequences. Many different DBLgamma domains were amplified from the cDNAs of placental and children's isolates. var2csa transcripts were the most abundant var transcripts of those tested in 11 of 12 placental isolates and 1 of 6 children's isolates. Gravidity did not affect the levels of var2csa transcripts. We concluded that placental malaria is frequently associated with transcription of var2csa but that other var genes are also expressed, and parasites expressing high levels of var2csa are not restricted to pregnant women. The diversity of var2csa sequences may be important for understanding immunity and for the development of vaccines for malaria during pregnancy.

SUBMITTER: Duffy MF

PROVIDER: S-EPMC1539630 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature

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Transcribed var genes associated with placental malaria in Malawian women.

Duffy Michael F MF Caragounis Aphrodite A Noviyanti Rintis R Kyriacou Helen M HM Choong Ee Ken EK Boysen Katja K Healer Julie J Rowe J Alexandra JA Molyneux Malcolm E ME Brown Graham V GV Rogerson Stephen J SJ

Infection and immunity 20060801 8

Determining the diversity of PfEMP1 sequences expressed by Plasmodium falciparum-infected erythrocytes isolated from placentas is important for attempts to develop a pregnancy-specific malaria vaccine. The DBLgamma and var2csa DBL3x domains of PfEMP1 molecules are believed to mediate placental sequestration of infected erythrocytes, so the sequences encoding these domains were amplified from the cDNAs of placental parasites by using degenerate oligonucleotides. The levels of specific var cDNAs w ...[more]

PMID: 16861676

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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

Transcribed var genes associated with placental malaria in Malawian women.

Publications

Transcribed var genes associated with placental malaria in Malawian women.

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