Browsing by Author "Fernander, Elizabeth M."

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    Elevated Plasma Soluble ST2 Levels are Associated With Neuronal Injury and Neurocognitive Impairment in Children With Cerebral Malaria
    (Case Western Reserve University, 2022-06-23) Fernander, Elizabeth M.; Adogamhe, Pontian; Datta, Dibyadyuti; Bond, Caitlin; Zhao, Yi; Bangirana, Paul; Conroy, Andrea L.; Opoka, Robert O.; John, Chandy C.; Pediatrics, School of Medicine
    Background: Murine experimental cerebral malaria studies suggest both protective and deleterious central nervous system effects from alterations in the interleukin-33 (IL-33)/ST2 pathway. Methods: We assessed whether soluble ST2 (sST2) was associated with neuronal injury or cognitive impairment in a cohort of Ugandan children with cerebral malaria (CM, n=224) or severe malarial anemia (SMA, n=193). Results: Plasma concentrations of sST2 were higher in children with CM than in children with SMA or in asymptomatic community children. Cerebrospinal fluid (CSF) sST2 levels were elevated in children with CM compared with North American children. Elevated plasma and CSF ST2 levels in children with CM correlated with increased endothelial activation and increased plasma and CSF levels of tau, a marker of neuronal injury. In children with CM who were ≥5 years of age at the time of their malaria episode, but not in children <5 years of age, elevated risk factor-adjusted plasma levels of sST2 were associated with worse scores for overall cognitive ability and attention over a 2-year follow-up. Conclusions: The study findings suggest that sST2 may contribute to neuronal injury and long-term neurocognitive impairment in older children with CM.
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    The Role of PfEMP1 Expression and Immunity in Ugandian Children with Severe Malaria
    (2022-05) Fernander, Elizabeth M.; John, Chandy; Bauer, Margaret; Gilk, Stacey; Tran, Tuan
    Severe malaria, primarily caused by Plasmodium falciparum infection, is among the leading causes of childhood mortality globally. A key virulence factor and source of antigenic variation and immune evasion during infection is P. falciparum erythrocyte membrane protein 1 (PfEMP1). Encoded for by approximately 60 var genes, this complex protein mediates cytoadherence of infected erythrocytes to the host endothelium and is a prominent immune target for the anti-malarial immune response in children. During severe malaria, specific domains of PfEMP1 that bind to endothelial protein C receptor (EPCR) and intercellular adhesion molecule-1 (ICAM-1) on host endothelial cells, are more prevalently expressed. The interaction of these proteins and infected erythrocytes mediates the sequestration of infected erythrocytes and plays a role in severe malaria pathogenesis. Antibodies to these domains develop over time with exposure to the parasite and are thought to contribute to immunity against severe malaria in children. In this study, whole blood samples from children with different forms of severe malaria, enrolled in two observational prospective cohort studies were used to quantify the expression of PfEMP1 domains using RT-qPCR and to measure the antibody response to PfEMP1 domains via a bead-based multiplex immunoassay. Using these samples, we demonstrated that although the expression of var transcripts encoding PfEMP1 domains was generally similar across children with different forms of severe malaria, the expression of variants encoding specific EPCR-binding domains was associated with thrombocytopenia and severe anemia. The antibody response to PfEMP1 domains in children with severe malaria was highest in children with SMA and children with asymptomatic parasitemia, but not associated with decreased risk of additional malaria episodes. Overall, the results of this study suggest that PfEMP1 is acting similarly across different forms of severe malaria but that it can be related to pathogenesis and severe malaria immunity.