Dataset Information

Characterization of Plasmodium berghei Homologues of T-cell Immunomodulatory Protein as a New Potential Candidate for Protecting against Experimental Cerebral Malaria.

ABSTRACT: The pathogenesis of cerebral malaria is biologically complex and involves multi-factorial mechanisms such as microvascular congestion, immunopathology by the pro-inflammatory cytokine and endothelial dysfunction. Recent data have suggested that a pleiotropic T-cell immunomodulatory protein (TIP) could effectively mediate inflammatory cytokines of mammalian immune response against acute graft-versus-host disease in animal models. In this study, we identified a conserved homologue of TIP in Plasmodium berghei (PbTIP) as a membrane protein in Plasmodium asexual stage. Compared with PBS control group, the pathology of experimental cerebral malaria (ECM) in rPbTIP intravenous injection (i.v.) group was alleviated by the downregulation of pro-inflammatory responses, and rPbTIP i.v. group elicited an expansion of regulatory T-cell response. Therefore, rPbTIP i.v. group displayed less severe brain pathology and feverish mice in rPbTIP i.v. group died from ECM. This study suggested that PbTIP may be a novel promising target to alleviate the severity of ECM.

SUBMITTER: Cui A

PROVIDER: S-EPMC6526220 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Characterization of Plasmodium berghei Homologues of T-cell Immunomodulatory Protein as a New Potential Candidate for Protecting against Experimental Cerebral Malaria.

Cui Ai A Li Yucen Y Zhou Xia X Wang Lin L Luo Enjie E

The Korean journal of parasitology 20190430 2

The pathogenesis of cerebral malaria is biologically complex and involves multi-factorial mechanisms such as microvascular congestion, immunopathology by the pro-inflammatory cytokine and endothelial dysfunction. Recent data have suggested that a pleiotropic T-cell immunomodulatory protein (TIP) could effectively mediate inflammatory cytokines of mammalian immune response against acute graft-versus-host disease in animal models. In this study, we identified a conserved homologue of TIP in Plasmo ...[more]

PMID: 31104402

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Project description:Cerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection with acute brain lesions. Genetic variations in both host and parasite have been associated with susceptibility to CM, but the underlying molecular mechanism remains unclear. Here, we demonstrate that variants of human apolipoprotein E (hApoE) impact the outcome of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). Mice carrying the hApoE2 isoform have fewer intracerebral hemorrhages and are more resistant to ECM than mice bearing the hApoE3, hApoE4, or endogenous murine ApoE (mApoE). hApoE2 mice infected with PbA showed increased splenomegaly and IFN-γ levels in serum but reduced cerebral cell apoptosis that correlated with the survival advantage against ECM. In addition, upregulated expression of genes associated with lipid metabolism and downregulated expression of genes linked to immune responses were observed in the brain tissue of hApoE2 mice relative to ECM-susceptible mice after PbA infection. Notably, serum cholesterol and the cholesterol content of brain-infiltrating CD8+ T cells are significantly higher in infected hApoE2 mice, which might contribute to a significant reduction in the sequestration of brain CD8+ T cells. Consistent with the finding that fewer brain lesions occurred in infected hApoE2 mice, fewer behavioral deficits were observed in the hApoE2 mice. Finally, a meta-analysis of publicly available data also showed an increased hApoE2 allele in the malaria-endemic African population, suggesting malaria selection. This study shows that hApoE2 protects mice from ECM through suppression of CD8+ T cell activation and migration to the brain and enhanced cholesterol metabolism.IMPORTANCECerebral malaria (CM) is the deadliest complication of malaria infection with an estimated 15%-25% mortality. Even with timely and effective treatment with antimalarial drugs such as quinine and artemisinin derivatives, survivors of CM may suffer long-term cognitive and neurological impairment. Here, we show that human apolipoprotein E variant 2 (hApoE2) protects mice from experimental CM (ECM) via suppression of CD8+ T cell activation and infiltration to the brain, enhanced cholesterol metabolism, and increased IFN-γ production, leading to reduced endothelial cell apoptosis, BBB disruption, and ECM symptoms. Our results suggest that hApoE can be an important factor for risk assessment and treatment of CM in humans.

Dataset Information

Characterization of Plasmodium berghei Homologues of T-cell Immunomodulatory Protein as a New Potential Candidate for Protecting against Experimental Cerebral Malaria.

Publications

Characterization of Plasmodium berghei Homologues of T-cell Immunomodulatory Protein as a New Potential Candidate for Protecting against Experimental Cerebral Malaria.

Similar Datasets

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