Dataset Information

Common strategies to prevent and modulate experimental cerebral malaria in mouse strains with different susceptibilities.

ABSTRACT: Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection, predominantly experienced by children and nonimmune adults, which results in significant mortality and long-term sequelae. Previous studies have reported distinct susceptibility gene loci in CBA/CaH (CBA) and C57BL/6 (B6) mice with experimental CM (ECM) caused by infection with Plasmodium berghei ANKA. Here we present an analysis of genome-wide expression profiles in brain tissue taken from B6 and CBA mice with ECM and report significant heterogeneity between the two mouse strains. Upon comparison of the leukocyte composition of ECM brain tissue, microglia were expanded in B6 mice but not CBA mice. Furthermore, circulating levels of gamma interferon, interleukin-10, and interleukin-6 were significantly higher in the serum of B6 mice than in that of CBA mice with ECM. Two therapeutic strategies were applied to B6 and CBA mice, i.e., (i) depletion of regulatory T (Treg) cells prior to infection and (ii) depletion of CD8(+) T cells after the establishment of ECM. Despite the described differences between susceptible mouse strains, depletion of Treg cells before infection attenuated ECM in both B6 and CBA mice. In addition, the depletion of CD8(+) T cells when ECM symptoms are apparent leads to abrogation of ECM in B6 mice and a lack of progression of ECM in CBA mice. These results may have important implications for the development of effective treatments for human CM.

SUBMITTER: Randall LM

PROVIDER: S-EPMC2446712 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Common strategies to prevent and modulate experimental cerebral malaria in mouse strains with different susceptibilities.

Randall Louise M LM Randall Louise M LM Amante Fiona H FH McSweeney Karli A KA Zhou Yonghong Y Stanley Amanda C AC Haque Ashraful A Jones Malcolm K MK Hill Geoff R GR Boyle Glen M GM Engwerda Christian R CR

Infection and immunity 20080512 7

Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection, predominantly experienced by children and nonimmune adults, which results in significant mortality and long-term sequelae. Previous studies have reported distinct susceptibility gene loci in CBA/CaH (CBA) and C57BL/6 (B6) mice with experimental CM (ECM) caused by infection with Plasmodium berghei ANKA. Here we present an analysis of genome-wide expression profiles in brain tissue taken from B6 and CBA mice with EC ...[more]

PMID: 18474652

Similar Datasets

Project description:Cerebral malaria (CM) is the most severe manifestation of Plasmodium falciparum infection in children and non-immune adults. Previous work has documented a persistent cognitive impairment in children who survive an episode of CM that is mimicked in animal models of the disease. Potential therapeutic interventions for this complication have not been investigated, and are urgently needed. HMG-CoA reductase inhibitors (statins) are widely prescribed for cardiovascular diseases. In addition to their effects on the inhibition of cholesterol synthesis, statins have pleiotropic immunomodulatory activities. Here we tested if statins would prevent cognitive impairment in a murine model of cerebral malaria. Six days after infection with Plasmodium berghei ANKA (PbA) mice displayed clear signs of CM and were treated with chloroquine, or chloroquine and lovastatin. Intravital examination of pial vessels of infected animals demonstrated a decrease in functional capillary density and an increase in rolling and adhesion of leukocytes to inflamed endothelium that were reversed by treatment with lovastatin. In addition, oedema, ICAM-1, and CD11b mRNA levels were reduced in lovastatin-treated PbA-infected mice brains. Moreover, HMOX-1 mRNA levels are enhanced in lovastatin-treated healthy and infected brains. Oxidative stress and key inflammatory chemokines and cytokines were reduced to non-infected control levels in animals treated with lovastatin. Fifteen days post-infection cognitive dysfunction was detected by a battery of cognition tests in animals rescued from CM by chloroquine treatment. In contrast, it was absent in animals treated with lovastatin and chloroquine. The outcome was similar in experimental bacterial sepsis, suggesting that statins have neuroprotective effects in severe infectious syndromes in addition to CM. Statin treatment prevents neuroinflammation and blood brain barrier dysfunction in experimental CM and related conditions that are associated with cognitive sequelae, and may be a valuable adjuvant therapeutic agent for prevention of cognitive impairment in patients surviving an episode of CM.

Project description:Analysis of transcriptional response to Plasmodium berghei ANKA infection in cerebral malaria susceptible C57BL/6 mouse brains as well as cerebral malaria resistant BXH2 mice which carry a severe hypomorphic Irf8-R294C allele. Interferon Regulatory Factor 8 (IRF8) is required for development, maturation and expression of anti-microbial defenses of myeloid cells. BXH2 mice harbor a loss-of-function allele at Irf8 (Irf8-R294C) that causes susceptibility to infection with intracellular pathogens, including Mycobacterium tuberculosis. We report that XH2 are completely resistant to the development of cerebral malaria following Plasmodium berghei ANKA infection. Comparative transcriptional profiling of brain RNA as well as chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) was used to identify IRF8-regulated genes whose expression is associated with pathological acute neuroinflammation. Genes up-regulated by infection were strongly enriched for IRF8 binding sites, suggesting that IRF8 acts as a transcriptional activator in inflammatory programs. These lists were enriched for myeloid-specific pathways, including interferon responses, antigen presentation and Th1 polarizing cytokines. We show that inactivation of several of these downstream target genes confers protection against experimental cerebral malaria. We also report strong overlap between genes bound and regulated by IRF8 during cerebral malaria and genes regulated in the lungs of M. tuberculosis infected mice. This IRF8-dependent network contains several genes recently identified as risk factors in acute and chronic human inflammatory conditions. In summary, this work defines a common core of IRF8-bound genes forming a critical inflammatory host-response network. Comparison of whole brain transcript profiles for wildype C57BL/6 mice versus severely hypomorphic Irf8-R294C BXH2 mice following experimental infection with Plasmodium berghei ANKA (d7). Baseline (d0) profiles are also compared. Pleaes note that each sample record represents 2-4 replicates and sample data table contains mean, standard error of the mean (SEM), and quality for the replicates. The non_normalized data matrix contains raw data for each replicate (total 12 samples).

Dataset Information

Common strategies to prevent and modulate experimental cerebral malaria in mouse strains with different susceptibilities.

Publications

Common strategies to prevent and modulate experimental cerebral malaria in mouse strains with different susceptibilities.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets