Host Biomarkers and Biological Pathways That Are Associated with the Expression of Experimental Cerebral Malaria in Mice

Oakley, Miranda S.; McCutchan, Thomas F.; Anantharaman, Vivek; Ward, Jerrold M.; Faucette, Laurence; Erexson, Cindy R.; Mahajan, Babita; Zheng, Hong; Majam, Victoria; Aravind, L.; Kumar, Sanjai

doi:10.1128/iai.00525-08

Cited by 31 publications

(31 citation statements)

References 70 publications

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“…Erythropoiesis, the differentiation of hematopoietic stem cells into mature red blood cells, is characterized by the extrusion of nuclei from orthochromatic erythroblasts to form enucleated reticulocytes and subsequent mature red blood cells (17). Previously, we reported simultaneous downregulation of transcription but upregulation of translation of the hemoglobin-␣ gene in brain tissue of mice with ECM (32). Based on these results, we hypothesized that low levels of hemoglobin-␣ RNA were a result of a paucity of (nucleated) immature erythrocytes within the brain due to decreased production of erythrocytes, while elevations in hemoglobin-␣ protein were caused by an abundance of mature erythrocytes due to excess hemorrhaging within the brain.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, microarray studies were performed using samples collected on day 6 or 7 postinfection in order to minimize variations that may arise due to the stage of infection. Synthesis, incorporation of label, and purification of cDNA were performed as previously described (30,32), and then labeled cDNAs from matched samples (approximately 30 pmol each) were combined and hybridized to a custom-designed murine oligonucleotide chip containing 37,500 probes (Agilent Technologies, Santa Clara, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Previously, to better understand the pathogenic mechanisms operating during ECM, we used the Plasmodium berghei ANKA murine model of experimental cerebral malaria (ECM), a useful surrogate of human CM (9), to identify over 200 brainspecific biomarkers of ECM by comparing the tissue transcrip-tional profiles of moribund mice to those of nonmoribund mice and three types of resistant mice (32). In subsequent studies, we assessed the biological relevance of a small subset of these biomarkers and demonstrated that two molecules, CD14 and galectin-3, play a direct role in the pathogenesis of disease (31).…”

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Molecular Correlates of Experimental Cerebral Malaria Detectable in Whole Blood

et al. 2011

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Cerebral malaria (CM) is a primary cause of deaths caused by Plasmodium falciparum in young children in sub-Saharan Africa. Laboratory tests based on early detection of host biomarkers in patient blood would help in the prognosis and differential diagnosis of CM. Using the Plasmodium berghei ANKA murine model of experimental cerebral malaria (ECM), we have identified over 300 putative diagnostic biomarkers of ECM in the circulation by comparing the whole-blood transcriptional profiles of resistant mice (BALB/c) to those of two susceptible strains (C57BL/6 and CBA/CaJ). Our results suggest that the transcriptional profile of whole blood captures the molecular and immunological events associated with the pathogenesis of disease. We find that during ECM, erythropoiesis is dysfunctional, thrombocytopenia is evident, and glycosylation of cell surface components may be modified. Furthermore, analysis of immunity-related genes suggests that slightly distinct mechanisms of immunopathogenesis may operate in susceptible C57BL/6 and CBA/CaJ mice. Furthermore, our data set has allowed us to create a molecular signature of ECM composed of a subset of circulatory markers. Complement component C1q, ␤-chain, nonspecific cytotoxic cell receptor protein 1, prostate stem cell antigen, DnaJC, member 15, glutathione S-transferase omega-1, and thymidine kinase 1 were overexpressed in blood during the symptomatic phase of ECM, as measured by quantitative real-time PCR analysis. These studies provide the first host transcriptome database that is uniquely altered during the pathogenesis of ECM in blood. A subset of these mediators of ECM warrant validation in P. falciparum-infected young African children as diagnostic markers of CM.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Molecular Correlates of Experimental Cerebral Malaria Detectable in Whole Blood

et al. 2011

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“…Infection was then induced in experimental mice by i.p. injection of 10 6 Pb2A parasites and mice were monitored for clinical systems of ECM as described previously (27)(28)(29). Parasitemia (Parasitized RBCs / Total RBCs 3 100) was determined by examining Giesma-stained thin blood films.…”

Section: Mice and Parasite Infectionsmentioning

confidence: 99%

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

Oakley

Sahu

Lotspeich-Cole

et al. 2013

The Journal of Immunology

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The pathogenesis of experimental cerebral malaria (ECM) is an immunologic process, mediated in part by Th1 CD4+ T cells. However, the role of the Th1 CD4+ T cell differentiation program on the ability to control parasitemia and susceptibility to ECM disease during blood stage malaria has never been assessed directly. Using the Plasmodium berghei ANKA murine model of ECM and mice deficient for the transcription factor T-bet (the master regulator of Th1 cells) on the susceptible C57BL/6 background, we demonstrate that although T-bet plays a role in the regulation of parasite burden, it also promotes the pathogenesis of ECM. T-bet−deficient (Tbx21−/−) mice had higher parasitemia than wild type controls did during the ECM phase of disease (17.7 ± 3.1% versus 10.9 ± 1.5%). In addition, although 100% (10/10) of wild type mice developed ECM by day 9 after infection, only 30% (3/10) of Tbx21−/− mice succumbed to disease during the cerebral phase of infection. Resistance to ECM in Tbx21−/− mice was associated with diminished numbers of IFN-γ–producing CD4+ T cells in the spleen and a lower accumulation of CD4+ and CD8+ T cells in the brain. An augmented Th2 immune response characterized by enhanced production of activated GATA-3+ CD4+ T cells and elevated levels of the eotaxin, MCP-1, and G-CSF cytokines was observed in the absence of T-bet. Our results suggest that in virulent malarias, immune modulation or therapy resulting in an early shift toward a Th2 response may help to ameliorate the most severe consequences of malaria immunopathogenesis and the prospect of host survival.

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“…Equivalent amounts of labeled cRNA transcripts were next hybridized to a custom-designed Agilent SurePrint oligonucleotide array (Agilent Technologies) with 44,000 features (including 5,254 distinct 60-mer probes for Pf 3D7 transcripts, each spotted 8 times). The microarray chip was then scanned at 5 micron resolution and image-analyzed using Feature Extraction software version 9 and the data was filtered using NIAID microarray database tools (mAdb.niaid.nih.gov) as previously described [12] [13] [14]. …”

Section: Methodsmentioning

confidence: 99%

Molecular Markers of Radiation Induced Attenuation in Intrahepatic Plasmodium falciparum Parasites

et al. 2016

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Experimental immunization with radiation attenuated sporozoites (RAS) and genetically attenuated sporozoites has proved to be a promising approach for malaria vaccine development. However, parasite biomarkers of growth attenuation and enhanced immune protection in response to radiation remain poorly understood. Here, we report on the effect of an attenuating dose of γ-irradiation (15 krad) on the Plasmodium falciparum sporozoite (PfSPZ) ultrastructure by electron microscopy, growth rate of liver stage P. falciparum in liver cell cultures, and genome-wide transcriptional profile of liver stage parasites by microarray. We find that γ-irradiation treated PfSPZ retained a normal cellular structure except that they were vacuous with a partially disrupted plasma membrane and inner membrane complex. A similar infection rate was observed by γ-irradiation-treated and untreated PfSPZ in human HCO-4 liver cells (0.47% versus 0.49%, respectively) on day 3 post-infection. In the microarray studies, cumulatively, 180 liver stage parasite genes were significantly transcriptionally altered on day 3 and/or 6 post-infection. Among the transcriptionally altered biomarkers, we identified a signature of seven candidate parasite genes that associated with functionally diverse pathways that may regulate radiation induced cell cycle arrest of the parasite within the hepatocyte. A repertoire of 14 genes associated with protein translation is transcriptionally overexpressed within the parasite by radiation. Additionally, 37 genes encode proteins expressed on the cell surface or exported into the host cell, 4 encode membrane associated transporters, and 10 encode proteins related to misfolding and stress-related protein processing. These results have significantly increased the repertoire of novel targets for 1) biomarkers of safety to define proper attenuation, 2) generating genetically attenuated parasite vaccine candidates, and 3) subunit candidate vaccines against liver stage malaria.

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Host Biomarkers and Biological Pathways That Are Associated with the Expression of Experimental Cerebral Malaria in Mice

Cited by 31 publications

References 70 publications

Molecular Correlates of Experimental Cerebral Malaria Detectable in Whole Blood

Molecular Correlates of Experimental Cerebral Malaria Detectable in Whole Blood

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

Molecular Markers of Radiation Induced Attenuation in Intrahepatic Plasmodium falciparum Parasites

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