Genome-Wide Expression Profiling in Malaria Infection Reveals Transcriptional Changes Associated with Lethal and Nonlethal Outcomes

Schaecher, Kurt E.; Kumar, Sanjai; Yadava, Anjali; Vahey, Maryanne; Ockenhouse, Christian F.

doi:10.1128/iai.73.9.6091-6100.2005

Cited by 30 publications

(30 citation statements)

References 36 publications

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“…S3). Although these response patterns such as up-regulation of proinflammatory pathways largely agreed with those of previous microarray expressional profiling studies (8,36,37), our results clearly showed strainspecific responses and complex disease phenotypes/pathology that were greatly influenced by parasite genetic background. We therefore focused our investigation on the role of the IFN-I and putative CD14 signaling responses in the control of parasitemia and pathogenesis.…”

Section: Parasitemia and Pathology In Mice Infected With N67 And N67csupporting

confidence: 90%

Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality

Tian

Xiao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

143

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Malaria infection triggers vigorous host immune responses; however, the parasite ligands, host receptors, and the signaling pathways responsible for these reactions remain unknown or controversial. Malaria parasites primarily reside within RBCs, thereby hiding themselves from direct contact and recognition by host immune cells. Host responses to malaria infection are very different from those elicited by bacterial and viral infections and the host receptors recognizing parasite ligands have been elusive. Here we investigated mouse genome-wide transcriptional responses to infections with two strains of Plasmodium yoelii (N67 and N67C) and discovered differences in innate response pathways corresponding to strain-specific disease phenotypes. Using in vitro RNAi-based gene knockdown and KO mice, we demonstrated that a strong type I IFN (IFN-I) response triggered by RNA polymerase III and melanoma differentiation-associated protein 5, not Toll-like receptors (TLRs), binding of parasite DNA/RNA contributed to a decline of parasitemia in N67-infected mice. We showed that conventional dendritic cells were the major sources of early IFN-I, and that surface expression of phosphatidylserine on infected RBCs might promote their phagocytic uptake, leading to the release of parasite ligands and the IFN-I response in N67 infection. In contrast, an elevated inflammatory response mediated by CD14/TLR and p38 signaling played a role in disease severity and early host death in N67C-infected mice. In addition to identifying cytosolic DNA/RNA sensors and signaling pathways previously unrecognized in malaria infection, our study demonstrates the importance of parasite genetic backgrounds in malaria pathology and provides important information for studying human malaria pathogenesis.

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Section: Parasitemia and Pathology In Mice Infected With N67 And N67csupporting

confidence: 90%

Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality

Tian

Xiao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

143

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“…Because reticulocytes are the sole source of hemoglobin mRNA, this finding suggested a possible reduction in the circulating-reticulocyte count. This possibility is consistent with previous reports of impaired erythropoiesis in mice infected with lethal murine malaria strains (7,54) and in clinical cases of severe malaria (27). To further investigate the possible implications of the reduction in hemoglobin chain expression in ECM, we measured the expression of hemoglobin ␣1 chain protein in the brain tissue.…”

Section: Resultssupporting

confidence: 73%

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

et al. 2008

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Cerebral malaria (CM) is a primary cause of malaria-associated deaths among young African children. Yet no diagnostic tools are available that could be used to predict which of the children infected with Plasmodium falciparum malaria will progress to CM. We used the Plasmodium berghei ANKA murine model of experimental cerebral malaria (ECM) and high-density oligonucleotide microarray analyses to identify host molecules that are strongly associated with the clinical symptoms of ECM. Comparative expression analyses were performed with C57BL/6 mice, which have an ECM-susceptible phenotype, and with mice that have ECM-resistant phenotypes: CD8 knockout and perforin knockout mice on the C57BL/6 background and BALB/c mice. These analyses allowed the identification of more than 200 host molecules (a majority of which had not been identified previously) with altered expression patterns in the brain that are strongly associated with the manifestation of ECM. Among these host molecules, brain samples from mice with ECM expressed significantly higher levels of p21, metallothionein, and hemoglobin ␣1 proteins by Western blot analysis than mice unaffected by ECM, suggesting the possible utility of these molecules as prognostic biomarkers of CM in humans. We suggest that the higher expression of hemoglobin ␣1 in the brain may be associated with ECM and could be a source of excess heme, a molecule that is considered to trigger the pathogenesis of CM. Our studies greatly enhance the repertoire of host molecules for use as diagnostics and novel therapeutics in CM.

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“…Genome-wide expression profiling is being increasingly applied to dissect the complex details of the host response to malaria infection [10-16]. Delahaye et al .…”

Section: Introductionmentioning

confidence: 99%

Simultaneous host and parasite expression profiling identifies tissue-specific transcriptional programs associated with susceptibility or resistance to experimental cerebral malaria

et al. 2006

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BackgroundThe development and outcome of cerebral malaria (CM) reflects a complex interplay between parasite-expressed virulence factors and host response to infection. The murine CM model, Plasmodium berghei ANKA (PbA), which simulates many of the features of human CM, provides an excellent system to study this host/parasite interface. We designed "combination" microarrays that concurrently detect genome-wide transcripts of both PbA and mouse, and examined parasite and host transcriptional programs during infection of CM-susceptible (C57BL/6) and CM-resistant (BALB/c) mice.ResultsAnalysis of expression data from brain, lung, liver, and spleen of PbA infected mice showed that both host and parasite gene expression can be examined using a single microarray, and parasite transcripts can be detected within whole organs at a time when peripheral blood parasitemia is low. Parasites display a unique transcriptional signature in each tissue, and lung appears to be a large reservoir for metabolically active parasites. In comparisons of susceptible versus resistant animals, both host and parasite display distinct, organ-specific transcriptional profiles. Differentially expressed mouse genes were related to humoral immune response, complement activation, or cell-cell interactions. PbA displayed differential expression of genes related to biosynthetic activities.ConclusionThese data show that host and parasite gene expression profiles can be simultaneously analysed using a single "combination" microarray, and that both the mouse and malaria parasite display distinct tissue- and strain-specific responses during infection. This technology facilitates the dissection of host-pathogen interactions in experimental cerebral malaria and could be extended to other disease models.

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Genome-Wide Expression Profiling in Malaria Infection Reveals Transcriptional Changes Associated with Lethal and Nonlethal Outcomes

Cited by 30 publications

References 36 publications

Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality

Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality

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

Simultaneous host and parasite expression profiling identifies tissue-specific transcriptional programs associated with susceptibility or resistance to experimental cerebral malaria

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