Predominance of Interferon-Related Responses in the Brain during Murine Malaria, as Identified by Microarray Analysis

Miu, Jenny; Hunt, Nicholas H.; Ball, Helen J.

doi:10.1128/iai.01650-07

Cited by 27 publications

(37 citation statements)

References 66 publications

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“…Thus, expression of caspase-12 appears protective in this context. Caspase-12 has previously been reported to be upregulated in the brains of P. berghei-infected mice (30). Consistent with our own observations, this is suggestive of a possible immune-regulatory process whereby caspase-12 production is induced in an attempt to control the excessive inflammatory response to the Plasmodium infection.…”

Section: Discussionsupporting

confidence: 91%

Caspase-12 Dampens the Immune Response to Malaria Independently of the Inflammasome by Targeting NF-κB Signaling

Labbé¹,

Miu²,

Yeretssian

et al. 2010

The Journal of Immunology

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Pathogen sensing by the inflammasome activates inflammatory caspases that mediate inflammation and cell death. Caspase-12 antagonizes the inflammasome and NF-κB and is associated with susceptibility to bacterial sepsis. A single-nucleotide polymorphism (T125C) in human Casp12 restricts its expression to Africa, Southeast Asia, and South America. Here, we investigated the role of caspase-12 in the control of parasite replication and pathogenesis in malaria and report that caspase-12 dampened parasite clearance in blood-stage malaria and modulated susceptibility to cerebral malaria. This response was independent of the caspase-1 inflammasome, as casp1−/− mice were indistinguishable from wild-type animals in response to malaria, but dependent on enhanced NF-κB activation. Mechanistically, caspase-12 competed with NEMO for association with IκB kinase-α/β, effectively preventing the formation of the IκB kinase complex and inhibiting downstream transcriptional activation by NF-κB. Systemic inhibition of NF-κB or Ab neutralization of IFN-γ reversed the increased resistance of casp12−/− mice to blood-stage malaria infection.

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Section: Discussionsupporting

confidence: 91%

Caspase-12 Dampens the Immune Response to Malaria Independently of the Inflammasome by Targeting NF-κB Signaling

Labbé¹,

Miu²,

Yeretssian

et al. 2010

The Journal of Immunology

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“…Recently, several laboratories have utilized microarray technology to identify the host molecules associated with the pathogenesis of ECM in mice (15,31,35,55). The major biomarkers of ECM identified by transcriptional analysis included immune response genes and molecules associated with apoptosis pathways (15,31,35).…”

Section: Discussionmentioning

confidence: 99%

“…The major biomarkers of ECM identified by transcriptional analysis included immune response genes and molecules associated with apoptosis pathways (15,31,35). In one study that measured transcriptional alterations based on changes during the early stages of P. berghei infection in CM-susceptible and CM-resistant mice, detection of potent inflammatory responses, expression of molecules associated with brain injury repair, and early disturbances of brain metabolic energy metabolism were reported (14).…”

Section: Discussionmentioning

confidence: 99%

“…In our data set, levels of both proapoptotic and antiapoptotic genes were altered during ECM. Two recent studies also reported alterations in the expression of proapoptotic pathway genes during the cerebral phase in mice (31,35). We focused our attention on p21 (the kinase inhibitor of the Cip/Kip family), a molecule important in the regulation of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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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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“…ϩ T cells prior to end-stage disease, markedly increases the expression of major histocompatibility complex I (MHC-I) molecules, ICAM-1 cell adhesion molecules, and CXCR3 ligands in endothelial cells (3,5). Together, these changes contribute to the recruitment of leukocytes, particularly CD8 ϩ T cells, to the brain microvasculature (3,6).…”

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confidence: 99%

IRGM3 Contributes to Immunopathology and Is Required for Differentiation of Antigen-Specific Effector CD8⁺T Cells in Experimental Cerebral Malaria

et al. 2015

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C erebral malaria (CM) is the most severe manifestation of Plasmodium falciparum malaria infection in humans, and it is responsible for more than half a million deaths annually, predominantly in sub-Saharan Africa (1). Gamma interferon (IFN-␥) production by leukocytes is a prominent feature of malarial infection. Typically, this IFN-␥ contributes to parasite clearance; however, it may also drive pathology (2). Clinically, the brain dysfunction that occurs during CM manifests as seizures and coma, with progression to death occurring in the absence of treatment. While a definitive understanding of the pathological events underlying CM remains elusive, considerable evidence supports a role for IFN-␥ (3).Infection of C57BL/6 mice with blood-stage Plasmodium berghei ANKA (PbA) leads to experimental cerebral malaria (ECM), which reproduces many features of human CM (4). IFN-␥, produced either by NK cells or by CD4ϩ T cells prior to end-stage disease, markedly increases the expression of major histocompatibility complex I (MHC-I) molecules, ICAM-1 cell adhesion molecules, and CXCR3 ligands in endothelial cells (3,5). Together, these changes contribute to the recruitment of leukocytes, particularly CD8 ϩ T cells, to the brain microvasculature (3, 6). Current evidence indicates that CD8 ϩ T cell-derived IFN-␥ itself does not contribute to pathology (7). Instead, cross-presentation of malaria antigen on central nervous system (CNS) microvascular endothelial cells and recognition by CD8 ϩ cytotoxic T cells (8) leads to endothelial damage in a granzyme B-and perforin-dependent manner (9, 10). Despite the accumulation of knowledge of the effects of IFN-␥ in Plasmodium infection, its actions are highly pleiotropic; therefore, it is likely that IFN-␥-dependent pathways that influence disease progression are yet to be identified.Among the nearly 2,000 genes that are known to be modulated by IFN-␥ (11), the p47 immunity-related GTPases (IRGs) are critical for protection against a range of intracellular bacteria, protozoa, and viruses in diverse cell types (12, 13). A subset of IRGs (IRGM1-IRGM3 in mice and the constitutively expressed IRGMa-IRGMd, resulting from alternative splicing, in humans) Citation Guo J, McQuillan JA, Yau B, Tullo GS, Long CA, Bertolino P, Roediger B, Weninger W, Taylor GA, Hunt NH, Ball HJ, Mitchell AJ. 2015. IRGM3 contributes to immunopathology and is required for differentiation of antigen-specific effector CD8 ϩ T cells in experimental cerebral malaria.

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Predominance of Interferon-Related Responses in the Brain during Murine Malaria, as Identified by Microarray Analysis

Cited by 27 publications

References 66 publications

Caspase-12 Dampens the Immune Response to Malaria Independently of the Inflammasome by Targeting NF-κB Signaling

Caspase-12 Dampens the Immune Response to Malaria Independently of the Inflammasome by Targeting NF-κB Signaling

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

IRGM3 Contributes to Immunopathology and Is Required for Differentiation of Antigen-Specific Effector CD8⁺T Cells in Experimental Cerebral Malaria

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Predominance of Interferon-Related Responses in the Brain during Murine Malaria, as Identified by Microarray Analysis

Cited by 27 publications

References 66 publications

Caspase-12 Dampens the Immune Response to Malaria Independently of the Inflammasome by Targeting NF-κB Signaling

Caspase-12 Dampens the Immune Response to Malaria Independently of the Inflammasome by Targeting NF-κB Signaling

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

IRGM3 Contributes to Immunopathology and Is Required for Differentiation of Antigen-Specific Effector CD8+T Cells in Experimental Cerebral Malaria

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Product

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IRGM3 Contributes to Immunopathology and Is Required for Differentiation of Antigen-Specific Effector CD8⁺T Cells in Experimental Cerebral Malaria