Interferon‐γ is essential for the development of cerebral malaria

Rudin, W.; Favre, Nicolas; Bordmann, G.; Ryffel, Bernhard

doi:10.1002/eji.1830270403

Cited by 76 publications

(63 citation statements)

References 29 publications

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“…Importantly, IL-1 and IL-6 can stimulate chemokine secretion (30,77); thus, their release may offer a means of locally amplifying the immunological response. Consistent with these findings, extensive data have documented high IL-1 and IL-6 levels in both human (3)(4)(5) and murine malaria (12,13), which have been implicated in both antiparasitic activity and disease severity. Similarly, in vitro studies have revealed IL-1 and IL-6 induction in response to P. falciparum (15) and to HZ (21,23,24).…”

Section: Discussionsupporting

confidence: 54%

“…In addition to data from P. falciparum-infected patients, cytokine (e.g., TNF-␣, IFN-␥, IL-6) and chemokine (e.g., MCP-1, IFN-␥-inducible protein-10 (IP-10), RANTES) induction has also been reported in experimental models of murine malaria (12)(13)(14), in which it appears to be involved in both protective immunity and pathogenesis. Moreover, in vitro studies have provided evidence of leukocyte activation during malaria infection.…”

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confidence: 98%

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Hemozoin-Inducible Proinflammatory Events In Vivo: Potential Role in Malaria Infection

Jaramillo

Plante

Ouellet

et al. 2004

The Journal of Immunology

123

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During malaria infection, high levels of proinflammatory molecules (e.g., cytokines, chemokines) correlate with disease severity. Even if their role as activators of the host immune response has been studied, the direct contribution of hemozoin (HZ), a parasite metabolite, to such a strong induction is not fully understood. Previous in vitro studies demonstrated that both Plasmodium falciparum HZ and synthetic HZ (sHZ), β-hematin, induce macrophage/monocyte chemokine and proinflammatory cytokine secretion. In the present study, we investigated the proinflammatory properties of sHZ in vivo. To this end, increasing doses of sHZ were injected either i.v. or into an air pouch generated on the dorsum of BALB/c mice over a 24-h period. Our results showed that sHZ is a strong modulator of leukocyte recruitment and more specifically of neutrophil and monocyte populations. In addition, evaluation of chemokine and cytokine mRNA and protein expression revealed that sHZ induces the expression of chemokines, macrophage-inflammatory protein (MIP)-1α/CCL3, MIP-1β/CCL4, MIP-2/CXCL2, and monocyte chemoattractant protein-1/CCL2; chemokine receptors, CCR1, CCR2, CCR5, CXCR2, and CXCR4; cytokines, IL-1β and IL-6; and myeloid-related proteins, S100A8, S100A9, and S100A8/A9, in the air pouch exudates. Of interest, chemokine and cytokine mRNA up-regulation were also detected in the liver of i.v. sHZ-injected mice. In conclusion, our study demonstrates that sHZ is a potent proinflammatory agent in vivo, which could contribute to the immunopathology related to malaria.

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Section: Discussionsupporting

confidence: 54%

mentioning

confidence: 98%

Hemozoin-Inducible Proinflammatory Events In Vivo: Potential Role in Malaria Infection

Jaramillo

Plante

Ouellet

et al. 2004

The Journal of Immunology

123

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“…IFN-␥ produced by other types of cells could play a role in ECM. Indeed, IFN-␥ was shown to be required for PbA-induced endothelial ICAM-1 up-regulation (27), which might be involved in the interaction of effector CD8 lymphocytes with APC.…”

Section: Discussionmentioning

confidence: 99%

Perforin-Dependent Brain-Infiltrating Cytotoxic CD8+ T Lymphocytes Mediate Experimental Cerebral Malaria Pathogenesis

Nitcheu¹,

Bonduelle

Combadière

et al. 2003

The Journal of Immunology

267

303

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Experimental cerebral malaria (ECM) resulting from Plasmodium berghei ANKA infection involves T lymphocytes. However, the mechanisms of T cell-mediated pathogenesis remain unknown. We found that, in contrast to ECM-susceptible C57BL6 mice, perforin-deficient (PFP-KO) mice were resistant to ECM in the absence of brain lesions, whereas cytoadherence of parasitized erythrocytes and massive accumulation of activated/effector CD8 lymphocytes were observed in both groups of mice. ECM is induced in PFP-KO mice after adoptive transfer of cytotoxic CD8+ cells from infected C57BL6 mice, which were directed to the brain of PFP-KO mice. This specific recruitment might involve chemokine/chemokine receptors, since their expression was up-regulated on activated CD8 cells, and susceptibility to ECM was delayed in CCR5-KO mice. Thus, lymphocyte cytotoxicity and cell trafficking are key players in ECM pathogenesis.

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“…or PbK (14 days p.i.) upon real-time PCR validation, highlighting the importance of IFN-␥ during the pathogenesis of FMCM (1,13,51).…”

Section: Discussionmentioning

confidence: 99%

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

2008

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Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. We examined global gene expression patterns during fatal murine CM (FMCM) and noncerebral malaria (NCM) by microarray analysis. There was differential expression of a number of genes, including some not yet characterized in the pathogenesis of FMCM. Some gene induction was observed during Plasmodium berghei infection regardless of the development of CM, and there was a predominance of genes linked to interferon responses, even in NCM. However, upon real-time PCR validation and quantitation, these genes were much more highly expressed in FMCM than in NCM. The observed changes included genes belonging to pathways such as interferon signaling, major histocompatibility complex processing and presentation, apoptosis, and immunomodulatory and antimicrobial processes. We further characterized differentially expressed genes by examining the cellular source of their expression as well as their temporal expression patterns during the course of malaria infection. These data identify a number of novel genes that represent interesting candidates for further investigation in FMCM.Malaria is a devastating disease affecting developing countries in the tropical and subtropical regions of the world. Cerebral malaria (CM), a severe manifestation of Plasmodium falciparum infection, can lead to neurological complications and death (64). Murine models of malaria are important tools for studying the pathogenesis of malaria, with numerous clinical and histopathological similarities between human and murine malaria having been described (19). Comparisons between fatal murine CM (FMCM) and noncerebral malaria (NCM) provide valuable insights into the pathogenesis of CM.A number of significant changes in the murine brain that characterize CM have been described, including breakdown of the blood-brain barrier (62), redistribution and activation of glia (31,32,34), apoptosis of endothelial cells and astrocytes (46,47), metabolic changes (44, 48), and distinct patterns of chemokine gene expression (38).A recent approach to identifying novel changes within the brain during CM is to profile gene expression changes using microarray technology (9, 30). Microarray studies can generate a plethora of data that pinpoint involvement of unknown or poorly characterized genes, stimulating investigation of their biological functions. Some studies have used microarrays to examine global gene expression patterns during murine malaria, defining gene expression profiles that are associated with susceptibility or resistance to murine CM (26, 27), identifying genes in the brain that discriminate between different outcomes of Plasmodium infection (5), or describing trends in gene expression within the brain (55). Studies on the spleen have been performed to find genes that differentiate between cerebral and noncerebral (55) and between lethal and nonlethal (52) forms of murine malaria. Microarrays also have been used to examine Plasmodium infection in humans (14, 41) and monke...

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Interferon‐γ is essential for the development of cerebral malaria

Cited by 76 publications

References 29 publications

Hemozoin-Inducible Proinflammatory Events In Vivo: Potential Role in Malaria Infection

Hemozoin-Inducible Proinflammatory Events In Vivo: Potential Role in Malaria Infection

Perforin-Dependent Brain-Infiltrating Cytotoxic CD8+ T Lymphocytes Mediate Experimental Cerebral Malaria Pathogenesis

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

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