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Beta interferon suppresses the development of experimental cerebral malaria.

ABSTRACT: Cerebral malaria (CM) is a major complication of Plasmodium falciparum infection, particularly in children. The pathogenesis of cerebral malaria involves parasitized red blood cell (RBC)-mediated vascular inflammation, immune stimulation, loss of blood-brain barrier integrity, and obstruction of cerebral capillaries. Therefore, blunting vascular inflammation and immune cell recruitment is crucial in limiting the disease course. Beta interferon (IFN-?) has been used in the treatment of diseases, such as multiple sclerosis (MS) but has not yet been explored in the treatment of CM. Therefore, we sought to determine whether IFN-? also limits disease progression in experimental cerebral malaria (ECM). Plasmodium berghei-infected mice treated with IFN-? died later and showed increased survival, with improved blood-brain barrier function, compared to infected mice. IFN-? did not alter systemic parasitemia. However, we identified multiple action sites that were modified by IFN-? administration. P. berghei infection resulted in increased expression of chemokine (C-X-C motif) ligand 9 (CXCL9) in brain vascular endothelial cells that attract T cells to the brain, as well as increased T-cell chemokine (C-X-C motif) receptor 3 (CXCR3) expression. The infection also increased the cellular content of intercellular adhesion molecule 1 (ICAM-1), a molecule important for attachment of parasitized RBCs to the endothelial cell. In this article, we report that IFN-? treatment leads to reduction of CXCL9 and ICAM-1 in the brain, reduction of T-cell CXCR3 expression, and downregulation of serum tumor necrosis factor alpha (TNF-?). In addition, IFN-?-treated P. berghei-infected mice also had fewer brain T-cell infiltrates, further demonstrating its protective effects. Hence, IFN-? has important anti-inflammatory properties that ameliorate the severity of ECM and prolong mouse survival.

SUBMITTER: Morrell CN

PROVIDER: S-EPMC3067534 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Beta interferon suppresses the development of experimental cerebral malaria.

Morrell Craig N CN Srivastava Kalyan K Swaim Annemarie A Lee M Teresa MT Chen Jun J Nagineni Chandrashakaharam C Hooks John J JJ Detrick Barbara B

Infection and immunity 20110118 4

Cerebral malaria (CM) is a major complication of Plasmodium falciparum infection, particularly in children. The pathogenesis of cerebral malaria involves parasitized red blood cell (RBC)-mediated vascular inflammation, immune stimulation, loss of blood-brain barrier integrity, and obstruction of cerebral capillaries. Therefore, blunting vascular inflammation and immune cell recruitment is crucial in limiting the disease course. Beta interferon (IFN-β) has been used in the treatment of diseases, ...[more]

PMID: 21245265

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Project description:UnlabelledMalaria is an infectious disease caused by parasites of several Plasmodium spp. Cerebral malaria (CM) is a common form of severe malaria resulting in nearly 700,000 deaths each year in Africa alone. At present, there is no adjunctive therapy for CM. Although the mechanisms underlying the pathogenesis of CM are incompletely understood, it is likely that both intrinsic features of the parasite and the human host's immune response contribute to disease. The kinase mammalian target of rapamycin (mTOR) is a central regulator of immune responses, and drugs that inhibit the mTOR pathway have been shown to be antiparasitic. In a mouse model of CM, experimental CM (ECM), we show that the mTOR inhibitor rapamycin protects against ECM when administered within the first 4 days of infection. Treatment with rapamycin increased survival, blocked breakdown of the blood-brain barrier and brain hemorrhaging, decreased the influx of both CD4(+) and CD8(+) T cells into the brain and the accumulation of parasitized red blood cells in the brain. Rapamycin induced marked transcriptional changes in the brains of infected mice, and analysis of transcription profiles predicted that rapamycin blocked leukocyte trafficking to and proliferation in the brain. Remarkably, animals were protected against ECM even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen. These results open a new avenue for the development of highly selective adjunctive therapies for CM by targeting pathways that regulate host and parasite metabolism.ImportanceMalaria is a highly prevalent infectious disease caused by parasites of several Plasmodium spp. Malaria is usually uncomplicated and resolves with time; however, in about 1% of cases, almost exclusively among young children, malaria becomes severe and life threatening, resulting in nearly 700,000 deaths each year in Africa alone. Among the most severe complications of Plasmodium falciparum infection is cerebral malaria with a fatality rate of 15 to 20%, despite treatment with antimalarial drugs. Cerebral malaria takes a second toll on African children, leaving survivors at high risk of debilitating neurological defects. At present, we have no effective adjunctive therapies for cerebral malaria, and developing such therapies would have a large impact on saving young lives in Africa. Here we report results that open a new avenue for the development of highly selective adjunctive therapies for cerebral malaria by targeting pathways that regulate host and parasite metabolism.

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Beta interferon suppresses the development of experimental cerebral malaria.

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Beta interferon suppresses the development of experimental cerebral malaria.

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