Beta interferon suppresses the development of experimental cerebral malaria.
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, such as multiple sclerosis (MS) but has not yet been explored in the treatment of CM. Therefore, we sought to determine whether IFN-β also limits disease progression in experimental cerebral malaria (ECM). Plasmodium berghei-infected mice treated with IFN-β died later and showed increased survival, with improved blood-brain barrier function, compared to infected mice. IFN-β did not alter systemic parasitemia. However, we identified multiple action sites that were modified by IFN-β 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-β 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-α). In addition, IFN-β-treated P. berghei-infected mice also had fewer brain T-cell infiltrates, further demonstrating its protective effects. Hence, IFN-β has important anti-inflammatory properties that ameliorate the severity of ECM and prolong mouse survival.
Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
Craig N
CN
Morrell
Kalyan
K
Srivastava
Annemarie
A
Swaim
M Teresa
MT
Lee
Jun
J
Chen
Chandrashakaharam
C
Nagineni
John J
JJ
Hooks
Barbara
B
Detrick
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000096:biosynthesis; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D016899:Interferon-beta / Q000627:therapeutic use*; D016779:Malaria, Cerebral / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei; D054367:Receptors, CXCR3 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D054370:Chemokine CXCL9; C515188:Cxcr3 protein, mouse; D007155:Immunologic Factors; D054367:Receptors, CXCR3; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D016899:Interferon-beta
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