scholarly journals S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria

2017 ◽  
Vol 85 (9) ◽  
Author(s):  
Robyn E. Elphinstone ◽  
Rickvinder Besla ◽  
Eric A. Shikatani ◽  
Ziyue Lu ◽  
Alfred Hausladen ◽  
...  
Keyword(s):  
T Cell ◽  
Cerebral Malaria ◽  
Clinical Outcomes ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Blood Brain Barrier Integrity

ABSTRACT Artesunate remains the mainstay of treatment for cerebral malaria, but it is less effective in later stages of disease when the host inflammatory response and blood-brain barrier integrity dictate clinical outcomes. Nitric oxide (NO) is an important regulator of inflammation and microvascular integrity, and impaired NO bioactivity is associated with fatal outcomes in malaria. Endogenous NO bioactivity in mammals is largely mediated by S-nitrosothiols (SNOs). Based on these observations, we hypothesized that animals deficient in the SNO-metabolizing enzyme, S-nitrosoglutathione reductase (GSNOR), which exhibit enhanced S-nitrosylation, would have improved outcomes in a preclinical model of cerebral malaria. GSNOR knockout (KO) mice infected with Plasmodium berghei ANKA had significantly delayed mortality compared to WT animals (P < 0.0001), despite higher parasite burdens (P < 0.01), and displayed markedly enhanced survival versus the wild type (WT) when treated with the antimalarial drug artesunate (77% versus 38%; P < 0.001). Improved survival was associated with higher levels of protein-bound NO, decreased levels of CD4+ and CD8+ T cells in the brain, improved blood-brain barrier integrity, and improved coma scores, as well as higher levels of gamma interferon. GSNOR KO animals receiving WT bone marrow had significantly reduced survival following P. berghei ANKA infection compared to those receiving KO bone barrow (P < 0.001). Reciprocal transplants established that survival benefits of GSNOR deletion were attributable primarily to the T cell compartment. These data indicate a role for GSNOR in the host response to malaria infection and suggest that strategies to disrupt its activity will improve clinical outcomes by enhancing microvascular integrity and modulating T cell tissue tropism.

scholarly journals Beta Interferon Suppresses the Development of Experimental Cerebral Malaria

2011 ◽  
Vol 79 (4) ◽  
pp. 1750-1758 ◽  
Author(s):  
Craig N. Morrell ◽  
Kalyan Srivastava ◽  
AnneMarie Swaim ◽  
M. Teresa Lee ◽  
Jun Chen ◽  
...  
Keyword(s):  
T Cell ◽  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Vascular Inflammation ◽  
Brain Barrier ◽  
Experimental Cerebral Malaria ◽  
Beta Interferon ◽  
Cxcr3 Expression ◽  
Blood Brain ◽  
The Brain

ABSTRACTCerebral malaria (CM) is a major complication ofPlasmodium falciparuminfection, 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. bergheiinfection 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-treatedP. 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.

scholarly journals Damage to the Blood-Brain Barrier during Experimental Cerebral Malaria Results from Synergistic Effects of CD8+T Cells with Different Specificities

2014 ◽  
Vol 82 (11) ◽  
pp. 4854-4864 ◽  
Author(s):  
Chek Meng Poh ◽  
Shanshan W. Howland ◽  
Gijsbert M. Grotenbreg ◽  
Laurent Rénia
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Synergistic Effects ◽  
Brain Barrier ◽  
High Dose ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Blood Brain

ABSTRACTCD8+T cells play a pathogenic role in the development of murine experimental cerebral malaria (ECM) induced byPlasmodium bergheiANKA (PbA) infection in C57BL/6 mice. Only a limited number of CD8+epitopes have been described. Here, we report the identification of a new epitope from the bergheilysin protein recognized by PbA-specific CD8+T cells. Induction and functionality of these specific CD8+T cells were investigated in parallel with previously reported epitopes, using new tools such as tetramers and reporter cell lines that were developed for this study. We demonstrate that CD8+T cells of diverse specificities induced during PbA infection share many characteristics. They express cytolytic markers (gamma interferon [IFN-γ], granzyme B) and chemokine receptors (CXCR3, CCR5) and damage the blood-brain barrierin vivo. Our earlier finding that brain microvessels in mice infected with PbA, but not with non-ECM-causing strains, cross-presented a shared epitope was generalizable to these additional epitopes. Suppressing the induction of specific CD8+T cells through tolerization with a high-dose peptide injection was unable to confer protection against ECM, suggesting that CD8+T cells of other specificities participate in this process. The tools that we developed can be used to further investigate the heterogeneity of CD8+T cell responses that are involved in ECM.

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