scholarly journals KCC1 Activation protects Mice from the Development of Experimental Cerebral Malaria

2017 ◽  
Author(s):  
Elinor Hortle ◽  
Lora Starrs ◽  
Fiona Brown ◽  
Stephen Jane ◽  
David Curtis ◽  
...  
Keyword(s):  
T Cells ◽  
Plasmodium Falciparum ◽  
Inflammatory Response ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
K Channel ◽  
Experimental Cerebral Malaria ◽  
Important Mediator ◽  
Tnf Α ◽  
Altered Response

AbstractPlasmodium falciparum malaria causes half a million deaths per year, with up to 9% of this mortality caused by cerebral malaria (CM). One of the major processes contributing to the development of CM is an excess of host inflammatory cytokines. Recently K+ signaling has emerged as an important mediator of the inflammatory response to infection; we therefore investigated whether mice carrying an ENU induced activation of the electroneutral K+ channel KCC1 had an altered response to Plasmodium berghei. Here we show that Kcc1M935K/M935K mice are protected from the development of experimental cerebral malaria, and that this protection is associated with an increased CD4+ T cells and TNF-α response. This is the first description of a K+ channel affecting the development of experimental cerebral malaria.

scholarly journals Suppression of Plasmodium MIF-CD74 Signaling Protects Against Severe Malaria

2021 ◽  
Author(s):  
Alvaro Baeza Garcia ◽  
Edwin Siu ◽  
Xin Du ◽  
Lin Leng ◽  
Blandine Franke-Fayard ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Response ◽  
Cerebral Malaria ◽  
Macrophage Migration Inhibitory Factor ◽  
Molecular Mechanisms ◽  
Macrophage Migration ◽  
Erythrocytic Stage ◽  
Experimental Cerebral Malaria ◽  
Brain Microvessels

AbstractMalaria begins when mosquito-borne Plasmodium sporozoites invade hepatocytes and usurp host pathways to support the differentiation and multiplication of erythrocyte-infective merozoite progeny. The deadliest complication of infection, cerebral malaria, accounts for the majority of malarial fatalities. Although our understanding of the cellular and molecular mechanisms underlying the pathology remains incomplete, recent studies support the contribution of systemic and neuroinflammation as the cause of cerebral edema and blood-brain barrier (BBB) dysfunction. All Plasmodium species encode an orthologue of the innate cytokine, Macrophage Migration Inhibitory Factor (MIF), which functions in mammalian biology to regulate innate responses. Plasmodium MIF (PMIF) similarly signals through the host MIF receptor CD74, leading to an enhanced inflammatory response. We investigated the PMIF-CD74 interaction in the onset of experimental cerebral malaria (ECM) using CD74 deficient (Cd74−/−) mice, which were found to be protected from ECM. The protection was associated with the inability of brain microvessels from Cd74−/− hosts to present parasite antigen to sequestered Plasmodium-specific CD8+ T cells. Infection of mice with PMIF-deficient sporozoites (PbAmif-) also protected mice from ECM, highlighting the pivotal role of PMIF in the pre-erythrocytic stage of the infection. A novel pharmacologic PMIF-selective antagonist reduced PMIF/CD74 signaling and fully protected mice from ECM. These findings reveal a conserved mechanism for Plasmodium usurpation of host CD74 signaling and suggest a tractable approach for new pharmacologic intervention.

scholarly journals Protein Kinase C θ Deficiency Increases Resistance of C57BL/6J Mice to Plasmodium berghei Infection-Induced Cerebral Malaria

2010 ◽  
Vol 78 (10) ◽  
pp. 4195-4205 ◽  
Author(s):  
Ariel Ohayon ◽  
Jacob Golenser ◽  
Rosa Sinay ◽  
Ami Tamir ◽  
Amnon Altman ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase C ◽  
T Cell ◽  
Protein Kinase ◽  
Immune Responses ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Neurological Symptoms ◽  
Experimental Cerebral Malaria ◽  
Kinase C

ABSTRACT Protein kinase C θ (PKCθ) functions as a core component of the immunological synapse and serves as a key protein in the integrated T-cell antigen receptor (TCR)/CD28-induced signaling cascade leading to T-cell activation. However, the involvement of PKCθ in host-mediated immune responses to pathogens has not been thoroughly investigated. We tested the consequences of PKCθ ablation on the host response to infection by Plasmodium berghei ANKA (PbA). We found that both PKCθ+/+ and PKCθ−/− C57BL/6J mice are susceptible to infection with PbA. However, despite a similar parasite burden, PKCθ+/+ mice had an earlier onset of neurological signs, characteristics of experimental cerebral malaria (ECM), resulting in an earlier death. These mice suffered from an early and pronounced splenomegaly with a concomitant increase in the total number of CD4+ splenic T cells. In contrast, a large proportion of PbA-infected PKCθ−/− mice overcame the acute phase characterized by neurological symptoms and survived longer than PKCθ+/+ mice. The partial resistance of PKCθ−/− mice to ECM was associated with an impaired production of Th1-type cytokines, including gamma interferon and tumor necrosis factor alpha/lymphotoxin-α, which are known to exacerbate symptoms leading to ECM. In addition, PbA infection-induced LFA-1 expression in CD8+ T cells was suppressed in PKCθ-deficient T cells, suggesting a diminished ability to adhere to endothelial cells and sequester in brain microvasculature, which may explain the decrease in neurological symptoms. These data implicate PKCθ in CD4+ Th1+ and CD8+ T-cell-mediated immune responses during PbA infection that contribute to the development of ECM.

scholarly journals Accumulation of Plasmodium berghei-Infected Red Blood Cells in the Brain Is Crucial for the Development of Cerebral Malaria in Mice

2010 ◽  
Vol 78 (9) ◽  
pp. 4033-4039 ◽  
Author(s):  
Fernanda G. Baptista ◽  
Ana Pamplona ◽  
Ana C. Pena ◽  
Maria M. Mota ◽  
Sylviane Pied ◽  
...  
Keyword(s):  
T Cells ◽  
Red Blood Cells ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Blood Cells ◽  
Human Infection ◽  
Experimental Cerebral Malaria ◽  
Human Pathology ◽  
The Brain ◽  
Malaria Model

ABSTRACT Cerebral malaria is the most severe complication of human infection with Plasmodium falciparum. It was shown that Plasmodium berghei ANKA-induced cerebral malaria was prevented in 100% of mice depleted of CD8+ T cells 1 day prior to the development of neurological signs. However, the importance of parasites in the brains of these mice was never clearly investigated. Moreover, the relevance of this model to human cerebral malaria has been questioned many times, especially concerning the relative importance of leukocytes versus parasitized erythrocytes sequestered in the brain. Here, we show that mice protected from cerebral malaria by CD8+ T-cell depletion have significantly fewer parasites in the brain. Treatment of infected mice with an antimalarial drug 15 to 20 h prior to the estimated time of death also protected mice from cerebral malaria without altering the number of CD8+ T cells in the brain. These mice subsequently developed cerebral malaria with parasitized red blood cells in the brain. Our results clearly demonstrated that sequestration of CD8+ T cells in the brain is not sufficient for the development of cerebral malaria in C57BL/6 mice but that the concomitant presence of parasitized red blood cells is crucial for the onset of pathology. Importantly, these results also demonstrated that the experimental cerebral malaria model shares many features with human pathology and might be a relevant model to study its pathogenesis.

scholarly journals Eosinophils Suppress the Migration of T Cells Into the Brain of Plasmodium berghei-Infected Ifnar1-/- Mice and Protect Them From Experimental Cerebral Malaria

2021 ◽  
Vol 12 ◽  
Author(s):  
Johanna F. Scheunemann ◽  
Julia J. Reichwald ◽  
Patricia Jebett Korir ◽  
Janina M. Kuehlwein ◽  
Lea-Marie Jenster ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
T Cell Responses ◽  
Cytotoxic T Cell ◽  
Type I ◽  
Experimental Cerebral Malaria ◽  
Cell Responses ◽  
The Brain

Cerebral malaria is a potentially lethal disease, which is caused by excessive inflammatory responses to Plasmodium parasites. Here we use a newly developed transgenic Plasmodium berghei ANKA (PbAAma1OVA) parasite that can be used to study parasite-specific T cell responses. Our present study demonstrates that Ifnar1-/- mice, which lack type I interferon receptor-dependent signaling, are protected from experimental cerebral malaria (ECM) when infected with this novel parasite. Although CD8+ T cell responses generated in the spleen are essential for the development of ECM, we measured comparable parasite-specific cytotoxic T cell responses in ECM-protected Ifnar1-/- mice and wild type mice suffering from ECM. Importantly, CD8+ T cells were increased in the spleens of ECM-protected Ifnar1-/- mice and the blood-brain-barrier remained intact. This was associated with elevated splenic levels of CCL5, a T cell and eosinophil chemotactic chemokine, which was mainly produced by eosinophils, and an increase in eosinophil numbers. Depletion of eosinophils enhanced CD8+ T cell infiltration into the brain and increased ECM induction in PbAAma1OVA-infected Ifnar1-/- mice. However, eosinophil-depletion did not reduce the CD8+ T cell population in the spleen or reduce splenic CCL5 concentrations. Our study demonstrates that eosinophils impact CD8+ T cell migration and proliferation during PbAAma1OVA-infection in Ifnar1-/- mice and thereby are contributing to the protection from ECM.

scholarly journals Depletion of CD4+ or CD8+ T-cells prevents Plasmodium berghei induced cerebral malaria in end-stage disease

Parasitology ◽  
1997 ◽  
Vol 114 (1) ◽  
pp. 7-12 ◽  
Author(s):  
C. HERMSEN ◽  
T. VAN DE WIEL ◽  
E. MOMMERS ◽  
R. SAUERWEIN ◽  
W. ELING
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Plasmodium Berghei ◽  
Experimental Cerebral Malaria ◽  
Chloroquine Treatment ◽  
Stage Disease ◽  
End Stage ◽  
Further Development

The role of T-cells in development of experimental cerebral malaria was analysed in C57B1/6J and C57B1/10 mice infected with Plasmodium berghei K173 or Plasmodium berghei ANKA by treatment with anti-CD4 or anti-CD8 mAbs. Mice were protected against cerebral malaria (CM) when anti-CD4 or anti-CD8 mAbs were injected before or during infection. Even in mice in end-stage disease, i.e. with a body temperature below 35·5 °C, treatment with anti-CD4 or anti-CD8 antibodies or the combination protected against CM, whereas chloroquine treatment was completely ineffective in inhibiting further development of the cerebral syndrome.

CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4253-4259 ◽  
Author(s):  
Elodie Belnoue ◽  
Michèle Kayibanda ◽  
Jean-Christophe Deschemin ◽  
Mireille Viguier ◽  
Matthias Mack ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
Wild Type ◽  
Experimental Cerebral Malaria ◽  
Pathologic Features ◽  
Th1 Cytokine ◽  
The Brain ◽  
Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

TNF-α inhibits the CD3-mediated upregulation of voltage-gated K+ channel (Kv1.3) in human T cells

2010 ◽  
Vol 391 (1) ◽  
pp. 909-914 ◽  
Author(s):  
Bo Pang ◽  
Haifeng Zheng ◽  
Dong Hoon Shin ◽  
Kyeong Cheon Jung ◽  
Jae Hong Ko ◽  
...  
Keyword(s):  
T Cells ◽  
K Channel ◽  
Voltage Gated ◽  
Human T Cells ◽  
Tnf Α

scholarly journals The systemic inflammatory response is involved in the regulation of K+channel expression in brain via TNF-α-dependent and -independent pathways

FEBS Letters ◽  
2004 ◽  
Vol 572 (1-3) ◽  
pp. 189-194 ◽  
Author(s):  
Rubén Vicente ◽  
Mireia Coma ◽  
Silvia Busquets ◽  
Rodrigo Moore-Carrasco ◽  
Francisco J López-Soriano ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Systemic Inflammatory Response ◽  
K Channel ◽  
Tnf Α ◽  
Channel Expression

scholarly journals Invariant Vα14 Chain NKT Cells Promote Plasmodium berghei Circumsporozoite Protein-Specific Gamma Interferon- and Tumor Necrosis Factor Alpha-Producing CD8+ T Cells in the Liver after Poxvirus Vaccination of Mice

2005 ◽  
Vol 73 (2) ◽  
pp. 849-858 ◽  
Author(s):  
Simone Korten ◽  
Richard J. Anderson ◽  
Carolyn M. Hannan ◽  
Eric G. Sheu ◽  
Robert Sinden ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Necrosis Factor ◽  
Plasmodium Berghei ◽  
Tumor Necrosis ◽  
Nkt Cells ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT Understanding the protective mechanism in the liver induced by recombinant vaccines against the pre-erythrocytic stages of malaria is important for vaccine development. Most studies in mice have focused on splenic and peripheral blood T cells and identified gamma interferon (IFN-γ)-producing CD8+ T cells as correlates of protection, which can be induced by prime-boost vaccination with recombinant poxviruses. Invariant natural killer T (Vα14iNKT) cells can also protect against liver stage malaria, when activated, and are abundant in the liver. Since poxviruses have nonspecific immunomodulating effects, which are incompletely understood, we investigated whether recombinant poxviruses affect the protective properties of hepatic Vα14iNKT cells and thus vaccine efficacy. We show that intradermal vaccination with recombinant poxviruses activated Vα14iNKT cells and NK cells in the livers of BALB/c mice while inducing IFN-γ- and tumor necrosis factor alpha (TNF-α)-producing pre-erythrocytic stage antigen-specific CD8+ T cells. Greater numbers of hepatic Vα14iNKT cells secreted interleukin-4 than IFN-γ. Vaccinated Vα14iNKT-cell-deficient mice had lower, but still protective levels of hepatic and splenic IFN-γ+ and TNF-α+ CD8+ T cells and better protection rates later after challenge with Plasmodium berghei sporozoites. Therefore, vaccine-activated hepatic Vα14iNKT cells help in generating specific T cells but are not required for protection induced by recombinant poxviruses. Furthermore, double-positive INF-γ+/TNF-α+ CD8+ T cells were enriched in protected livers, suggesting that cells expressing both of these cytokines may be most relevant for protection.

scholarly journals Efficacy of Proveblue (Methylene Blue) in an Experimental Cerebral Malaria Murine Model

2013 ◽  
Vol 57 (7) ◽  
pp. 3412-3414 ◽  
Author(s):  
Jérome Dormoi ◽  
Sébastien Briolant ◽  
Camille Desgrouas ◽  
Bruno Pradines
Keyword(s):  
Methylene Blue ◽  
Cerebral Malaria ◽  
Murine Model ◽  
Plasmodium Berghei ◽  
Active Metabolite ◽  
Line Treatment ◽  
First Line ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
First Line Treatment

ABSTRACTAlthough 100% of untreated mice infected withPlasmodium bergheidied with specific signs of cerebral malaria and 100% of mice treated with 3 mg/kg dihydroartemisinin, the active metabolite of artesunate, which is used as the first-line treatment for severe malaria, also died but showed no specific signs of cerebral malaria, 78% of mice treated with 10 mg/kg Proveblue (methylene blue) and 78% of mice treated with a combination of 3 mg dihydroartemisinin and 10 mg/kg Proveblue survived and showed no specific signs of cerebral malaria or detectable parasites.

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