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 Macrophage migration inhibitory factor: a neuroendocrine modulator of chronic inflammation

2003 ◽  
Vol 179 (1) ◽  
pp. 15-23 ◽  
Author(s):  
JA Baugh ◽  
SC Donnelly
Keyword(s):  
Inflammatory Response ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Molecular Mechanisms ◽  
Adaptive Immune Response ◽  
Gene Promoter ◽  
Chronic Inflammatory Disease ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Promoter Polymorphisms

The diverse actions of macrophage migration inhibitory factor (MIF) within the immuno-neuroendocrine system are yet to be fully understood, but it is clear that MIF plays a pivotal role in the regulation of both the innate and adaptive immune response. An emerging body of data presently indicates that MIF's position within the cytokine cascade is to act in concert with glucocorticoids to control the 'set point' and magnitude of the immune and inflammatory response. In this article we will review the actions of MIF within the immune system and discuss the overlapping and contrasting aspects of MIF and glucocorticoid biology. In particular we will focus on the role of MIF within the immuno-neuroendocrine interface and suggest molecular mechanisms by which MIF may counter-regulate glucocorticoid function. Finally we will discuss emerging evidence that functional MIF gene-promoter polymorphisms render one susceptible to elevated MIF expression, and the development of an exaggerated immune/inflammatory response that potentiates the progression to chronic inflammatory disease.

scholarly journals γδ-T cells promote IFN-γ–dependent Plasmodium pathogenesis upon liver-stage infection

2019 ◽  
Vol 116 (20) ◽  
pp. 9979-9988 ◽  
Author(s):  
Julie C. Ribot ◽  
Rita Neres ◽  
Vanessa Zuzarte-Luís ◽  
Anita Q. Gomes ◽  
Liliana Mancio-Silva ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cerebral Malaria ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Γδ T Cells ◽  
Experimental Cerebral Malaria ◽  
Liver Stage ◽  
Ifn Γ ◽  
Stage Infection

Cerebral malaria (CM) is a major cause of death due to Plasmodium infection. Both parasite and host factors contribute to the onset of CM, but the precise cellular and molecular mechanisms that contribute to its pathogenesis remain poorly characterized. Unlike conventional αβ-T cells, previous studies on murine γδ-T cells failed to identify a nonredundant role for this T cell subset in experimental cerebral malaria (ECM). Here we show that mice lacking γδ-T cells are resistant to ECM when infected with Plasmodium berghei ANKA sporozoites, the liver-infective form of the parasite and the natural route of infection, in contrast with their susceptible phenotype if challenged with P. berghei ANKA-infected red blood cells that bypass the liver stage of infection. Strikingly, the presence of γδ-T cells enhanced the expression of Plasmodium immunogenic factors and exacerbated subsequent systemic and brain-infiltrating inflammatory αβ-T cell responses. These phenomena were dependent on the proinflammatory cytokine IFN-γ, which was required during liver stage for modulation of the parasite transcriptome, as well as for downstream immune-mediated pathology. Our work reveals an unanticipated critical role of γδ-T cells in the development of ECM upon Plasmodium liver-stage infection.

scholarly journals Limited Role of CD4+Foxp3+Regulatory T Cells in the Control of Experimental Cerebral Malaria

2009 ◽  
Vol 183 (11) ◽  
pp. 7014-7022 ◽  
Author(s):  
Christiane Steeg ◽  
Guido Adler ◽  
Tim Sparwasser ◽  
Bernhard Fleischer ◽  
Thomas Jacobs
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cerebral Malaria ◽  
Experimental Cerebral Malaria ◽  
Limited Role

scholarly journals Chemokine Receptor CCR2 Is Not Essential for the Development of Experimental Cerebral Malaria

2003 ◽  
Vol 71 (6) ◽  
pp. 3648-3651 ◽  
Author(s):  
Elodie Belnoue ◽  
Fabio T. M. Costa ◽  
Ana M. Vigário ◽  
Tatiana Voza ◽  
Françoise Gonnet ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Chemokine Receptor ◽  
Experimental Cerebral Malaria ◽  
T Cell Migration ◽  
Mice Brain ◽  
The Brain ◽  
Deficient Mice ◽  
Chemokine Receptor Ccr2

ABSTRACT Infection with Plasmodium berghei ANKA induces cerebral malaria in susceptible mice. Brain-sequestered CD8+ T cells are responsible for this pathology. We have evaluated the role of CCR2, a chemokine receptor expressed on CD8+ T cells. Infected CCR2-deficient mice were as susceptible to cerebral malaria as wild-type mice were, and CD8+ T-cell migration to the brain was not abolished.

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 On the Pathogenic Role of Brain-Sequestered αβ CD8+T Cells in Experimental Cerebral Malaria

2002 ◽  
Vol 169 (11) ◽  
pp. 6369-6375 ◽  
Author(s):  
Elodie Belnoue ◽  
Michèle Kayibanda ◽  
Ana M. Vigario ◽  
Jean-Christophe Deschemin ◽  
Nico van Rooijen ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Pathogenic Role ◽  
Experimental Cerebral Malaria

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.

scholarly journals Role of the Macrophage Migration Inhibitory Factor in the Pathophysiology of Pre-Eclampsia

2021 ◽  
Vol 22 (4) ◽  
pp. 1823
Author(s):  
Tullia Todros ◽  
Luana Paulesu ◽  
Simona Cardaropoli ◽  
Alessandro Rolfo ◽  
Bianca Masturzo ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Late Onset ◽  
Maternal Serum ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Placental Development ◽  
Major Player

Proinflammatory cytokines are produced in pregnancy in response to the invading pathogens and/or nonmicrobial causes such as damage-associated molecules and embryonic semi-allogenic antigens. While inflammation is essential for a successful pregnancy, an excessive inflammatory response is implicated in several pathologies including pre-eclampsia (PE). This review focuses on the proinflammatory cytokine macrophage migration inhibitory factor (MIF), a critical regulator of the innate immune response and a major player of processes allowing normal placental development. PE is a severe pregnancy-related syndrome characterized by exaggerated inflammatory response and generalized endothelial damage. In some cases, usually of early onset, it originates from a maldevelopment of the placenta, and is associated with intrauterine growth restriction (IUGR) (placental PE). In other cases, usually of late onset, pre-pregnancy maternal diseases represent risk factors for the development of the disease (maternal PE). Available data suggest that low MIF production in early pregnancy could contribute to the abnormal placentation. The resulting placental hypoxia in later pregnancy could produce high release of MIF in maternal serum typical of placental PE. More studies are needed to understand the role of MIF, if any, in maternal PE.

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