Chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are required for the development of murine cerebral malaria

Campanella, Gabriele; Tager, Andrew M.; Khoury, Joseph K. El; Thomas, Seddon Y.; Abrazinski, Tabitha A.; Manice, Lindsay A.; Colvin, Richard A.; Luster, Andrew D.

doi:10.1073/pnas.0801544105

Cited by 260 publications

(351 citation statements)

References 19 publications

(14 reference statements)

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“…The unique antiviral function of CXCL10 seems critical and indispensable for host defense during the early phase of DENV infection. Interestingly, this early role may not be restricted to DENV infection, because the production of CXCL10 by neurons has been reported for other infections of the CNS (21,36). Therefore, it is plausible that CXCL10 provides unique innate host defense to viral diseases that target neurons by providing an important means of protecting neurons from further infection before the adaptive immune response (recruitment of effector lymphocytes) is mounted.…”

Section: Discussionmentioning

confidence: 99%

Resistance to Dengue Virus Infection in Mice Is Potentiated by CXCL10 and Is Independent of CXCL10-Mediated Leukocyte Recruitment

Liao

2010

The Journal of Immunology

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CXCL10 is an IFN-inducible chemokine ligand that binds CXCR3, a receptor that is expressed on lymphocytes; CXCL10 shares the CXCR3 receptor with another two ligands, CXCL9 and CXCL11. Previously, we found that CXCL10−/− mice were more susceptible than wild-type (WT) mice to dengue virus (DENV) infection. In this study, we explored the mechanisms underlying this enhanced susceptibility. We found that viral loads were higher in the brains of CXCL10−/− mice than in WT mice. Presuming a defect in effector lymphocyte migration, we investigated whether recruitment of effector T cells and Ab-secreting cells to the infected tissues were impaired in CXCL10−/− mice. Unexpectedly, compared with WT, CXCL10−/− mice had comparable numbers of total infiltrating T cells, higher numbers of CXCR3+ T cells, and higher numbers of Ab-secreting cells in the brain. Additionally, we found that CXCL10 was induced in neurons following DENV infection and that CXCL10 competed with DENV for binding to cell surface heparan sulfate, a coreceptor for DENV entry, thus inhibiting binding of DENV to neuronal cells. These results demonstrate that the enhanced susceptibility of CXCL10−/− mice to DENV infection is not due to a defect in recruitment of effector lymphocytes but rather to an antiviral activity that promotes viral clearance.

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Section: Discussionmentioning

confidence: 99%

Resistance to Dengue Virus Infection in Mice Is Potentiated by CXCL10 and Is Independent of CXCL10-Mediated Leukocyte Recruitment

Liao

2010

The Journal of Immunology

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“…It is currently known that parasite sequestration is exacerbated by cytokine-mediated up-regulation of host endothelial receptors that bind to parasitized erythrocytes (i.e., intracellular adhesion molecule-1, vascular cellular adhesion molecule) (15,33,35,36). Studies in mice with deficiency in several inflammatory mediators (e.g., TNF-α) (37), other cytokines, and chemokines (38) suggest that the ECM model used in this study is mainly a cytokine-associated encephalopathy. Furthermore, it is accepted that severe anemia, another important cause of disease severity common to P. falciparum and Plasmodium vivax malaria, does not occur as a result of destruction of iRBCs per se, because for every iRBC destroyed during malaria, ∼32 non-iRBCs are removed from the circulation (39).…”

Section: Discussionmentioning

confidence: 99%

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Franklin

Ishizaka

Lamphier

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

106

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Excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria.immunotherapy | innate immunity | nucleic acid recognition | inflammation

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“…In mice, cerebral malaria is characterized by a complex cascade of events including breakdown of the bloodbrain barrier, sequestration of iRBCs in the brain microvessels, accumulation of leukocytes in the brain, and the production of proinflammatory cytokines (25,26). The analyses of a variety of mice deficient in cytokines (27,28), chemokines and chemokine receptors (29)(30)(31), and TLRs (32) have implicated a variety of immune mechanisms in resistance to cerebral malaria but have not led to a clear picture of the underlying cause of disease pathology. Although the genetic alterations in the SLE-prone mice described here are well defined, the cellular and molecular mechanism by which these alterations result in autoimmunity is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

Genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice

Waisberg¹,

Тарасенко²,

Vickers³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Plasmodium falciparum has exerted tremendous selective pressure on genes that improve survival in severe malarial infections. Systemic lupus erythematosus (SLE) is an autoimmune disease that is six to eight times more prevalent in women of African descent than in women of European descent. Here we provide evidence that a genetic susceptibility to SLE protects against cerebral malaria. Mice that are prone to SLE because of a deficiency in FcγRIIB or overexpression of Toll-like receptor 7 are protected from death caused by cerebral malaria. Protection appears to be by immune mechanisms that allow SLE-prone mice better to control their overall inflammatory responses to parasite infections. These findings suggest that the high prevalence of SLE in women of African descent living outside of Africa may result from the inheritance of genes that are beneficial in the immune control of cerebral malaria but that, in the absence of malaria, contribute to autoimmune disease.

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Chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are required for the development of murine cerebral malaria

Cited by 260 publications

References 19 publications

Resistance to Dengue Virus Infection in Mice Is Potentiated by CXCL10 and Is Independent of CXCL10-Mediated Leukocyte Recruitment

Resistance to Dengue Virus Infection in Mice Is Potentiated by CXCL10 and Is Independent of CXCL10-Mediated Leukocyte Recruitment

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria

Genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice

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