CXCR3 determines strain susceptibility to murine cerebral malaria by mediating T lymphocyte migration toward IFN‐γ‐induced chemokines

Abstract

Cerebral malaria (CM) results from the binding of infected erythrocytes and leukocytes to brain endothelia. The precise mechanisms underlying lymphocyte recruitment and activation in CM remain unclear. Therefore, the expression of various chemokines was quantified in brains of mice infected with Plasmodium berghei ANKA (PbA). Several chemokines attracting monocytes and activated T-lymphocytes were expressed at high levels. Their expression was almost completely abrogated in IFN-c ligand and receptor KO mice, indicating that IFN-c is an essential chemokine inducer in vivo. Surprisingly, the expression levels of chemokines, IFN-c and also adhesion molecules in the brain were not lower in CM-resistant Balb/c and DBA/2 mice compared to CM-sensitive C57BL/6 and DBA/1 mice, although T lymphocyte sequestration in the brain was significantly less in CMresistant than in CM-sensitive mice. This difference correlated with a higher up-regulation of the CXC chemokine receptor (CXCR)-3 on splenic T cells and a higher chemotactic response to IFN-c-inducible protein-10 (IP-10) in C57BL/6 compared to Balb/c mice. In conclusion, parasite-induced IFN-c in the brain results in high local expression levels of specific chemokines for monocytes and lymphocytes. The strain-dependent susceptibility to develop CM is more related to the expression of CXCR3 in circulating leukocytes than to the chemokine expression levels in the brain.

Beta Interferon Suppresses the Development of Experimental Cerebral Malaria

“…Components of the IFN system are known to be important in the development of ECM (15,21). As previously reported, high levels of IFN-␥ were produced in response to Plasmodium infection, and IFN␥ Ϫ/Ϫ mice were protected against ECM (25).…”

“…Three recent studies have reported that CXCR3 is important for the development of ECM. First, the strain-dependent susceptibility to develop ECM is closely related to the expression of CXCR3 on T cells (9,21). Second, mice deficient in CXCR3 were protected from ECM (2,9,17,21).…”

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

“…The chemokine receptors CXCR3 and, to a lesser extent, CCR5 are involved in ECM development, as abrogation of these receptors in mice conferred some protection against ECM (32)(33)(34)(35). With the ability to identify by tetramer staining CD8 ϩ T cells recognizing malaria epitopes Pb1, Pb2, and F4 during infection, we set out to determine if these cells express such markers.…”

Current Advances in Cerebral Malaria Associated Encephalopathy

“…More recently, a pioneering study conducted both in India and Ghana, identified CXCL10 as a serum and CSF biomarker associated with increased risk of fatal P. falciparum-mediated CM in humans (Armah, Wilson et al 2007;Jain, Armah et al 2008;Wilson, Huang et al 2008). Subsequently, studies from a murine CM model also confirmed the importance of CXCL10/CXCR3 interactions in the pathogenesis of fatal CM through the recruitment and activation of pathogenic CD8+ T cells (Belnoue, Potter et al 2008; Van den Steen, Deroost et al 2008). CXCL10-/-and CXCR3-/-mice are partially resistant to P. berghei-mediated CM.…”

“…In contrast, CD4+ natural regulatory T cells [CD4(+) Foxp3(+) CD25(+), Treg] in animals prevent cerebral malaria via CTLA-4 (but not IL-10) when expanded in vivo. In addition to CD4+ T cells, studies from a murine CM model also confirmed that CXCL10/CXCR3 interactions in the pathogenesis of fatal CM is through the recruitment and activation of pathogenic CD8+ T cells (Belnoue, Potter et al 2008;Van den Steen, Deroost et al 2008). The reason why CXCR3-/-mice were resistant to CM is potentially due to a reduction in the number of CD8+ T cells (Miu, Mitchell et al 2008).…”