Mechanistically, our data show that the type I IFN response to PbA is essential for CXCL9 and CXCL10 expression that govern pathogenic T-cell recruitment to the brain, and ECM pathology (Fig. 7). Indeed, the increased

survival, reduced neurological signs, ischemia and microvascular pathology, and brain morphologic changes seen by MRI/MRA in the absence of type I IFN signaling were associated with a lower T-cell response in the brain. We documented earlier the parallel between flow cytometry analysis of brain CD8+ T-cell number and activation and the expression of T-cell response markers such as IFN-γ measured by qPCR [8]. Here, ECM protection was concurrent with decreased PCI-32765 cost brain levels of CD3ε, CD8α, Granzyme B, IFN-γ, and IL-12Rβ2 expression, although these decreases were less prominent than in ECM resistant IFN-γR1−/− mice. The reduced Granzyme B expression in ECM-protected IFNR-deficient mice was in line with the reported essential role of CD8+ T-cell Granzyme B expression mTOR inhibitor for ECM development [38].

Reduced brain T-cell sequestration and decrease in IFN-γ expression, essential for ECM development [11, 12], might explain the ECM protection seen in IFNAR1−/− mice. The reduced brain sequestration of activated effector CD8+ and CD4+ T lymphocytes upon PbA infection in IFNAR1-deficient mice was associated with a reduced membrane expression of CXCR3, a chemokine receptor associated with murine ECM [45]. T-cell chemoattractants, CXCR3 ligands CXCL9, CXCL10, and CXCL11 expression were strongly reduced in IFNAR1−/− mice and almost abrogated

in IFN-γR1−/− mice. Both CXCL9 and CXCL10 were shown to be essential for CD8+ T-cell trafficking to the brain and ECM development [39, 40]. They are the initial chemokines induced in the brain during ECM onset, 6 days post PbA infection, at a time when IFN-γ, CCL5, CCL3, or CCL2 are still low, thus likely induced by the innate immune response [39]. CXCL9 and CXCL10 induction was reported to be MyD88-dependent [46], attributed to TLR responses to PbA [39]. But IFNs are also strong inducers of CXCL9 and CXCL10. AT-rich Plasmodium DNA induced IFN-β via a pathway involving STING, TBK1, and IRF3/IRF7 signaling [42]. Early splenic release of IFN-α was reported 1–2 days post-PbA infection in mice [21]. Microglia respond to IFN-β IMP dehydrogenase by increasing chemokines and cytokines, and most prominently CXCR3 ligands CXCL9, CXCL10, and CXCL11 [47]. CXCL9 is further expressed by brain endothelial cells and astrocytes in response to IFN-γ, while CXCL10 is expressed by endothelial cells, neurons, astrocytes, and microglial cells in response to either type I IFNs or IFN-γ [39, 47, 48]. Thus, we propose that type I IFNs might be a missing link between innate and adaptive response to PbA, central for chemokines expression and pathogenic T-cell recruitment to the brain and ECM development.