Type I interferons contribute to experimental cerebral malaria development in response to sporozoite or blood-stage Plasmodium berghei ANKA

Cerebral malaria is a severe complication of Plasmodium falciparum infection. Although T-cell activation and type II IFN- are required for Plasmodium bergheiANKA (PbA)-induced murine experimental cerebral malaria (ECM), the role of type I IFN-/ in ECM development remains unclear. Here, we address the role of the IFN-/ pathway in ECM devel-opment in response to hepatic or blood-stage PbA infection, using mice deficient for types I or II IFN receptors. While IFN-R1(-/-) mice were fully resistant, IFNAR1(-/-) mice showed delayed and partial protection to ECM after PbA infection. ECM resistance in IFN-R1(-/-) mice correlated with unaltered cerebral microcirculation and absence of ischemia, while WT and IFNAR1(-/-) mice developed distinct microvascular pathologies. ECM resistance appeared to be independent of parasitemia. Instead, key mediators of ECM were attenuated in the absence of IFNAR1, including PbA-induced brain sequestration of CXCR3(+)-activated CD8(+) T cells. This was associated with reduced expression of Granzyme B, IFN-, IL-12R2, and T-cell-attracting chemokines CXCL9 and CXCL10 in IFNAR1(-/-) mice, more so in the absence of IFN-R1. Therefore, the type I IFN-/ receptor pathway contributes to brain T-cell responses and microvascular pathology, although it is not as essential as IFN- for the development of cerebral malaria upon hepatic or blood-stage PbA infection.