These studies pointed to complex crossregulations between type I and type II IFNs. Here, we investigated side-by-side the role of types I or II IFN pathways in ECM development in response to either hepatic or blood-stage

PbA infection. We confirmed that IFN-γR1−/− mice are fully resistant to ECM after PbA merozoite infection [11, 12] and documented for the first time their absence of brain pathology and Nutlin-3a in vivo vascular flow perturbation by MRI/MRA. Further, we extended the study to show ECM resistance of IFN-γR1−/− mice after PbA liver-stage/sporozoite infection. On the other hand, IFNAR1−/− mice showed partial protection or delay in ECM development after PbA sporozoite or merozoite infection. Therefore, we show for the first time that the types I or II IFN pathways are central to ECM development following sporozoite-initiated infection.

Type I IFN pathway was reported to suppress T-cell dependent parasite control during blood-stage PbA infection [21]. Here however, ECM protection was not associated with a decrease in parasitemia or thrombocytopenia in either type I Ibrutinib purchase or type II IFNR-deficient mice, after hepatic or blood-stage PbA infection. Therefore, our data are not in line with the previous study of Haque et al. [21], which concluded that IFNAR1−/− mice exhibited protection against cerebral malaria associated with reduced parasitemia and increased T-cell mediated

parasite control, but are in agreement with that of Sharma et al. [42] that reported no difference in parasitemia in IFNAR1−/− mice after blood-stage PbA infection. However, protection against cerebral malaria of IFNAR1−/− mice was shown in one survival Silibinin curve in Sharma et al. [42], which is only partial in our hands. Differences in deletion, genetic background or experimental conditions might account for the difference in the extent of protection of the IFNAR−/− mice used. We used mice deficient for IFNAR1 subunit, deleted for exon 3–4, from Muller et al. [43] while Haque et al. [21] used IFNAR1−/− mice deleted for exon 5, from Hwang et al. [44]; Sharma et al. did not mention the origin of the IFNAR1−/− mice they used [42]. Furthermore, the role of type I IFNs in ECM development after sporozoite infection was not addressed in these studies, and we report for the first time the role of type I and type II IFNs in cerebral malaria pathogenesis after sporozoite infection. PbA-associated lung inflammation was unaffected in IFNAR1−/− and IFN-γR1−/− mice, pointing to an effect on ECM adaptive response rather than on systemic parasite control and inflammatory response.