title: Type I interferons contribute to experimental cerebral malaria development in response to sporozoite or blood-stage Plasmodium berghei ANKA.
abstract: Cerebral malaria is a severe complication of Plasmodium falciparum infection. Although T-cell activation and type II IFN-γ are required for Plasmodium berghei ANKA (PbA)-induced murine experimental cerebral malaria (ECM), the role of type I IFN-α/β in ECM development remains unclear. Here, we address the role of the IFN-α/β 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-γR1⁻/⁻ mice were fully resistant, IFNAR1⁻/⁻ mice showed delayed and partial protection to ECM after PbA infection. ECM resistance in IFN-γR1⁻/⁻ 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-γ, IL-12Rβ2, and T-cell-attracting chemokines CXCL9 and CXCL10 in IFNAR1⁻/⁻ mice, more so in the absence of IFN-γR1. Therefore, the type I IFN-α/β receptor pathway contributes to brain T-cell responses and microvascular pathology, although it is not as essential as IFN-γ for the development of cerebral malaria upon hepatic or blood-stage PbA infection.
authors.affiliation: CNRS, UMR7355, Orléans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orleans, Orléans, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Palomo
authors.forename: Mathilde
authors.initials: M
authors.lastname: Fauconnier
authors.forename: Laurie
authors.initials: L
authors.lastname: Coquard
authors.forename: Maïlys
authors.initials: M
authors.lastname: Gilles
authors.forename: Sandra
authors.initials: S
authors.lastname: Meme
authors.forename: Frederic
authors.initials: F
authors.lastname: Szeremeta
authors.forename: Lizette
authors.initials: L
authors.lastname: Fick
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Franetich
authors.forename: Muazzam
authors.initials: M
authors.lastname: Jacobs
authors.forename: Dieudonnée
authors.initials: D
authors.lastname: Togbe
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Beloeil
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Valerie F J
authors.initials: VF
authors.lastname: Quesniaux
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000469:parasitology; D002465:Cell Movement / Q000235:genetics; D002531:Cerebellum / Q000276:immunology* / Q000469:parasitology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018450:Disease Progression; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D007511:Ischemia / Q000235:genetics; D016779:Malaria, Cerebral / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000235:genetics; D023421:Models, Animal; D010962:Plasmodium berghei / Q000276:immunology*; D010963:Plasmodium falciparum / Q000276:immunology*; D054367:Receptors, CXCR3 / Q000378:metabolism; D017471:Receptors, Interferon / Q000235:genetics; D034101:Sporozoites / Q000276:immunology
chemical_list: D007370:Interferon Type I; D054367:Receptors, CXCR3; D017471:Receptors, Interferon
keywords: Chemokines; Experimental cerebral malaria; Merozoites; Sporozoites; Type I interferons (IFNs)