title: Spatiotemporal requirements for IRF7 in mediating type I IFN-dependent susceptibility to blood-stage Plasmodium infection.
abstract: Type I IFN signaling suppresses splenic T helper 1 (Th1) responses during blood-stage Plasmodium berghei ANKA (PbA) infection in mice, and is crucial for mediating tissue accumulation of parasites and fatal cerebral symptoms via mechanisms that remain to be fully characterized. Interferon regulatory factor 7 (IRF7) is considered to be a master regulator of type I IFN responses. Here, we assessed IRF7 for its roles during lethal PbA infection and nonlethal Plasmodium chabaudi chabaudi AS (PcAS) infection as two distinct models of blood-stage malaria. We found that IRF7 was not essential for tissue accumulation of parasites, cerebral symptoms, or brain pathology. Using timed administration of anti-IFNAR1 mAb, we show that late IFNAR1 signaling promotes fatal disease via IRF7-independent mechanisms. Despite this, IRF7 significantly impaired early splenic Th1 responses and limited control of parasitemia during PbA infection.  Finally, IRF7 also suppressed antiparasitic immunity and Th1 responses during nonlethal PcAS infection. Together, our data support a model in which IRF7 suppresses antiparasitic immunity in the spleen, while IFNAR1-mediated, but IRF7-independent, signaling contributes to pathology in the brain during experimental blood-stage malaria.
authors.affiliation: Malaria Immunology Laboratory, QIMR Berghofer Institute, Brisbane, Australia.
authors.forename: Chelsea L
authors.initials: CL
authors.lastname: Edwards
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Best
authors.forename: Sin Yee
authors.initials: SY
authors.lastname: Gun
authors.forename: Carla
authors.initials: C
authors.lastname: Claser
authors.forename: Kylie R
authors.initials: KR
authors.lastname: James
authors.forename: Marcela Montes
authors.initials: MM
authors.lastname: de Oca
authors.forename: Ismail
authors.initials: I
authors.lastname: Sebina
authors.forename: Fabian de Labastida
authors.initials: Fde L
authors.lastname: Rivera
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Amante
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hertzog
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
authors.forename: Laurent
authors.initials: L
authors.lastname: Renia
authors.forename: Ashraful
authors.initials: A
authors.lastname: Haque
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology; D004198:Disease Susceptibility; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D005786:Gene Expression Regulation; D006790:Host-Parasite Interactions; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology*; D016779:Malaria, Cerebral / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000276:immunology; D016788:Plasmodium chabaudi / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013154:Spleen / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology; D018417:Th1 Cells / Q000276:immunology* / Q000469:parasitology; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; C508032:Ifnar1 protein, mouse; D050839:Interferon Regulatory Factor-7; C494235:Irf7 protein, mouse; D053633:Receptor, Interferon alpha-beta
keywords: Cytokines; Immune regulation; Interferons; Malaria; T helper cells