title: Type I interferons suppress CD4⁺ T-cell-dependent parasite control during blood-stage Plasmodium infection.
abstract: During blood-stage Plasmodium infection, large-scale invasion of RBCs often occurs before the generation of cellular immune responses. In Plasmodium berghei ANKA (PbA)-infected C57BL/6 mice, CD4(+)  T cells controlled parasite numbers poorly, instead providing early help to pathogenic CD8(+)  T cells. Expression analysis revealed that the transcriptional signature of CD4(+)  T cells from PbA-infected mice was dominated by type I IFN (IFN-I) and IFN-γ-signalling pathway-related genes. A role for IFN-I during blood-stage Plasmodium infection had yet to be established. Here, we observed IFN-α protein production in the spleen of PbA-infected C57BL/6 mice over the first 2 days of infection. Mice deficient in IFN-I signalling had reduced parasite burdens, and displayed none of the fatal neurological symptoms associated with PbA infection. IFN-I substantially inhibited CD4(+)  T-bet(+)  T-cell-derived IFN-γ production, and prevented this emerging Th1 response from controlling parasites. Experiments using BM chimeric mice revealed that IFN-I signalled predominantly via radio-sensitive, haematopoietic cells, but did not suppress CD4(+)  T cells via direct signalling to this cell type. Finally, we found that IFN-I suppressed IFN-γ production, and hampered efficient control of parasitaemia in mice infected with non-lethal Plasmodium chabaudi. Thus, we have elucidated a novel regulatory pathway in primary blood-stage Plasmodium infection that suppresses CD4(+)  T-cell-mediated parasite control.
authors.affiliation: Immunology and Infection Laboratory, Queensland Institute of Medical Research and The Australian Centre for Vaccine Development, Herston, QLD, Australia. ashraful.haque@qimr.edu.au
authors.forename: Ashraful
authors.initials: A
authors.lastname: Haque
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Best
authors.forename: Anne
authors.initials: A
authors.lastname: Ammerdorffer
authors.forename: Laure
authors.initials: L
authors.lastname: Desbarrieres
authors.forename: Marcela Montes
authors.initials: MM
authors.lastname: de Oca
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Amante
authors.forename: Fabian
authors.initials: F
authors.lastname: de Labastida Rivera
authors.forename: Paul
authors.initials: P
authors.lastname: Hertzog
authors.forename: Glen M
authors.initials: GM
authors.lastname: Boyle
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D002478:Cells, Cultured; D057131:Immune Evasion; D007165:Immunosuppression Therapy; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008018:Life Cycle Stages; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000276:immunology* / Q000472:pathogenicity; D016788:Plasmodium chabaudi / Q000276:immunology* / Q000472:pathogenicity; D015398:Signal Transduction / Q000276:immunology; D020825:T-Box Domain Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D018183:Transplantation Chimera; D014774:Virulence; D000098815:T-bet Transcription Factor
chemical_list: D007370:Interferon Type I; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma