Abstract
Type I interferons (T1IFNs) are among the earliest cytokines produced during infections due to their direct regulation by innate immune signaling pathways. Reports have suggested that T1IFNs are produced during malaria infection, but little is known about the in vivo cellular origins of T1IFNs or their role in protection. We have found that in addition to plasmacytoid dendritic cells, splenic red pulp macrophages (RPMs) can generate significant quantities of T1IFNs in response to P. chabaudi infection in a TLR9-, MYD88-, and IRF7-dependent manner. Furthermore, T1IFNs regulate expression of interferon-stimulated genes redundantly with Interferon-gamma (IFNG), resulting in redundancy for resistance to experimental malaria infection. Despite their role in sensing and promoting immune responses to infection, we observe that RPMs are dispensable for control of parasitemia. Our results reveal that RPMs are early sentinels of malaria infection, but that effector mechanisms previously attributed to RPMs are not essential for control.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Female
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Flow Cytometry
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Immunity, Innate / genetics
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Immunity, Innate / immunology
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Interferon Regulatory Factor-7 / genetics
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Interferon Regulatory Factor-7 / immunology
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Interferon Regulatory Factor-7 / metabolism
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Interferon Type I / genetics
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Interferon Type I / immunology*
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Interferon Type I / metabolism
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Macrophages / immunology*
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Macrophages / metabolism
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Malaria / immunology*
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Malaria / metabolism
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Malaria / parasitology
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Mice
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / immunology
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Myeloid Differentiation Factor 88 / metabolism
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Oligonucleotide Array Sequence Analysis
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Plasmodium chabaudi / immunology*
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Plasmodium chabaudi / physiology
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Receptor, Interferon alpha-beta / genetics
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Receptor, Interferon alpha-beta / immunology
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Receptor, Interferon alpha-beta / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics
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Signal Transduction / immunology
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Spleen / immunology*
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Spleen / metabolism
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Time Factors
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Toll-Like Receptor 9 / genetics
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Toll-Like Receptor 9 / immunology
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Toll-Like Receptor 9 / metabolism
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Transcriptome / genetics
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Transcriptome / immunology
Substances
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Ifnar1 protein, mouse
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Interferon Regulatory Factor-7
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Interferon Type I
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Irf7 protein, mouse
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Myeloid Differentiation Factor 88
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Toll-Like Receptor 9
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Receptor, Interferon alpha-beta