Abstract
Francisella tularensis, the causative agent of tularemia, infects host macrophages, which triggers production of the proinflammatory cytokines interleukin 1beta (IL-1beta) and IL-18. We elucidate here how host macrophages recognize F. tularensis and elicit this proinflammatory response. Using mice deficient in the DNA-sensing inflammasome component AIM2, we demonstrate here that AIM2 is required for sensing F. tularensis. AIM2-deficient mice were extremely susceptible to F. tularensis infection, with greater mortality and bacterial burden than that of wild-type mice. Caspase-1 activation, IL-1beta secretion and cell death were absent in Aim2(-/-) macrophages in response to F. tularensis infection or the presence of cytoplasmic DNA. Our study identifies AIM2 as a crucial sensor of F. tularensis infection and provides genetic proof of its critical role in host innate immunity to intracellular pathogens.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Calcium Signaling / immunology
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Caspase 1 / genetics
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Caspase 1 / immunology
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Caspase 1 / metabolism
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Cells, Cultured
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DNA-Binding Proteins
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Francisella tularensis / immunology*
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Francisella tularensis / pathogenicity
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Humans
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Immunity, Innate*
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Interferon Regulatory Factor-3 / genetics
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Interferon Regulatory Factor-3 / immunology
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Interferon Regulatory Factor-3 / metabolism
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Interferon Type I / immunology
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology
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L-Lactate Dehydrogenase / genetics
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L-Lactate Dehydrogenase / immunology
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L-Lactate Dehydrogenase / metabolism
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Macrophages / immunology
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Macrophages / metabolism*
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Macrophages / pathology
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Mice
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Mice, Knockout
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Multiprotein Complexes / genetics
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Multiprotein Complexes / immunology
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Multiprotein Complexes / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / immunology*
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Nuclear Proteins / metabolism*
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Protein Multimerization
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Tularemia / genetics
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Tularemia / immunology*
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Tularemia / metabolism
Substances
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Aim2 protein, mouse
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DNA-Binding Proteins
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Interferon Regulatory Factor-3
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Interferon Type I
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Interleukin-1beta
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Irf3 protein, mouse
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Multiprotein Complexes
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Nuclear Proteins
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L-Lactate Dehydrogenase
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Caspase 1