Abstract
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a virulent pathogen that induces rapid host death. Here we observed that host survival after infection with S. Typhimurium was enhanced in the absence of type I interferon signaling, with improved survival of mice deficient in the receptor for type I interferons (Ifnar1(-/-) mice) that was attributed to macrophages. Although there was no impairment in cytokine expression or inflammasome activation in Ifnar1(-/-) macrophages, they were highly resistant to S. Typhimurium-induced cell death. Specific inhibition of the kinase RIP1 or knockdown of the gene encoding the kinase RIP3 prevented the death of wild-type macrophages, which indicated that necroptosis was a mechanism of cell death. Finally, RIP3-deficient macrophages, which cannot undergo necroptosis, had similarly less death and enhanced control of S. Typhimurium in vivo. Thus, we propose that S. Typhimurium induces the production of type I interferon, which drives necroptosis of macrophages and allows them to evade the immune response.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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GTPase-Activating Proteins / antagonists & inhibitors
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GTPase-Activating Proteins / metabolism*
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Immune Evasion
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Inflammasomes
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Interferon Type I / immunology
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Interferon Type I / metabolism*
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Macrophage Activation
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Macrophages / immunology
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Macrophages / microbiology
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Macrophages / physiology*
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Mice
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Mice, Inbred C57BL
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Receptor, Interferon alpha-beta / deficiency
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Receptor, Interferon alpha-beta / genetics
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Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
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Receptor-Interacting Protein Serine-Threonine Kinases / deficiency
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
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Salmonella Infections, Animal / immunology*
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Salmonella Infections, Animal / metabolism
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Salmonella Infections, Animal / microbiology
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Salmonella typhimurium / immunology
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Salmonella typhimurium / pathogenicity*
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Signal Transduction
Substances
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GTPase-Activating Proteins
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Ifnar1 protein, mouse
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Inflammasomes
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Interferon Type I
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Ralbp1 protein, mouse
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Receptor, Interferon alpha-beta
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk3 protein, mouse