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The N-Ethyl-N-Nitrosourea-Induced Goldenticket Mouse Mutant Reveals an Essential Function of Sting in the In Vivo Interferon Response to Listeria monocytogenes and Cyclic Dinucleotides

Author:
Sauer, John-Demian, Sotelo-Troha, Katia, von Moltke, Jakob, Monroe, Kathryn M., Rae, Chris S., Brubaker, Sky W., Hyodo, Mamoru, Hayakawa, Yoshihiro, Woodward, Joshua J., Portnoy, Daniel A., Vance, Russell E.
Source:
Infection and immunity 2011 v.79 no.2 pp. 688-694
ISSN:
0019-9567
Subject:
DNA, Listeria monocytogenes, N-ethyl-N-nitrosourea, RNA, adaptive immunity, bacterial infections, bites and stings, chromosome mapping, innate immunity, interferons, macrophages, mice, microbial detection, mutagenesis, mutagenicity, mutants, null alleles, pathogens
Abstract:
Type I interferons (IFNs) are central regulators of the innate and adaptive immune responses to viral and bacterial infections. Type I IFNs are induced upon cytosolic detection of microbial nucleic acids, including DNA, RNA, and the bacterial second messenger cyclic-di-GMP (c-di-GMP). In addition, a recent study demonstrated that the intracellular bacterial pathogen Listeria monocytogenes stimulates a type I IFN response due to cytosolic detection of bacterially secreted c-di-AMP. The transmembrane signaling adaptor Sting (Tmem173, Mita, Mpys, Eris) has recently been implicated in the induction of type I IFNs in response to cytosolic DNA and/or RNA. However, the role of Sting in response to purified cyclic dinucleotides or during in vivo L. monocytogenes infection has not been addressed. In order to identify genes important in the innate immune response, we have been conducting a forward genetic mutagenesis screen in C57BL/6 mice using the mutagen N-ethyl-N-nitrosourea (ENU). Here we describe a novel mutant mouse strain, Goldenticket (Gt), that fails to produce type I IFNs upon L. monocytogenes infection. By genetic mapping and complementation experiments, we found that Gt mice harbor a single nucleotide variant (T596A) of Sting that functions as a null allele and fails to produce detectable protein. Analysis of macrophages isolated from Gt mice revealed that Sting is absolutely required for the type I interferon response to both c-di-GMP and c-di-AMP. Additionally, Sting is required for the response to c-di-GMP and L. monocytogenes in vivo. Our results provide new functions for Sting in the innate interferon response to pathogens.
Agid:
289172