Abstract
The mouse cytomegalovirus (MCMV) resistome is the set of host genes with nonredundant functions in resistance to MCMV infection. By screening 3500 G3 germline mutant mice (∼1750 gamete equivalents), we have identified eight transmissible mutations that create MCMV susceptibility in C57BL/6 mice. Among these, a mutation called Domino was noted to cause macrophage susceptibility to vesicular stomatitis virus (VSV) in vitro. This accessory phenotype was not corrected by type I interferon (IFN), which suggested a defect of the type I IFN pathway. Domino corresponds to a point mutation that alters the DNA binding domain of STAT1, leading to a defect of STAT1 activation. Identification of the Domino mutation demonstrates that an in vivo MCMV susceptibility screen is feasible and illustrates how it can provide insight into the resistome. Moreover, some mutations are far more deleterious than Domino in MCMV-infected mice, consistent with the interpretation that certain protein(s) unrelated to IFN production or signaling are more important than IFNs with regard to their net antiviral effects.
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Acknowledgments
The authors are grateful to Carl Ware, Professor of the La Jolla Institute for Allergy and Immunology (La Jolla, CA), for providing the MCMV virus and for helpful discussions. This work was supported by NIH grant No. AI054523. This is TSRI manuscript No. 17947-IMM.
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The Mouse Genome Informatics (MGI) accession ID of the Domino allele described in this article is MGI: 3619019.
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Crozat, K., Georgel, P., Rutschmann, S. et al. Analysis of the MCMV resistome by ENU mutagenesis. Mamm Genome 17, 398–406 (2006). https://doi.org/10.1007/s00335-005-0164-2
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DOI: https://doi.org/10.1007/s00335-005-0164-2