Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons
Daisy X. Ji, Kristen C. Witt, Dmitri I. Kotov, Shally R. Margolis, Alexander Louie, Victoria Chevée, Katherine J. Chen, Moritz M. Gaidt, Harmandeep S Dhaliwal, Angus Y. Lee, Stephen L. Nishimura, Dario S. Zamboni, Igor Kramnik, Daniel A. Portnoy, K. Heran Darwin, Russell E. Vance
Abstract
Type I interferons (IFNs) are essential for anti-viral immunity, but often impair protective immune responses during bacterial infections. An important question is how type I IFNs are strongly induced during viral infections, and yet are appropriately restrained during bacterial infections. The Super susceptibility to tuberculosis 1 ( Sst1 ) locus in mice confers resistance to diverse bacterial infections. Here we provide evidence that Sp140 is a gene encoded within the Sst1 locus that represses type I IFN transcription during bacterial infections. We generated Sp140 –/– mice and found that they are susceptible to infection by Legionella pneumophila and Mycobacterium tuberculosis . Susceptibility of Sp140 –/– mice to bacterial infection was rescued by crosses to mice lacking the type I IFN receptor ( Ifnar –/– ). Our results implicate Sp140 as an important negative regulator of type I IFNs that is essential for resistance to bacterial infections.