Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons

Ji, D. X.; Witt, K. C.; Kotov, D. I.; Margolis, S. R.; Louie, A.; Chen, K. J.; Dhaliwal, H. S.; Lee, A. Y.; Zamboni, D. S.; Kramnik, I.; Portnoy, D. A.; Darwin, K. H.; Vance, R. E.

doi:10.1101/2020.01.07.897553

bioRxiv · 10.1101/2020.01.07.897553

Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons

Ji, D. X.·Witt, K. C.·Kotov, D. I.·Margolis, S. R.·Louie, A.·Chen, K. J.·Dhaliwal, H. S.·Lee, A. Y.·Zamboni, D. S.·Kramnik, I.·Portnoy, D. A.·Darwin, K. H.·Vance, R. E.

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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 find 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. Impact StatementRepression of type I interferons by SP140 is essential for resistance to Legionella pneumophila and Mycobacterium tuberculosis.

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Ji, D. X., Witt, K. C., Kotov, D. I., Margolis, S. R., Louie, A., Chen, K. J., Dhaliwal, H. S., Lee, A. Y., Zamboni, D. S., Kramnik, I., Portnoy, D. A., Darwin, K. H., Vance, R. E.. 2020-01-08. Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons. https://doi.org/10.1101/2020.01.07.897553

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