Project Summary/Abstract (Project 3, Vance) Intracellular bacterial pathogens remain a major cause of human mortality and morbidity. By working collaboratively with other P01 Projects, we focus in Project 3 on the role of type I interferons (IFNs) in the innate immune response to three intracellular bacterial pathogens: Listeria monocytogenes, Mycobacterium tuberculosis, and Legionella pneumophila. As we and others have shown previously, all three pathogens induce the expression of type I IFNs via the STING pathway. However, while type I IFNs are generally accepted to play a crucial role in orchestrating anti-viral immunity, the roles of type I IFNs in the responses to bacteria are complex. Indeed, our work and that of other laboratories has shown that type I IFNs tend to exacerbate infection by bacterial pathogens, including M. tuberculosis, L. pneumophila and L. monocytogenes. Our preliminary data suggest that type I IFN-dependent induction of the interleukin-1 receptor antagonist (IL-1Ra) is an important mechanism by which type I IFNs exacerbate bacterial infections. Our preliminary data also suggest the existence of regulatory pathways to prevent the adverse induction of type I IFNs during bacterial infections. We identify SP140 and MORC3 as two novel negative regulators of type I IFN expression. We propose three Aims to explain why type I IFNs hinder anti-bacterial immunity and to explain how interferons are normally properly regulated during bacterial infections, in both mice and humans. In Aim 1, we test the hypothesis that type I IFNs antagonize anti-bacterial immunity via induction of IL-1 receptor antagonist, and determine the underlying mechanism. In Aim 2, we dissect the mechanism by which SP140 negatively regulates type I IFN transcription during bacterial infections. In Aim 3, we identify and characterize MORC3 as a novel negative regulator of type I IFN in human cells, and determine its function during bacterial infection.

Project Narrative (Project 3, Vance) Intracellular bacterial pathogens cause significant mortality and morbidity worldwide. Here we propose to determine how innate immunity mediates resistance or susceptibility to three intracellular bacterial pathogens (Listeria monocytogenes, Legionella pneumophila, and Mycobacterium tuberculosis) with a particular focus on the role of type I interferons. We expect our work to lay a foundation for the rational therapeutic intervention in these infections.