STING is a Common Driver of Type I Interferon Responses to Diverse Bacteria in Macrophages

Pattern recognition receptors (PRRs) of the innate immune system detect conserved bacterial molecules, termed pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs) are considered the only PRRs that can detect all bacteria, regardless of virulence potential. These PRRs survey PAMPs in the extracellular and phagosomal space, where most bacteria are found. Other PRR families mostly consist of proteins that are localized to the cytosol of immune cells. Due to the membranous barrier of phagosomes, cytosolic PRRs should be restricted from accessing extracellular or phagosomal bacteria and are generally considered to detect pathogens that use virulence factors to disrupt membranes. Despite this rationale, disparate reports suggest that some non-pathogenic, phagosomal bacteria stimulate cytosolic PRRs. In this work, we tested the null hypothesis that TLRs are the only PRRs that commonly detect bacteria. We found that diverse bacteria, regardless of their pathogenicity, stimulated type I interferon (IFN-I) responses in macrophages. While optimal IFN-I responses to Gram-negative bacteria required TLRs, all bacteria stimulated IFN-I through the cytosolic PRR STING. Synthetic biology-based engineering of bacteria to produce distinct STING stimulatory cyclic dinucleotides (CDNs) revealed that CDN abundance within phagosomes is a key determinant of IFN-I induction by macrophages. The STING pathway therefore joins the TLRs as a common driver of innate immune responses to bacterial encounters.### Competing Interest StatementJCK consults and holds equity in Corner Therapeutics, Larkspur Biosciences and Neumora Therapeutics. None of these relationships influenced the manuscript.