Impact of STING Inflammatory Signaling during Intracellular Bacterial Infections

Abstract

The early detection of bacterial pathogens through immune sensors is an essential step in innate immunity. STING (Stimulator of Interferon Genes) has emerged as a key mediator of inflammation in the setting of infection by connecting pathogen cytosolic recognition with immune responses. STING detects bacteria by directly recognizing cyclic dinucleotides or indirectly by bacterial genomic DNA sensing through the cyclic GMP-AMP synthase (cGAS). Upon activation, STING triggers a plethora of powerful signaling pathways, including the production of type I interferons and proinflammatory cytokines. STING activation has also been associated with the induction of endoplasmic reticulum (ER) stress and the associated inflammatory responses. Recent reports indicate that STING-dependent pathways participate in the metabolic reprogramming of macrophages and contribute to the establishment and maintenance of a robust inflammatory profile. The induction of this inflammatory state is typically antimicrobial and related to pathogen clearance. However, depending on the infection, STING-mediated immune responses can be detrimental to the host, facilitating bacterial survival, indicating an intricate balance between immune signaling and inflammation during bacterial infections. In this paper, we review recent insights regarding the role of STING in inducing an inflammatory profile upon intracellular bacterial entry in host cells and discuss the impact of STING signaling on the outcome of infection. Unraveling the STING-mediated inflammatory responses can enable a better understanding of the pathogenesis of certain bacterial diseases and reveal the potential of new antimicrobial therapy.

Keywords: STING; bacteria; cyclic dinucleotides; infection; inflammation; type I interferon.

Figure 1

STING signaling in response to B. abortus infection. The intracellular bacteria, B. abortus, enters the host cell and forms the Brucella containing vacuole (BCV), to ensure survival. Upon the guanylate binding proteins (GBP)-mediated lysis of the BCV, bacterial components, such as Brucella DNA and bacterial cyclic di-nucleotides (CDNs), are exposed in the cytosol. The stimulator of interferon genes (STING) can directly sense bacterial CDNs or indirectly sense the Brucella DNA through the cyclic GMP-AMP synthase (cGAS). The recognition of CDNs through STING, triggers endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), culminating in type I interferon (IFN) and inflammatory cytokine production, through pathways not completely understood. Additionally, activated STING traffics from the ER to the Golgi, which facilitates TANK-binding kinase 1 (TBK1) recruitment and phosphorylation. Activated TBK1, phosphorylates interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB) to induce type I IFNs and other inflammatory cytokines. Additionally, STING contributes to the metabolic reprogramming in macrophages. STING activation, during B. abortus infection, leads to the accumulation of the metabolite succinate, through pathways not completely understood, which in turn favors mitochondrial ROS (mROS) generation. Succinate and mROS drive hypoxia-inducible factor1-alpha (HIF-1α) stabilization, leading to enhanced IL-1β release, nitric oxide (NO) production, and induction of a glycolytic metabolic profile. cGAMP: cyclic GMP-AMP; IKK: IκB kinase complex; and IκBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha.

Figure 2

Type I IFN effects and mechanisms of action during bacterial infections. Stimulator of interferon genes (STING) direct sensing of bacterial cyclic di-nucleotides (CDN), or indirect sensing of bacterial DNA through cyclic GMP-AMP synthase (cGAS), leads to the induction of type I interferons (IFN). Type I IFNs bind to the type I IFN receptor (IFNAR), leading to Janus kinase (JAK)–signal transducer activator of transcription (STAT; JAK-STAT) signaling. Activation of JAKs, results in tyrosine phosphorylation of STAT1 and STAT2, leading to the formation of the IFN-stimulated gene factor 3 (ISGF3) (STAT1-STAT2-IFN-regulatory factor 9 (IRF9)) signaling complex. This canonical signal transducer complex, translocates to the nucleus and binds to IFN-stimulated response elements (ISREs) in gene promoters, leading to the induction of numerous IFN-stimulated genes (ISGs). Type I IFNs activate multiple components of host innate and adaptive immune responses, and type I IFN effects range from protective to detrimental to the host and include a variety of possible mechanisms of action. The main effects and mechanisms of action described for the bacteria addressed in this review are represented in the figure. cGAMP: cyclic GMP-AMP (cGAMP) ER: endoplasmic reticulum; IRF3: Interferon regulatory factor 3; IFN-γ: interferon gamma; NO: nitric oxide; M1: inflammatory macrophages; M2: anti-inflammatory macrophages; and IL: interleukin.