Antigen-presenting cell activation requires intrinsic and extrinsic STING signaling after the phagocytosis of DNA-damaged cells.

Antigen-presenting cells (APCs) are readily activated after phagocytosing infected or DNA-damaged cells but not normal apoptotic cells for reasons that are not well understood. Here, we demonstrate that after DNA damage events, cytosolic dsDNA species trigger intrinsic STING signaling and the production of key immunogenic proteins, including CCL5, which renders such cells capable of APC activation upon phagocytosis. These events involve the generation of immunogenic STING-inducible endosomal vesicles (SIEVEs) additionally comprising critical autophagy-associated proteins associated with cytosolic DNA species.

Exogenous non-coding dsDNA-dependent trans-activation of phagocytes augments anti-tumor immunity.

Stimulator of interferon genes (STING)-dependent signaling is requisite for effective anti-microbial and anti-tumor activity. STING signaling is commonly defective in cancer cells, which enables tumor cells to evade the immunosurveillance system. We evaluate here whether intrinsic STING signaling in such tumor cells could be reconstituted by creating recombinant herpes simplex viruses (rHSVs) that express components of the STING signaling pathway.

Evaluation of the immunogenicity and efficacy of an rVSV vaccine against Zika virus infection in macaca nemestrina.

Zika virus (ZIKV) is a mosquito-borne flavivirus that causes an acute febrile illness. ZIKV can be transmitted between sexual partners and from mother to fetus. Infection is strongly associated with neurologic complications in adults, including Guillain-Barré syndrome and myelitis, and congenital ZIKV infection can result in fetal injury and congenital Zika syndrome (CZS).

Epigenetic state determines the in vivo efficacy of STING agonist therapy.

While STING-activating agents have shown limited efficacy in early-phase clinical trials, multiple lines of evidence suggest the importance of tumor cell-intrinsic STING function in mediating antitumor immune responses. Although STING signaling is impaired in human melanoma, its restoration through epigenetic reprogramming can augment its antigenicity and T cell recognition. In this study, we show that reversal of methylation silencing of STING in murine melanoma cell lines using a clinically available DNA methylation inhibitor can improve agonist-induced STING activation and type-I IFN induction, which, in tumor-bearing mice, can induce tumor regression through a CD8 T cell-dependent immune response.

STING signalling is terminated through ESCRT-dependent microautophagy of vesicles originating from recycling endosomes.

Stimulator of interferon genes (STING) is essential for the type I interferon response against a variety of DNA pathogens. Upon emergence of cytosolic DNA, STING translocates from the endoplasmic reticulum to the Golgi where STING activates the downstream kinase TBK1, then to lysosome through recycling endosomes (REs) for its degradation. Although the molecular machinery of STING activation is extensively studied and defined, the one underlying STING degradation and inactivation has not yet been fully elucidated.

Dectin-1/IL-15 Pathway Affords Protection against Extrapulmonary Aspergillus fumigatus Infection by Regulating Natural Killer Cell Survival.

Aspergillus fumigatus is a ubiquitous, yet potentially pathogenic, mold. The immune system employs innate receptors, such as dectin-1, to recognize fungal pathogens, but the immunological networks that afford protection are poorly explored. Here, we investigated the role of dectin-1 in anti-A.

STING Signaling Drives Production of Innate Cytokines, Generation of CD8 T Cells and Enhanced Protection Against Infection.

A variety of signaling pathways are involved in the induction of innate cytokines and CD8 T cells, which are major players in protection against acute infection. Previous data have demonstrated that a TBK-1/IRF3-dependent signaling pathway promotes IFN-β production in response to , but the role for STING, a main interactor of these proteins, remained to be addressed. Here, we demonstrated that STING signaling is required for production of IFN-β, IL-6, and IL-12 in response to infection and that STING absence negatively impacts activation of IRF-dependent pathways in response to the parasite.

STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases.

Aims: Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis.

STING regulates metabolic reprogramming in macrophages via HIF-1α during Brucella infection.

Macrophages metabolic reprogramming in response to microbial insults is a major determinant of pathogen growth or containment. Here, we reveal a distinct mechanism by which stimulator of interferon genes (STING), a cytosolic sensor that regulates innate immune responses, contributes to an inflammatory M1-like macrophage profile upon Brucella abortus infection. This metabolic reprogramming is induced by STING-dependent stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), a global regulator of cellular metabolism and innate immune cell functions.

Epigenetic reprogramming of tumor cell-intrinsic STING function sculpts antigenicity and T cell recognition of melanoma.

Lack or loss of tumor antigenicity represents one of the key mechanisms of immune escape and resistance to T cell-based immunotherapies. Evidence suggests that activation of stimulator of interferon genes (STING) signaling in tumor cells can augment their antigenicity by triggering a type I IFN-mediated sequence of autocrine and paracrine events. Although suppression of this pathway in melanoma and other tumor types has been consistently reported, the mechanistic basis remains unclear.

Brucella suppress STING expression via miR-24 to enhance infection.

Brucellosis, caused by a number of Brucella species, remains the most prevalent zoonotic disease worldwide. Brucella establish chronic infections within host macrophages despite triggering cytosolic innate immune sensors, including Stimulator of Interferon Genes (STING), which potentially limit infection. In this study, STING was required for control of chronic Brucella infection in vivo.

Virus infection is controlled by hematopoietic and stromal cell sensing of murine cytomegalovirus through STING.

Recognition of DNA viruses, such as cytomegaloviruses (CMVs), through pattern-recognition receptor (PRR) pathways involving MyD88 or STING constitute a first-line defense against infections mainly through production of type I interferon (IFN-I). However, the role of these pathways in different tissues is incompletely understood, an issue particularly relevant to the CMVs which have broad tissue tropisms. Herein, we contrasted anti-viral effects of MyD88 versus STING in distinct cell types that are infected with murine CMV (MCMV).

STING signaling and host defense against microbial infection.

The first line of host defense against infectious agents involves activation of innate immune signaling pathways that recognize specific pathogen-associated molecular patterns (PAMPs). Key triggers of innate immune signaling are now known to include microbial-specific nucleic acid, which is rapidly detected in the cytosol of the cell. For example, RIG-I-like receptors (RLRs) have evolved to detect viral RNA species and to activate the production of host defense molecules and cytokines that stimulate adaptive immune responses.

STING Signaling in Melanoma Cells Shapes Antigenicity and Can Promote Antitumor T-cell Activity.

STING (stimulator of IFN genes) signaling is an innate immune pathway for induction of a spontaneous antitumor T-cell response against certain immunogenic tumors. Although antigen-presenting cells are known to be involved in this process, insight into the participation of tumor cell-intrinsic STING signaling remains weak. In this study, we find diversity in the regulation of STING signaling across a panel of human melanoma cell lines.

Cyclic Dinucleotides Trigger STING-Dependent Unfolded Protein Response That Favors Bacterial Replication.

is a facultative intracellular bacterium that causes brucellosis, a prevalent zoonosis that leads to abortion and infertility in cattle, and undulant fever, debilitating arthritis, endocarditis, and meningitis in humans. Signaling pathways triggered by involves stimulator of IFN genes (STING), which leads to production of type I IFNs. In this study, we evaluated the pathway linking the unfolded protein response (UPR) and the endoplasmic reticulum-resident transmembrane molecule STING, during infection.

Ovarian Cancer Cells Commonly Exhibit Defective STING Signaling Which Affects Sensitivity to Viral Oncolysis.

Ovarian cancer is the sixth most prevalent cancer in women and the most lethal of the gynecologic malignancies. Treatments have comprised the use of immunotherapeutic agents as well as oncolytic viruses, with varying results for reasons that remain to be clarified. To better understand the mechanisms that may help predict treatment outcome, we have evaluated innate immune signaling in select ovarian cancer cell lines, governed by the Stimulator of Interferon Genes (STING), which controls self or viral DNA-triggered cytokine production.

Combating herpesvirus encephalitis by potentiating a TLR3-mTORC2 axis.

TLR3 is a sensor of double-stranded RNA that is indispensable for defense against infection with herpes simplex virus type 1 (HSV-1) in the brain. We found here that TLR3 was required for innate immune responses to HSV-1 in neurons and astrocytes. During infection with HSV-1, TLR3 recruited the metabolic checkpoint kinase complex mTORC2, which led to the induction of chemokines and trafficking of TLR3 to the cell periphery.

Liver Immune Cells Release Type 1 Interferon Due to DNA Sensing and Amplify Liver Injury from Acetaminophen Overdose.

Hepatocytes may rupture after a drug overdose, and their intracellular contents act as damage-associated molecular patterns (DAMPs) that lead to additional leukocyte infiltration, amplifying the original injury. Necrosis-derived DNA can be recognized as a DAMP, activating liver non-parenchymal cells (NPCs). We hypothesized that NPCs react to DNA by releasing interferon (IFN)-1, which amplifies acetaminophen (APAP)-triggered liver necrosis.

Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells.

The ability of dying cells to activate antigen-presenting cells (APCs) is carefully controlled to avoid unwarranted inflammatory responses. Here, we show that engulfed cells containing cytosolic double-stranded DNA species (viral or synthetic) or cyclic di-nucleotides (CDNs) are able to stimulate APCs via extrinsic STING (stimulator of interferon genes) signaling, to promote antigen cross-presentation. In the absence of STING agonists, dying cells were ineffectual in the stimulation of APCs in trans.

Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING.

The cellular sensor stimulator of interferon genes (STING) initiates type I interferon (IFN) and cytokine production following association with cyclic dinucleotides (CDNs) generated from intracellular bacteria or via a cellular synthase, cGAS, after binding microbial or self-DNA. Although essential for protecting the host against infection, unscheduled STING signaling is now known to be responsible for a variety of autoinflammatory disorders. Here, we report a gain-of-function mutation in STING (R284S), isolated from a patient who did not require CDNs to augment activity and who manifested a constitutively active phenotype.

Oncolytic Viruses as Antigen-Agnostic Cancer Vaccines.

Selective destruction of neoplastic tissues by oncolytic viruses (OVs) leads to antigen-agnostic boosting of neoantigen-specific cytotoxic T lymphocyte (CTL) responses, making OVs ideal companions for checkpoint blockade therapy. Here we discuss the mechanisms whereby OVs modulate both adjuvanticity and antigenicity of tumor cells. Suppression of antitumor immunity after OV therapy has not been observed, possibly because viral antigen expression diminishes as the antiviral response matures, thereby progressively honing the CTL response to tumor neoantigens.