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.

The role of STING signaling in central nervous system infection and neuroinflammatory disease

“…cGAS has been shown to bind a variety of different nucleic acids independent of sequence (Civril et al, 2013; L. Sun et al, 2013), so unsurprisingly cGAS‐STING signaling has been shown to also play a role in the response to a number of bacteria (reviewed extensively in Guimarães et al, 2021; N. Liu et al, 2022; Marinho et al, 2017). Interestingly, the production of IFNβ is detrimental to the clearance of many of these bacterial infections, including Brucella abortus (de Almeida et al, 2011) and Listeria monocytogenes (Archer et al, 2014; Jin et al, 2013; Sauer et al, 2011), suggesting the effects of STING signaling are highly context‐dependent.…”

The crucial regulatory role of type I interferon in inflammatory diseases

“…It serves a critical function in adjusting the host's immune response by releasing cytokines such as indoleamine 2,3-dioxygenase, inducible nitric oxide synthase (iNOS), immunoresponsive genes, and guanylate-binding proteins. The primary mechanism is through IFNγ, a part of the type II IFN family, which is indispensable for combating mycobacteria and other intracellular pathogens [ 236 , 237 ]. However, the effects of IFN-Is are dual-faced, potentially assisting or hindering the host's response to bacterial infections.…”

“…The low level of IFN-Is helps to initiate immune response and protect against the infection. They can inhibit bacterial growth and protect human and mouse cells by depleting l-tryptophan, an essential amino acid needed by bacteria for survival [ 236 ]. Furthermore, IFN-Is might protect against Chlamydia pneumoniae infection by working in tandem with IFNγ to suppress bacterial survival [ 238 ].…”

The role of bacterial cyclic di-adenosine monophosphate in the host immune response

“…STING functions as a direct PRR of cyclic dinucleotides (CDNs) such as c-di-AMP and c-di-GMP. Originating from intracellular bacteria as an essential adaptor, STING indirectly detects cytosolic DNA through cyclic GMP-AMP (cGAMP) synthase (cGAS) ( Aliakbar Tehrani et al, 2021 ; Guimarães et al, 2021 ). STING activation culminates in a robust inflammatory response associated with interferon regulatory factor 3 (IRF3) and the subsequent expression of IFN and other coregulated genes ( Guimarães et al, 2021 ).…”

“…Originating from intracellular bacteria as an essential adaptor, STING indirectly detects cytosolic DNA through cyclic GMP-AMP (cGAMP) synthase (cGAS) ( Aliakbar Tehrani et al, 2021 ; Guimarães et al, 2021 ). STING activation culminates in a robust inflammatory response associated with interferon regulatory factor 3 (IRF3) and the subsequent expression of IFN and other coregulated genes ( Guimarães et al, 2021 ). The helicase DDX41 is also a PRR that senses both c-di-GMP and c-di-AMP, and DDX41 has a higher affinity for c-di-GMP than STING.…”