The devastating effects of COVID-19 have underscored the critical need for effective prophylactic and therapeutic strategies to combat respiratory diseases. One promising avenue lies in the activation of the Stimulator of Interferon Gene (STING), a pivotal component of the host defense mechanisms against respiratory viral infections. While the role of the cGAS/STING signaling axis in the innate immune response to DNA viruses is well-documented, emerging evidence highlights its significance in countering RNA virus infections as well. This article delves into the role of STING activation during Influenza Virus (IFV) infection, exploring the therapeutic potential of STING agonists.
Introduction
Respiratory diseases caused by RNA viruses pose a persistent threat due to their rapid evolution and potential for widespread pandemics. Influenza virus, a negative-stranded RNA virus from the Orthomyxoviridae family, is a significant cause of respiratory illness globally. Annually, influenza epidemics, predominantly caused by the A(H1N1)pdm09 and A(H3N2) subtypes, result in approximately 5 million severe cases and up to 650,000 deaths worldwide. Given the substantial disease burden, developing effective antivirals to control influenza virus infection is imperative.
STING, located in the endoplasmic reticulum (ER), is crucial for activating host innate immune responses against microbial infections. Upon binding cyclic dinucleotides (CDNs), STING recruits and activates TANK-binding kinase 1 (TBK1) and other downstream factors, leading to the induction of antiviral genes, including interferons (IFNs) and interferon-stimulated genes (ISGs). Moreover, STING activation can induce autophagy-related gene 5 (ATG5)-dependent autophagy, restricting the replication of certain RNA viruses. This study investigates the antiviral effects of STING agonists against various strains of influenza virus using human and mouse macrophages and primary air–liquid interface (ALI) cultures of nasal epithelial cells.
STING Agonists and Their Mechanisms
Recent studies have identified dimeric amidobenzimidazole (diABZI) as a synthetic small molecule STING agonist with potent antiviral effects against multiple respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), parainfluenza virus type 3, and human rhinovirus 16. In our research, diABZI demonstrated significant antiviral activity against multiple strains of IFV, including A/H1N1, A/H3N2, B/Yamagata, and B/Victoria, in both mouse bone marrow-derived macrophages and the human monocytic cell line THP-1 differentiated with PMA.
In contrast, a pharmacological antagonist of STING (H-151) or the loss of STING in human macrophages led to enhanced viral replication and suppressed IFN expression. These findings underscore the pivotal role of STING in modulating the antiviral response against IFV. Furthermore, diABZI exhibited antiviral activity in primary ALI cultures of nasal epithelial cells, suggesting its potential as a therapeutic antiviral agent against IFV.
In deep…. Pharmacological Antagonist of STING (H-151): Comprehensive Analysis and Future Projections
STING, or Stimulator of Interferon Genes, is a crucial component of the innate immune system responsible for detecting cytosolic DNA and initiating an immune response. Its activation triggers the production of type I interferons and other proinflammatory cytokines, playing a vital role in antiviral and antitumor immune responses. However, dysregulated STING signaling is implicated in autoimmune diseases and inflammatory disorders. In this context, pharmacological antagonists targeting STING, such as H-151, have garnered significant interest for their therapeutic potential. This document provides a detailed analysis of H-151 as a pharmacological antagonist of STING, including its mechanism of action, preclinical and clinical studies, therapeutic applications, and future projections.
Mechanism of Action
H-151 is a small molecule inhibitor designed to specifically target and inhibit STING signaling. It functions by binding to the cyclic dinucleotide binding site of STING, thereby preventing its activation and downstream signaling cascades. This mechanism effectively blocks the production of type I interferons and proinflammatory cytokines, which are key mediators of immune responses.
Preclinical Studies
Preclinical studies evaluating the efficacy of H-151 have demonstrated promising results. For instance, research conducted in murine models of autoimmune diseases and inflammatory conditions showed that H-151 administration led to a reduction in disease severity, decreased levels of inflammatory cytokines, and improved overall immune homeostasis. These findings suggest that H-151 has the potential to be a valuable therapeutic agent for immune-mediated disorders.
Clinical Trials
While H-151 is primarily in the preclinical stage, there is growing anticipation for its progression into clinical trials. The design of phase I clinical trials is expected to focus on evaluating the safety, pharmacokinetics, and preliminary efficacy of H-151 in human subjects. These trials will provide essential data on dosing regimens, tolerability, and potential adverse effects, laying the foundation for further clinical development.
Therapeutic Applications
The therapeutic applications of H-151 extend across a spectrum of immune-related conditions. Its ability to modulate STING signaling makes it a potential candidate for the treatment of autoimmune diseases such as lupus, rheumatoid arthritis, and psoriasis. Additionally, H-151’s role in inhibiting inflammatory responses suggests utility in conditions characterized by excessive inflammation, including sepsis, acute respiratory distress syndrome (ARDS), and certain cancers.
Looking ahead, several key areas warrant attention in the development of H-151 as a pharmacological antagonist of STING. Firstly, further preclinical studies are needed to elucidate its efficacy in diverse disease models and optimize dosing strategies. Secondly, transitioning into clinical trials will provide crucial insights into its safety profile and therapeutic potential in humans. Lastly, ongoing research on STING biology and its implications in disease pathology will inform the rational design and refinement of STING antagonists like H-151, paving the way for innovative therapeutic interventions in immune-related disorders.
Antiviral Potential of diABZI
The antiviral effects of diABZI are mediated through its interaction with STING, leading to the activation of type I IFNs, NF-κB–driven cytokine production, and lymphocyte activation. This cascade results in the inhibition of viral replication and the prevention of severe respiratory disease. Notably, diABZI exhibited a potency comparable to 2′3′-cGAMP, another STING agonist. Compared to other immunotherapies like recombinant IFN, diABZI offers advantages such as lower cost, improved stability, room temperature storage, and the potential for low-dose treatments to be effective.
Role of STING in Antiviral Defense
STING plays a dual role in antiviral defense by controlling IFN expression to limit DNA viruses and regulating protein synthesis to inhibit RNA viral infection. Our study found that the antiviral activity of STING against IFV is not mediated by autophagy, mitochondrial DNA, or an inducible transcriptional response. Instead, STING regulates the translation of both viral and host mRNAs. Additionally, STING triggers autophagy through interactions with Rab7a, exerting anti-hantaviral effects independent of type I IFN responses.
Typically, the cGAS-STING pathway is crucial for producing IFNs and pro-inflammatory cytokines in response to DNA from invading pathogens. STING agonist treatment or overexpression significantly upregulated IFNs, pro-inflammatory cytokines (e.g., IL-1β), and ISGs (e.g., Mx1 and ISG56) upon hantavirus infection. This study examined whether IFV replication is restricted by STING-mediated autophagy and found it unlikely. Instead, STING-mediated inhibition of IFV appears to be driven by the production of type I IFNs and pro-inflammatory cytokines via activation of the TBK1-IRF3 pathway.
Air–Liquid Interface Culture System
The nasal airway epithelium, as the first line of defense against inhaled microorganisms, is a critical site for host-environment interaction. The ALI culture system, which reconstitutes a respiratory epithelium in vitro, has proven valuable for studying interactions between respiratory pathogens and the host. In our study, infectivity titers quantified using the TCID50 assay confirmed successful infection of ALI cultures with the A/H1N1 strain. Both diABZI and 2′3′-cGAMP significantly reduced viral infectivity in ALI cultures while enhancing cytokine release.
However, the elevated cytokine production could potentially affect barrier integrity within the ALI culture model and damage the airway epithelium. Therefore, optimizing the intracellular delivery of STING agonists and minimizing undesirable global inflammation will be crucial for their therapeutic application.
Implications for Therapeutic Development
Our data suggest that STING agonists hold promise as therapeutic agents against ongoing and emerging respiratory pathogens. Further investigation into the broad antiviral activity of STING agonists using the ALI culture system will help expand the current repertoire of FDA-approved antivirals against medically significant respiratory viruses. Given the dual role of STING in antiviral defense, its therapeutic potential warrants comprehensive evaluation in vivo to harness its full capabilities in combating viral infections.
Conclusion
In summary, the study highlights the significant antiviral potential of STING agonists, particularly diABZI, against multiple strains of influenza virus. The activation of the STING pathway offers a robust mechanism for inducing antiviral responses, which can be leveraged for therapeutic interventions against respiratory viruses. Further research is needed to optimize the delivery and dosage of STING agonists to maximize their efficacy while minimizing potential adverse effects. The promising results from this study pave the way for developing new antiviral strategies that target the innate immune system, offering hope for better management of respiratory viral infections in the future.
References
- World Health Organization. Influenza (Seasonal). WHO. Available from: https://www.who.int/news-room/fact-sheets/detail/influenza-(seasonal)
- Chen Q, Sun L, Chen ZJ. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol. 2016;17(10):1142-1149.
- Liu D, Wu H, Wang C, Li Y, Shen W, Zhang M. STING directly activates autophagy to tune the innate immune response. Cell Death Differ. 2015;22(11):2033-2045.
- Hopfner KP, Hornung V. Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat Rev Mol Cell Biol. 2020;21(9):501-521.
- Haag SM, Gulen MF, Reymond L, Gibelin A, Abrial C, Decout A, et al. Targeting STING with covalent small-molecule inhibitors. Nature. 2018;559(7713):269-273.
- Ramanjulu JM, Pesiridis GS, Yang J, Concha N, Singhaus R, Zhang SY, et al. Design of amidobenzimidazole STING receptor agonists with systemic activity. Nature. 2018;564(7736):439-443.
- Srikanth S, Woo JS. STING Signaling: The Molecular Basis for Immunity and Inflammation. J Mol Biol. 2019;431(15):2594-2614.
- Yi G, Brendel VP, Shu C, Li P, Palanathan S, Cheng Kao C. Single nucleotide polymorphisms of human STING can affect innate immune response to cyclic dinucleotides. PLoS One. 2013;8(10).
- Kao HF, Chen MW, Yeh IT, Wu LT, Huang SY, Chen YM. Air-liquid interface culture of nasal epithelial cells derived from patients with chronic rhinosinusitis. PLoS One. 2021;16(2).
- McWhirter SM, Barbalat R, Monroe KM, Fontana MF, Hyodo M, Joncker NT, et al. A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP. J Exp Med. 2009;206(9):1899-1911.
- Parvatiyar K, Zhang Z, Teles RM, Ouyang S, Jiang Y, Iyer SS, et al. The helicase DDX41 recognizes the bacterial secondary messenger cyclic di-GMP and may employ a dual sensor system for infection response. Nat Immunol. 2012;13(11):1155-1161.
- https://www.mdpi.com/1999-4915/16/6/855
