STING Agonist\nInduced Innate Immune Responses Drive\nAnti-Respiratory Virus Activity <i>In Vitro</i> with Limited\nAntiviral Efficacy <i>In Vivo</i>

The emergence of SARS-CoV-2 and seasonal outbreaks of\nother respiratory\nviruses highlight the urgent need for broad-spectrum antivirals to\ntreat respiratory tract infections. Stimulator of interferon genes\n(STING) is a key component of innate immune signaling and plays a\ncritical role in protection of the host against viral infections.\nPreviously the STING agonist diABZI-4, a diamidobenzimidazole-based\ncompound, demonstrated protection against SARS-CoV-2 both <i>in vitro</i> and <i>in vivo</i>. However, its broad-spectrum\nantiviral activity against other respiratory viruses in human airway\nepithelial cells, which are the primary targets of these infections,\nis not well established. In this study, we demonstrated that diABZI-4\nstimulated robust innate immune responses protecting lung cells against\na wide range of respiratory viruses, including influenza A virus (IAV),\ncommon cold coronaviruses, SARS-CoV-2, human rhinovirus (HRV), and\nhuman parainfluenza virus. diABZI-4 was highly active in physiologically\nrelevant human airway epithelial tissues grown at the air–liquid\ninterface, blocking replication of IAV, SARS-CoV-2, and HRV in these\ntissues. Furthermore, treatment of macrophages with diABZI-4 resulted\nin the secretion of cytokines that protected the primary airway epithelial\ncells from IAV infection. Despite the promising <i>in vitro</i> pan-antiviral activity, intranasal administration of diABZI-4 in\nmice provided early, but not sustained, inhibition of IAV replication\nin the lungs. These data highlight the complexities of the relationship\nbetween timing of STING agonist-driven inflammatory responses and\nviral replication dynamics, emphasizing the development challenge\nposed by STING agonists as potential therapeutics against respiratory\nviruses.