Preventing occludin tight-junction disruption via inhibition of microRNA-193b-5p attenuates viral load and influenza-induced lung injury

• Published in: Molecular therapy 2023-09, Vol.31 (9), p.2681-2701
• Main Authors: Vaswani, Chirag M., Varkouhi, Amir K., Gupta, Sahil, Ektesabi, Amin M., Tsoporis, James N., Yousef, Sadiya, Plant, Pamela J., da Silva, Adriana L., Cen, Yuchen, Tseng, Yi-Chieh, Batah, Sabrina S., Fabro, Alexandre T., Advani, Suzanne L., Advani, Andrew, Leong-Poi, Howard, Marshall, John C., Garcia, Cristiana C., Rocco, Patricia R.M., Albaiceta, Guillermo M., Sebastian-Bolz, Steffen, Watts, Tania H., Moraes, Theo J., Capelozzi, Vera L., dos Santos, Claudia.C.
• Format: Article
• Language: English
• Subjects: acute lung injury; acute respiratory distress syndrome; alveolar-capillary membrane; Animals; Antiviral Agents; antiviral immune response; Humans; Influenza A Virus, H1N1 Subtype - genetics; influenza virus; Influenza, Human - complications; Influenza, Human - genetics; Influenza, Human - metabolism; interferon beta; Lung Injury - metabolism; Mice; Mice, Inbred C57BL; microRNA; MicroRNAs - genetics; MicroRNAs - metabolism; miR-193b; occludin; Occludin - genetics; Occludin - metabolism; Original; tight junctions; Tight Junctions - metabolism; Viral Load
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2023.06.011

Virus-induced lung injury is associated with loss of pulmonary epithelial-endothelial tight junction integrity. While the alveolar-capillary membrane may be an indirect target of injury, viruses may interact directly and/or indirectly with miRs to augment their replication potential and evade the host antiviral defense system. Here, we expose how the influenza virus (H1N1) capitalizes on host-derived interferon-induced, microRNA (miR)-193b-5p to target occludin and compromise antiviral defenses. Lung biopsies from patients infected with H1N1 revealed increased miR-193b-5p levels, marked reduction in occludin protein, and disruption of the alveolar-capillary barrier. In C57BL/6 mice, the expression of miR-193b-5p increased, and occludin decreased, 5–6 days post-infection with influenza (PR8). Inhibition of miR-193b-5p in primary human bronchial, pulmonary microvascular, and nasal epithelial cells enhanced antiviral responses. miR-193b-deficient mice were resistant to PR8. Knockdown of occludin, both in vitro and in vivo, and overexpression of miR-193b-5p reconstituted susceptibility to viral infection. miR-193b-5p inhibitor mitigated loss of occludin, improved viral clearance, reduced lung edema, and augmented survival in infected mice. Our results elucidate how the innate immune system may be exploited by the influenza virus and how strategies that prevent loss of occludin and preserve tight junction function may limit susceptibility to virus-induced lung injury. [Display omitted] The temporal-dependent inhibition of microRNA-193b-5p reduces tight junction protein occludin transcript degradation, lung edema, and viral load, and augments survival in influenza-infected mice. The results elucidate how strategies that prevent loss of occludin and preserve tight junction function may limit susceptibility to virus-induced lung injury.