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Mol Ther
. 2023 Jun 19;S1525-0016(23)00322-2.
doi: 10.1016/j.ymthe.2023.06.011. Online ahead of print. Preventing Occludin Tight-Junction Disruption via Inhibition of microRNA-193b-5p Attenuates Viral Load and Influenza-induced Lung Injury
Chirag M Vaswani 1 , Amir K Varkouhi 2 , Sahil Gupta 3 , Amin M Ektesabi 4 , James N Tsoporis 5 , Sadiya Yousef 5 , Pamela J Plant 5 , Adriana L da Silva 6 , Yuchen Cen 7 , Yi-Chieh Tseng 7 , Sabrina S Batah 8 , Alexandre T Fabro 8 , Suzanne L Advani 5 , Andrew Advani 5 , Howard Leong-Poi 4 , John C Marshall 4 , Cristiana C Garcia 9 , Patricia R M Rocco 6 , Guillermo M Albaiceta 10 , Steffen Sebastian-Bolz 11 , Tania H Watts 12 , Theo J Moraes 13 , Vera L Capelozzi 14 , Claudia C Dos Santos 15
Affiliations
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.
. 2023 Jun 19;S1525-0016(23)00322-2.
doi: 10.1016/j.ymthe.2023.06.011. Online ahead of print. Preventing Occludin Tight-Junction Disruption via Inhibition of microRNA-193b-5p Attenuates Viral Load and Influenza-induced Lung Injury
Chirag M Vaswani 1 , Amir K Varkouhi 2 , Sahil Gupta 3 , Amin M Ektesabi 4 , James N Tsoporis 5 , Sadiya Yousef 5 , Pamela J Plant 5 , Adriana L da Silva 6 , Yuchen Cen 7 , Yi-Chieh Tseng 7 , Sabrina S Batah 8 , Alexandre T Fabro 8 , Suzanne L Advani 5 , Andrew Advani 5 , Howard Leong-Poi 4 , John C Marshall 4 , Cristiana C Garcia 9 , Patricia R M Rocco 6 , Guillermo M Albaiceta 10 , Steffen Sebastian-Bolz 11 , Tania H Watts 12 , Theo J Moraes 13 , Vera L Capelozzi 14 , Claudia C Dos Santos 15
Affiliations
- PMID: 37340634
- 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.