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

Autor(es):Mostrar menos -

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.

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR THERAPY; v. 31, n. 9, p. 21-pg., 2023-09-06.

Resumo

Virus-induced lung injury is associated with loss of pulmo-nary 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 inter-feron-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 disrup-tion 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). In-hibition of miR-193b-5p in primary human bronchial, pul-monary 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 suscepti-bility 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. (AU)

• Processo FAPESP: 18/20403-6 - Marcadores biomoleculares de proliferação e remodelamento em doenças respiratórias agudas e crônicas: promissores alvos terapêuticos
• Beneficiário: Vera Luiza Capelozzi
• Modalidade de apoio: Auxílio à Pesquisa - Temático