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PREVENTING OCCLUDIN TIGHT-JUNCTION DISRUPTION VIA INHIBITION OF MICRORNA-193B-5P ATTENUATES VIRAL LOAD AND INFLUENZA-INDUCED LUNG INJURY.
Vaswani, Chirag M. et al. | Data do documento: 2023
Autor(es)
Vaswani, Chirag M.
Varkouhi, Amir K.
Gupta, Sahil
Ektesabi, Amin M.
Tsoporis, James N.
Yousef, Sadiya
Plant, Pamela J.
Silva, Adriana L. da
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.
Santos, Claudia. C. dos
Afiliação
Department of Physiology. Temerty Faculty of Medicine. University of Toronto. Toronto, ON, Canada/Keenan Research Centre for Biomedical Science. St. Michael’s Hospital. Toronto, ON, Canada
Department of Chemistry and Environmental Science. New Jersey Institute of Technology. Newark, NJ, USA
Keenan Research Centre for Biomedical Science. St. Michael’s Hospital. Toronto, ON, Canada/Institute of Medical Sciences. Faculty of Medicine. University of Toronto. Toronto, ON, Canada/Faculty of Medicine. School of Medicine. The University of Queensland. Herston, Australia
Keenan Research Centre for Biomedical Science. St. Michael’s Hospital. Toronto, ON, Canada/Institute of Medical Sciences. Faculty of Medicine. University of Toronto. Toronto, ON, Canada
Keenan Research Centre for Biomedical Science. St. Michael’s Hospital. Toronto, ON, Canada
Keenan Research Centre for Biomedical Science. St. Michael’s Hospital. Toronto, ON, Canada
Keenan Research Centre for Biomedical Science. St. Michael’s Hospital. Toronto, ON, Canada
Laboratory of Pulmonary Investigation. Carlos Chagas Filho Institute of Biophysics. Federal University of Rio de Janeiro. Rio de Janeiro, RJ, Brazil/COVID-19 Virus Network from Ministry of Science, Technology, and Innovation. Brazilian Council for Scientific and Technological Development. Foundation Carlos Chagas Filho Research Support of the State of Rio de Janeiro. Rio de Janeiro, RJ, Brazil
Program in Translational Medicine. SickKids Research Institute. Toronto, ON, Canada
Program in Translational Medicine. SickKids Research Institute. Toronto, ON, Canada
Department of Pathology and Legal Medicine. Ribeirão Preto Medical School. University of São Paulo. São Paulo, SP, Brazil
Department of Pathology and Legal Medicine. Ribeirão Preto Medical School. University of São Paulo. São Paulo, SP, Brazil
Keenan Research Centre for Biomedical Science. St. Michael’s Hospital. Toronto, ON, Canada
Keenan Research Centre for Biomedical Science. St. Michael’s Hospital. Toronto, ON, Canada
Keenan Research Centre for Biomedical Science. St. Michael’s Hospital. Toronto, ON, Canada/Institute of Medical Sciences. Faculty of Medicine. University of Toronto. Toronto, ON, Canada
Keenan Research Centre for Biomedical Science. St. Michael’s Hospital. Toronto, ON, Canada/Institute of Medical Sciences. Faculty of Medicine. University of Toronto. Toronto, ON, Canada
Laboratory of Respiratory. Exanthematic Viruses, Enterovirus and Viral Emergencies. Oswaldo Cruz Institute. Oswaldo Cruz Foundation. Rio de Janeiro, RJ, Brazil/Integrated Research Group on Biomarkers. René Rachou Institute. Oswaldo Cruz Foundation. Belo Horizonte, MG, Brazil
Laboratory of Pulmonary Investigation. Carlos Chagas Filho Institute of Biophysics. Federal University of Rio de Janeiro. Rio de Janeiro, RJ, Brazil/COVID-19 Virus Network from Ministry of Science, Technology, and Innovation. Brazilian Council for Scientific and Technological Development. Foundation Carlos Chagas Filho Research Support of the State of Rio de Janeiro. Rio de Janeiro, RJ, Brazil
Departamento de Biología Funcional. Instituto Universitario de Oncología del Principado de Asturias. Universidad de Oviedo. Oviedo, Spain/Unidad de Cuidados Intensivos Cardiológicos. Hospital Universitario Central de Asturias. Oviedo, Spain/CIBER-Enfermedades Respiratorias. Instituto de Salud Carlos III. Madrid, Spain
Department of Physiology. Temerty Faculty of Medicine. University of Toronto. Toronto, ON, Canada
Department of Immunology. Temerty Faculty of Medicine. University of Toronto. Toronto, ON, Canada
Program in Translational Medicine. SickKids Research Institute. Toronto, ON, Canada/Department of Pediatrics University of Toronto and Respirology. Hospital for Sick Children. Toronto, ON, Canada
Department of Pathology. University of São Paulo. São Paulo, SP, Brazil
Department of Physiology. Temerty Faculty of Medicine. University of Toronto. Toronto, ON, Canad/ Keenan Research Centre for Biomedical Science. St. Michael’s Hospital. Toronto, ON, Canada/Institute of Medical Sciences. Faculty of Medicine. University of Toronto. Toronto, ON, Canada/Laboratory Medicine and Pathobiology. Faculty of Medicine. University of Toronto. Toronto, ON, Canada/Interdepartmental Division of Critical Care. St Michael’s Hospital. University of Toronto. Toronto, ON, Canada
Resumo em Inglês
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.
Palavras-chave em inglês
acute respiratory distress syndrome
acute lung injury
influenza virus
tight junctions
occludin
microRNA
miR-193b
interferon beta
alveolar-capillary membrane
antiviral immune response
 
Editor
Cell Press
Referência
VASWANI, Chirag M. et al. Preventing occludin tight-junction disruption via inhibition of microRNA-193b-5p attenuates viral load and influenza-induced lung injury. Molecular Therapy, v. 31, n. 8, 2023. doi.org/10.1016/j.ymthe.2023.06.011
ISSN
1525-0016