Therapeutic Targeting of Endosome and Mitochondrial Reactive Oxygen Species Protects Mice From Influenza Virus Morbidity

Frontiers in Pharmacology

Robert D. Brooks¹  Raymond Luong²  Eunice E. To³  John J. O’Leary⁴  Doug A. Brooks⁴  Stavros Selemidis⁵  Kylie M. Quinn⁵  Ross Vlahos⁵  Felicia Liong⁵  Steven Bozinovski⁵  Osezua Oseghale⁵  Jonathan R. Erlich⁵  Stella Liong⁵  Paris C. Papagianis⁵  Mark A. Miles⁵ 

[1] Cancer Research Institute and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia;Department of Pharmacology, Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia;F.M Kirby Neurobiology Centre, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States;Molecular Pathology Laboratory, Coombe Women and Infants’ University Hospital, Dublin, Ireland;School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia;Sir Patrick Dun’s Laboratory, Central Pathology Laboratory, Department of Histopathology Trinity College Dublin, Dublin, Ireland;

关键词: mitochondria;    endosome;    reactive oxygen;    NADPH oxidase;    influenza A virus;    inflammation;   

DOI  :  10.3389/fphar.2022.870156

来源: DOAJ

【 摘 要 】

There is an urgent need to develop effective therapeutic strategies including immunomodulators to combat influenza A virus (IAV) infection. Influenza A viruses increase ROS production, which suppress anti-viral responses and contribute to pathological inflammation and morbidity. Two major cellular sites of ROS production are endosomes via the NOX2-oxidase enzyme and the electron transport chain in mitochondria. Here we examined the effect of administration of Cgp91ds-TAT, an endosome-targeted NOX2 oxidase inhibitor, in combination with mitoTEMPO, a mitochondrial ROS scavenger and compared it to monotherapy treatment during an established IAV infection. Mice were infected with IAV (Hkx31 strain; 104PFU/mouse) and 24 h post infection were treated with Cgp91ds-TAT (0.2 mg/kg), mitoTEMPO (100 μg) or with a combination of these inhibitors [Cgp91ds-TAT (0.2 mg/kg)/mitoTEMPO (100 μg)] intranasally every day for up to 2 days post infection (pi). Mice were euthanized on Days 3 or 6 post infection for analyses of disease severity. A combination of Cgp91ds-TAT and mitoTEMPO treatment was more effective than the ROS inhibitors alone at reducing airway and neutrophilic inflammation, bodyweight loss, lung oedema and improved the lung pathology with a reduction in alveolitis following IAV infection. Dual ROS inhibition also caused a significant elevation in Type I IFN expression at the early phase of infection (day 3 pi), however, this response was suppressed at the later phase of infection (day 6 pi). Furthermore, combined treatment with Cgp91ds-TAT and mitoTEMPO resulted in an increase in IAV-specific CD8+ T cells in the lungs. In conclusion, this study demonstrates that the reduction of ROS production in two major subcellular sites, i.e. endosomes and mitochondria, by intranasal delivery of a combination of Cgp91ds-TAT and mitoTEMPO, suppresses the severity of influenza infection and highlights a novel immunomodulatory approach for IAV disease management.

【 授权许可】

Unknown