Delayed oseltamivir plus sirolimus treatment attenuates H1N1 virus-induced severe lung injury correlated with repressed NLRP3 inflammasome activation and inflammatory cell infiltration

Abstract

Severe influenza A virus infection causes high mortality and morbidity worldwide due to delayed antiviral treatment and inducing overwhelming immune responses, which contribute to immunopathological lung injury. Sirolimus, an inhibitor of mammalian target of rapamycin (mTOR), was effective in improving clinical outcomes in patients with severe H1N1 infection; however, the mechanisms by which it attenuates acute lung injury have not been elucidated. Here, delayed oseltamivir treatment was used to mimic clinical settings on lethal influenza A (H1N1) pdm09 virus (pH1N1) infection mice model. We revealed that delayed oseltamivir plus sirolimus treatment protects mice against lethal pH1N1 infection by attenuating severe lung damage. Mechanistically, the combined treatment reduced viral titer and pH1N1-induced mTOR activation. Subsequently, it suppressed the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated secretion of interleukin (IL)-1β and IL-18. It was noted that decreased NLRP3 inflammasome activation was associated with inhibited nuclear factor (NF)-κB activation, reduced reactive oxygen species production and increased autophagy. Additionally, the combined treatment reduced the expression of other proinflammatory cytokines and chemokines, and decreased inflammatory cell infiltration in lung tissue and bronchioalveolar lavage fluid. Consistently, it inhibited the mTOR-NF-κB-NLRP3 inflammasome-IL-1β axis in a lung epithelial cell line. These results demonstrated that combined treatment with sirolimus and oseltamivir attenuates pH1N1-induced severe lung injury, which is correlated with suppressed mTOR-NLRP3-IL-1β axis and reduced viral titer. Therefore, treatment with sirolimus as an adjuvant along with oseltamivir may be a promising immunomodulatory strategy for managing severe influenza.

An Update on Current Therapeutic Drugs Treating COVID-19

“…In a randomized clinical trial conducted on 38 patients with confirmed H1N1 pneumonia and on mechanical ventilator support, a group treated with corticosteroids and 2 mg/day of sirolimus for 14 days (N = 19) showed significantly better clinical outcomes compared with the group treated with corticosteroids only, including shorter median duration of ventilator used [105]. Delayed oseltamivir plus sirolimus treatment in pH1N1-infected mouse model further suggested a significant association between the sirolimus treatment and improved outcomes [106]. Additionally, a new trial by the Chinese University of Hong Kong is planned to begin in August 2020 to investigate the effect of sirolimus and oseltamivir on normalization of respiratory status and changes in biomarkers (viral RNA concentration, 10 cytokines/ chemokines and pro-inflammatory mediators) and several other clinical endpoints in influenza patients [107].…”

Influenza virus-related critical illness: pathophysiology and epidemiology

“…Table 1 Host and viral mechanisms of influenza-associated pathogenesis Targeting host inflammation has been of increasing interest for the development of new therapeutics for severe influenza. One study used the well-characterized mTOR inhibitor rapamycin/sirolimus to suppress inflammation, leading to improved outcomes, correlated with reduced inflammasome activity [23,24]. Targeting the mTOR pathway as a means to reduce inflammation and promote recovery implicates host metabolism in the etiology of severe influenza disease, given the central role mTOR plays in nutrient sensing.…”

Critical care management of adults with community-acquired severe respiratory viral infection

“…Inhibitors of the mTOR pathway like sirolimus combined with oseltamivir have shown inconsistent effects in murine models of severe influenza [32,33]. Sirolimus also can modulate inflammatory responses through its immunosuppressive properties [34].…”