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.
Highlights
Influenza A virus (IAV) infection represents a leading threat to global public health
NOD-like receptor family pyrin domain containing 3 (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 mammalian target of rapamycin (mTOR)-NLRP3-IL-1β axis and reduced viral titer
The severity and lethality of influenza A virus infection are frequently aggravated by virus-induced tissue destruction and overwhelming immune responses
Summary
Influenza A virus (IAV) infection represents a leading threat to global public health. Combined therapy with antiviral medications and immunomodulators, which inhibit viral replication, and reduce the damaging consequences of host immune responses, has been believed to be beneficial in the treatment for severe influenza pneumonia [8,9,10]. Rapamycin (sirolimus) is an inhibitor of mammalian target of rapamycin (mTOR) It blocks host pathways needed for viral replication [11,12,13], and modulates the immune responses during infection [14,15,16]. It may be a promising drug for treating influenza. The mechanisms of action of sirolimus plus oseltamivir in severe pneumonia induced by influenza infection have not been elucidated
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