Date Published: November 13, 2018
Publisher: Public Library of Science
Author(s): Xuehong Jia, Bo Liu, Linlin Bao, Qi Lv, Fengdi Li, Hui Li, Yunqing An, Xulong Zhang, Bin Cao, Chen Wang, Paul G. Thomas.
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.
Influenza A virus (IAV) infection represents a leading threat to global public health. New estimates have indicated that up to approximately 645,000 influenza-associated respiratory deaths occur annually . Our previous clinical data showed that critically ill patients infected with influenza A (H1N1) pdm09 virus (pH1N1) is usually accompanied by acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which is characterized by sudden onset of respiratory failure, refractory hypoxemia, and noncardiogenic pulmonary edema, and pathologically by necrosis of bronchiolar walls, diffuse alveolar injury, and substantial inflammatory cell infiltration . Our experimental and clinical studies on severe influenza infection have indicated that virus-induced tissue destruction and dysregulated systemic inflammation are associated with the severity and progression of the disease [2–7]. Combined therapy with antiviral medications and immunomodulators, which not only inhibit viral replication, but also reduce the damaging consequences of host immune responses, has been believed to be beneficial in the treatment for severe influenza pneumonia [8–10].
Pandemic influenza infection causes substantial mortality. Oseltamivir is most effective against the infection only when it is administered within 48 h from the onset of symptoms. However, in clinical settings, patients usually can’t receive treatment until overt illness symptoms occur after infection, by which time viral load may already be high. Therefore, the high inoculum and delayed therapy used in the presently reported mouse model can better simulate the real clinical situation.