[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]
OPEN ACCESS / PEER-REVIEWED / RESEARCH ARTICLE
Delayed oseltamivir plus sirolimus treatment attenuates H1N1 virus-induced severe lung injury correlated with repressed NLRP3 inflammasome activation and inflammatory cell infiltration
Xuehong Jia , Bo Liu , Linlin Bao , Qi Lv, Fengdi Li, Hui Li, Yunqing An, Xulong Zhang , Bin Cao , Chen Wang
Published: November 13, 2018 / DOI: https://doi.org/10.1371/journal.ppat.1007428 / This is an uncorrected proof.
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.
The severity and lethality of influenza A virus infection are frequently aggravated by virus-induced tissue destruction and overwhelming immune responses. Combined therapy with antiviral medications and immunomodulators, which not only inhibit viral replication, but also reduce the damaging consequences of host immune responses, will be beneficial in the treatment of severe influenza. In the present study, we revealed that pH1N1-induced activation of mTOR promotes lung immunopathological injury, which is correlated with upregulated NF-κB activity and increased reactive oxygen species production. Subsequently, it induces NLRP3 inflammasome activation and the secretion of IL-1β and IL-18. Combined treatment with oseltamivir and the mTOR inhibitor sirolimus (as an adjuvant) not only blocks viral replication, but also suppresses mTOR-NLRP3-IL-1β axis-mediated immune damage, thus protecting mice against lethal pH1N1 infection. Our findings provide the theoretical and experimental basis for the clinical investigation of sirolimus as an adjunct treatment for severe influenza.
Citation: Jia X, Liu B, Bao L, Lv Q, Li F, Li H, et al. (2018) Delayed oseltamivir plus sirolimus treatment attenuates H1N1 virus-induced severe lung injury correlated with repressed NLRP3 inflammasome activation and inflammatory cell infiltration. PLoS Pathog 14(11): e1007428. https://doi.org/10.1371/journal.ppat.1007428
Editor: Paul G. Thomas, St. Jude Children’s Research Hospital, UNITED STATES
Received: April 10, 2018; Accepted: October 22, 2018; Published: November 13, 2018
Copyright: © 2018 Jia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This work was supported by grants from National Natural Science Foundation of China (81373114) (http://www.nsfc.gov.cn/) and Beijing Municipal Natural Science Foundation (7182013) (http://bjnsf.bjkw.gov.cn/) to XZ, National Science Grant for Distinguished Young Scholars (81425001/H0104) (http://www.nsfc.gov.cn/) and National Key Technology Support Program from Ministry of Science and Technology (2015BAI12B11) (http://www.most.gov.cn/) to BC, and CAMS Innovation Fund for Medical Sciences (2016-I2M-1-014, 2016-12M-006) (www.pumc.edu.cn/) to LB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Keywords: Influenza A; H1N1pdm09; Antivirals; Oseltamivir; Sirolimus; Animal Models.