Sirolimus alters lung pathology and viral load following influenza A virus infection

Abstract

BackgroundInhibitors of mTOR, such as sirolimus, have been shown to induce thymus involution and inflammatory lung disease in mice. The latter effect supports the role of this serine/threonine kinase in ameliorating lung inflammation. Other studies have shown sirolimus reduces/delays lung disease associated with various strains of influenza A virus (IAV). Thus, the effects of mTOR inhibitors on influenza infection deserve further studies.MethodsHere, we examined the changes in lung viral copies, pathology and pulmonary function associated with IAV (A/PR/8/34) infection in mice treated with sirolimus.ResultsBody weight loss peaked between days 6–11 post-infection and was more severe in IAV-infected mice that were administered sirolimus as compared to mice that received IAV alone (p = 0.030). Natural log viral gene copies, mean ± SD per mg lung tissue, in IAV-infected mice that were administered sirolimus were 17.31 ± 1.27 on day 4, 19.31 ± 7.46 on day 10, and 0 on day 25. The corresponding number of copies in mice that received IAV alone were 18.56 ± 0.95 on day 4 (p = 0.132), 1.52 ± 1.39 on day 10 (p = 0.008), and 0 on day 25. Lung pathology was evident on days 4, 10, and 25 post infection, with mean ± SD inflammatory score of 9.0 ± 4.5 in IAV-infected mice that were administered sirolimus, as compared to 11.5 ± 4.5 (p = 0.335) in mice received IAV alone (maximum score, 26.0). Impaired lung function was evident in IAV-infected mice on days 4 and 10, as demonstrated by increased airway resistance and decreased compliance.ConclusionsIn this model, the effects of sirolimus on influenza infection included severe weight loss and modified viral replication, respiratory function and lung inflammation. The adverse events associated with sirolimus treatment are consistent with its potent immunosuppressive activity and, thus, preclude its use in IAV infection.

The role of adjuvant immunomodulatory agents for treatment of severe influenza

“…Mice treated with sirolimus had more body weight loss during the illness, and a higher viral load on Day 10 than controls that did not receive sirolimus. However, there was a trend, suggesting lower lung inflammation score as seen in histology specimens (mean score 9.0 ± 4.5 vs 11.5 ± 4.5, p = .335), and improved compliance on mechanical ventilation in the mice that received sirolimus, consistent with drug-promoting apoptosis that lowered experimental lung injury associated with influenza infection ( Alsuwaidi et al, 2017 ).…”

Dysregulation in mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells

“…11 Some studies have shown that everolimus, another mTOR inhibitor, and sirolimus are weakly active against influenza A virus. 19,20 Everolimus delayed death but was not able to reduce mortality in lethal mouse infection model of influenza A (H1N1 and H5N1). 19 Sirolimus was even shown to negatively affect the lung pathology probably due to its immunosuppressive effect.…”

“…19 Sirolimus was even shown to negatively affect the lung pathology probably due to its immunosuppressive effect. 20 It has also been reported to block viral protein expression and virion release, improving the prognosis in patients with severe H1N1 pneumonia and acute respiratory failure. 21 On the other hand, rapamycin treatment was shown to degrade antiviral barriers and could thus be potentially harmful in pathogenic viral infections.…”

Hypercapnia Suppresses Macrophage Antiviral Activity and Increases Mortality of Influenza A Infection via Akt1

“…Serial images were stitched into a highresolution macroscopic montage. Tissues were evaluated blindly using an inflammatory histopathologic score (HPS) system that assigns values of 0 to 26 (least to most severe) based on assessment of quantity and quality of peribronchial inflammatory infiltrates, luminal exudates, perivascular and parenchymal infiltrates and thickening of the membrane wall, as described previously (36,37). This scoring system has been previously validated in other mouse models of respiratory infections (37,38).…”