Rapamycin Does Not Impede Survival or Induction of Antibody Responses to Primary and Heterosubtypic Influenza Infections in Mice

Liepkalns, Justine S.; Pandey, Aseem; Hofstetter, Amelia R.; Kumar, Amrita; Jones, Enitra N; Cao, Weiping; Liu, Feng; Levine, Min Z.; Sambhara, Suryaprakash; Gangappa, Shivaprakash

doi:10.1089/vim.2016.0056

Cited by 4 publications

(9 citation statements)

References 30 publications

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“…Overall, our data support the concept that mTOR signaling plays a protective role in IAV-induced lung inflammation [13]. The higher viral load on day 10 post-infection (Fig.…”

Section: Discussionsupporting

confidence: 88%

“…Our results indicate that sirolimus administration causes more severe weight loss associated with increased viral replication. Overall, our data support the concept that mTOR signaling plays a protective role in IAV-induced lung inflammation [ 13 ]. The higher viral load on day 10 post-infection (Fig.…”

Section: Discussionsupporting

confidence: 87%

“…Everolimus-treated mice exhibited reduced lung hemorrhage and lung weight in response to lethal H1N1 and H5N1 infections; the treatment delayed death but did not prevent mortality [ 12 ]. More recently, sirolimus was shown not to influence survival or antibody responses to influenza infections in mice [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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“…Overall, our data support the concept that mTOR signaling plays a protective role in IAV-induced lung inflammation [13]. The higher viral load on day 10 post-infection (Fig.…”

Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 87%

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

et al. 2017

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“…As an immunosuppressant drug, improper medication is not conducive to achieve the homeostasis of immune response, which not only inhibits excessive immune response, but also does not impede cellular and humoral responses to promote virus clearance. The dosage of sirolimus used in our study (initial dosage, 0.6 μg/g; maintenance dosage, 0.3 μg/g) was similar to those used in a clinical trial (2 mg/day) and previous studies in mice (0.6–1 μg/g) which indicated the protective roles of sirolimus [ 17 , 18 ]. Moreover, using different virus strains and infective doses may lead to different results.…”

Section: Discussionsupporting

confidence: 63%

“…It was reported that sirolimus combined with oseltamivir and corticosteroid treatment decreases viral titer and improves respiratory function in patients with severe H1N1 virus-induced pneumonia [ 17 ]. Furthermore, sirolimus contributes to delay the onset of morbidity in PR8 virus-infected mice [ 18 ]. Moreover, everolimus, a derivative of sirolimus, significantly reduces viral titer, lung weight, and hemorrhage score in H5N1 virus-infected mice [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Rapamycin not dietary restriction improves resilience against pathogens: a meta-analysis

Phillips

Simons

2022

GeroScience

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Dietary restriction (DR) and rapamycin both increase lifespan across a number of taxa. Despite this positive effect on lifespan and other aspects of health, reductions in some physiological functions have been reported for DR, and rapamycin has been used as an immunosuppressant. Perhaps surprisingly, both interventions have been suggested to improve immune function and delay immunosenescence. The immune system is complex and consists of many components. Therefore, arguably, the most holistic measurement of immune function is survival from an acute pathogenic infection. We reanalysed published post-infection short-term survival data of mice (n = 1223 from 23 studies comprising 46 effect sizes involving DR (n = 17) and rapamycin treatment (n = 29) and analysed these results using meta-analysis. Rapamycin treatment significantly increased post infection survival rate (lnHR = − 0.72; CI = − 1.17, -0.28; p = 0.0015). In contrast, DR reduced post-infection survival (lnHR = 0.80; CI = 0.08, 1.52; p = 0.03). Importantly, the overall effect size of rapamycin treatment was significantly lower (p < 0.001) than the estimate from DR studies, suggesting opposite effects on immune function. Our results show that immunomodulation caused by rapamycin treatment is beneficial to the survival from acute infection. For DR, our results are based on a smaller number of studies, but do warrant caution as they indicate possible immune costs of DR. Our quantitative synthesis suggests that the geroprotective effects of rapamycin extend to the immune system and warrants further clinical trials of rapamycin to boost immunity in humans.

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Rapamycin Does Not Impede Survival or Induction of Antibody Responses to Primary and Heterosubtypic Influenza Infections in Mice

Cited by 4 publications

References 30 publications

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

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

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

Rapamycin not dietary restriction improves resilience against pathogens: a meta-analysis

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