Content area
Full text
Background
Inhibitors of mTOR, such as, sirolimus, temsirolimus and everolimus, have been shown to induce inflammatory lung disease in mice [1]. This effect underscores the anti-inflammatory function of mTOR and supports its role in ameliorating lung inflammation [2]. The primary complex of mTOR mediates anti-inflammatory responses in the lung [2]. Sirolimus has also been shown to induce severe immunosuppression in mice, as a result of thymus involution due to cortical lymphocyte apoptosis [3].
In addition, inhibitors of mTOR are known to impair cellular bioenergetics [4, 5]. In one study, a prior brief exposure of Jurkat cells to sirolimus resulted in ~20% decrease in cellular respiration. This effect was accompanied by accumulation of cellular lactate and other biomarkers of anaerobic metabolism [4]. In another in vitro study, sirolimus administration decreased cellular respiration in several murine organs by 20-40% [5]. In contrast, the calcineurin inhibitors tacrolimus and cyclosporine exhibited no effects on mitochondrial respiration in the same tissues [5]. The impact of these metabolic derangements on the cytotoxicity of mTOR inhibitors, especially with respect to viral infections, has yet to be fully elucidated [6].
Influenza A virus (IAV) is a leading cause of lower respiratory tract infection that can result in severe lung disease [7]. The host immune response and virus-induced tissue damage both contribute to the severity of IAV-induced lung disease. At molecular level, IAV infection suppresses lung cellular respiration [8].
The combination of sirolimus and corticosteroid was reported to improve the outcome of patients with severe H1N1-induced pneumonia [9, 10]. However, the underlying mechanism to account for the therapeutic benefit of inhibition of mTOR activity during IAV infection remains unclear. A recent study has shown that sirolimus treatment during H3N2 virus infection protected mice against lethal secondary H5N1 virus infection [11]. Transfer of serum was sufficient to protect naïve mice against H5N1 infection. This enhanced protection mediated by the sirolimus treated mice was attributed to altered B cell class switching and the induction of effective cross-reactive antibodies [11]. 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].
Taken together,...