SARS-CoV-2 entry into lungs through respiratory droplets Alveolar (Type II) Epithelial cell zoomSARS-CoV-2 bindingACE2 and entry into Alveolar (Type II) Epithelial cell SARS-CoV-2 replication into Alveolar (Type II) Epithelial cell Cell apoptosis releasing DAMPs Innate immune cells recruitment ROS releasing Innate immune response with chemokines and cytokines release DC Zoom Binding SARS-CoV-2 to TLR Activation of NFkB signaling pathway Activation of PI3K/AKT/mTOR signaling pathway Activation NLRP3 inflammasome pathway by the ROS as result of SARS-CoV-2 binding ACE2 Production of IL-1 by Caspase-1 from pro- IL-1 Caspase-1 mediate cell pyroptosis Rapamycin blocks mTOR and finally limits IL-1 and IL-6 production as well as pyroptosis Preferential differentiation of ETC, TH1 and TH17 by activation of mTORC1 pathway by ROS ROS, Pyroptosis, extensive and prolonged cytokines release lead to immunosenescence Expression of senescent markers such as PD-1 Senescent Associated Secretory Phenotype (SASP) with IL-1, IL-6, IL-8, TNF, Chemokines, MMPs, and Growth Factors Critical phase of SARS-CoV-2 infection with Cytokine Storm and immunoscenescence SASP and Pyroptosis lead to Macrophages, Monocytes, PMNs recruitment and cytokines release. mTOR forms two complexes: mTORC1 mediates TH1 and TH17 differentiation at the time of viral antigenic presentation by dendritic cells (DC) [9]; mTORC2 mediates TH2 differentiation; while both complexes restrict regulatory T-cell (Treg) differentiation [7]. With regards to T cells, mTORC1 activation is consequence of oxidative stress, which can be blocked by of cytokine storm in severe COVID-19 [14]. In these patients, the potential of rapamycin, a specific mTOR inhibitor that can promote autophagy and suppress the SASP, to reverse T-cell senescence can be discussed [15]. In elderly with increased senescent PD-1+ T-cells, everolimus (an analog of rapamycin) enhanced immune function, and improved T-cell responses to antigenic stimulation with an acceptable risk/benefit balance [4]. In elderly with coronary artery disease, rapamycin reduced serum senescence markers through IL-6 suppression [16]. In patients infected with the H1N1 influenza virus, early adjuvant rapamycin therapy during a short period (2?mg/day for 14?days) was significantly associated with an increased viral clearance, a greater improvement in lung injury (i.e. less hypoxemia), and a decrease of multiple organ dysfunction. The duration of ventilation in survivors was also shortened [17]. In a mouse model, H1N1 causes acute lung injury in an IL-17-dependent manner [18]. mTOR blockade with rapamycin might inhibit the expansion of Th17 cells in COVID-19 patients such as in Systemic Lupus Erythematosus patients [19,20]. H1N1 and SARS-CoV-2 both activate mTOR, and NLRP3 inflammasome pathway [5,21] leading to the production IL-1, the mediator of lung inflammation, fever and fibrosis [5,17] and induces pyroptosis, a hyperinflammatory form of cell death [22]. Rapamycin inhibits H1N1-induced mTOR pathway activation, and thus IL-1 secretion [21]. In COVID-19, the binding of SARS-CoV-2 to Toll Like Receptor (TLR), which leads to IL-1 production, could be reversed by rapamycin [23]. Furthermore, rapamycin AC-4-130 promotes de novo expression of Foxp3 in naive T cells, leading to Treg proliferation and survival in vivo and in vitro [9]. As a result, rapamycin inhibits effector T-cell proliferation and promotes Treg accumulation [9]. In addition, rapamycin was recently identified inside a network-based drug repurposing study as a candidate for potential use in COVID-19 [23]. When given at the early onset of the cytokine storm phase, rapamycin, through the down-regulation of the SASP, of the mTOR-NLRP3-IL-1 Rabbit Polyclonal to DHRS4 axis, of the IL-6 pathway, and of senescent T-cell quantity, might prevent progression to severe forms of COVID-19 (Fig. 1 ). Open in a separate windowpane Fig. 1 Rapamycin use in COVID-19. SARS-CoV-2 access into lungs through respiratory droplets Alveolar (Type II) Epithelial AC-4-130 cell zoomSARS-CoV-2 bindingACE2 and access into Alveolar (Type II) Epithelial cell SARS-CoV-2 replication into Alveolar (Type II) Epithelial cell Cell apoptosis liberating DAMPs Innate immune cells recruitment ROS liberating Innate immune response with chemokines and cytokines launch DC Focus Binding SARS-CoV-2 to TLR Activation of NFkB signaling pathway Activation of PI3K/AKT/mTOR AC-4-130 signaling pathway Activation NLRP3 inflammasome pathway from the ROS as result of SARS-CoV-2 binding ACE2 Production of IL-1 by Caspase-1 from pro- IL-1 Caspase-1 mediate cell pyroptosis Rapamycin blocks mTOR and finally limits IL-1 and AC-4-130 IL-6 production as well as pyroptosis Preferential differentiation of ETC, TH1 and TH17 by activation of mTORC1 pathway by ROS ROS, Pyroptosis, considerable and long term cytokines release lead to immunosenescence Manifestation of senescent markers such as PD-1 Senescent Associated Secretory Phenotype (SASP) with IL-1, IL-6, IL-8, TNF, Chemokines, MMPs, and Growth Factors.