ABSTRACT
The ongoing pandemic of the novel coronavirus SARS-CoV-2 (COVID-19) has created a major challenge for the public health worldwide. The reported cases indicate that the outbreak is more widespread than initially assumed. Around 18 million people have been infected with 689,000 reported deaths (August 2020;the number is increasing daily);with a high mutation rate, this virus poses an even more serious threat worldwide. The actual source of COVID-19 is still un-clear;even if the initial reports link it to the Chinese seafood wet market in Wuhan, other animals such as birds, snakes, and many small mammals including bats are also linked with this novel coro-navirus. The structure of the COVID-19 shows distinctive proteins among which spike proteins have a pivotal role in host cell attachment and virus-cell membrane fusion in order to facilitate virus infection. Currently, no specific antiviral treatment or vaccine is available. Various drug can-didates, including SARS-CoV and MERS-CoV protease inhibitors, neuraminidase inhibitors, RNA synthesis inhibitors, ACE2 inhibitors and lungs supportive therapy, are under trials. Cell-based therapy also appeared with remarkable treatment possibilities. In this article, we endeavored to succinctly cover the current and available treatment options, including pharmaceuticals, cell-based therapy, and traditional medicine. We also focused on the extent of damages by this novel coron-avirus in India, Pakistan, and Bangladesh;the strategies adopted and the research activities initiat-ed so far by these densely populated countries (neighboring China) are explained in this review.Copyright © 2021 Bentham Science Publishers.
ABSTRACT
Background: SARS-CoV-2 infection in immunocompromised individuals has been associated with prolonged virus shedding and the development of novel viral variants. Rapamycin and rapamycin analogs (rapalogs, including everolimus, temsirolimus, and ridaforolimus) are FDA-approved for use as mTOR inhibitors in multiple clinical settings, including cancer and autoimmunity, but a common side effect of these drugs is immunosuppression and increased susceptibility to infection. Immune impairment caused by rapalog use is traditionally attributed to their impacts on T cell signaling and cytokine production. Methods: We used replication-competent SARS-CoV-2 and HIV pseudotyped with betacoronavirus Spike proteins to assess how rapalog pretreatment of cells ex vivo and rodent animals in vivo impacts susceptibility to Spike-mediated infection. Results: We show that exposure to rapalogs increases cellular susceptibility to SARS-CoV-2 infection by antagonizing components of the constitutive and interferon-induced cell-intrinsic immune response. Pre-treatment of cells (including human lung epithelial cells and primary human small airway epithelial cells) with rapalogs promoted the early stages of SARS-CoV-2 infection by facilitating Spike-mediated virus entry. Rapalogs also boosted infection mediated by Spike from SARS-CoV and MERS-CoV in addition to hemagglutinin of influenza A virus and glycoprotein from vesicular stomatitis virus, suggesting that rapalogs downmodulate antiviral defenses that pose a common barrier to these viral fusion proteins. By identifying one rapalog (ridaforolimus) that lacks this function, we demonstrate that the extent to which rapalogs promote virus entry is linked to their capacity to trigger the lysosomal degradation of IFITM2 and IFITM3, intrinsic inhibitors of virus-cell membrane fusion. Mechanistically, rapalogs that promote virus entry inhibit the mTOR-mediated phosphorylation of TFEB, a transcription factor controlling lysosome biogenesis and lysosomal degradation pathways such as autophagy. In contrast, TFEB phosphorylation by mTOR was not inhibited by ridaforolimus. In the hamster model of SARS-CoV-2 infection, injection of rapamycin four hours prior to virus exposure resulted in elevated virus titers in lungs, accelerated weight loss, and decreased survival. Conclusion: Our findings indicate that preexisting use of certain rapalogs may elevate host susceptibility to SARS-CoV-2 infection and disease by activating a lysosome-mediated suppression of intrinsic immunity.