Crudele Annalisa, Smeriglio Antonella, Ingegneri Mariarosaria, Panera Nadia, Bianchi Marzia, Braghini Maria Rita, Pastore Anna, Tocco Valeria, Carsetti Rita, Zaffina Salvatore, Alisi Anna, Trombetta Domenico
Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres 31, 98166 Messina, Italy.
Antioxidants (Basel). 2022 Jul 27;11(8):1466. doi: 10.3390/antiox11081466.
The SARS-CoV-2 pandemic has caused approximately 6.3 million deaths, mainly due to the acute respiratory distress syndrome or multi-organ failure that characterizes COVID-19 acute disease. Post-acute COVID-19 syndrome, also known as long-COVID, is a condition characterized by a complex of symptoms that affects 10-20% of the individuals who have recovered from the infection. Scientific and clinical evidence demonstrates that long-COVID can develop in both adults and children. It has been hypothesized that multi-organ effects of long-COVID could be associated with the persistence of virus RNA/proteins in host cells, but the real mechanism remains to be elucidated. Therefore, we sought to determine the effects of the exogenous expression of the papain-like protease (PLpro) domain of the non-structural protein (NSP3) of SARS-CoV-2 in polarized human airway (Calu-3), intestinal (Caco-2), and liver (HepG2) epithelial cells, and to evaluate the ability of the natural antioxidant hydroxytyrosol (HXT) in neutralizing these effects. Our results demonstrated that PLpro was able to induce a cascade of inflammatory genes and proteins (mainly associated with the interferon pathway) and increase the apoptotic rate and expression of several oxidative stress markers in all evaluated epithelial cells. Noteably, the treatment with 10 μM HXT reverted PL-pro-dependent effects almost completely. This study provides the first evidence that SARS-CoV-2 PLpro remaining in host cells after viral clearance may contribute to the pathogenetic mechanisms of long-COVID. These effects may be counteracted by natural antioxidants. Further clinical and experimental studies are necessary to confirm this hypothesis.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）大流行已导致约630万人死亡，主要原因是COVID-19急性疾病所特有的急性呼吸窘迫综合征或多器官衰竭。急性COVID-19后综合征，也称为长期COVID，是一种以一系列症状为特征的疾病，影响着10%-20%从感染中康复的个体。科学和临床证据表明，成人和儿童都可能出现长期COVID。据推测，长期COVID的多器官影响可能与病毒RNA/蛋白质在宿主细胞中的持续存在有关，但真正的机制仍有待阐明。因此，我们试图确定SARS-CoV-2非结构蛋白（NSP3）的木瓜样蛋白酶（PLpro）结构域在极化的人气道（Calu-3）、肠道（Caco-2）和肝脏（HepG2）上皮细胞中的外源性表达的影响，并评估天然抗氧化剂羟基酪醇（HXT）中和这些影响的能力。我们的结果表明，PLpro能够在所有评估的上皮细胞中诱导一系列炎症基因和蛋白质（主要与干扰素途径相关），并增加几种氧化应激标志物的凋亡率和表达。值得注意的是，用10μM HXT处理几乎完全逆转了PLpro依赖性效应。这项研究提供了首个证据，表明病毒清除后留在宿主细胞中的SARS-CoV-2 PLpro可能促成长期COVID的发病机制。这些影响可能被天然抗氧化剂抵消。需要进一步的临床和实验研究来证实这一假设。
