Gao Yan, Kok Wai Ling, Sharma Vikram, Illsley Charlotte Sara, Hanks Sally, Tredwin Christopher, Hu Bing
Stem Cells & Regenerative Medicine Laboratory, Peninsula Dental School, Faculty of Health, University of Plymouth, 16 Research Way, Plymouth, PL6 8BU, UK.
School of Biomedical Sciences, Faculty of Health, University of Plymouth, 16 Research Way, Plymouth, PL6 8BU, UK.
Cell Death Discov. 2023 May 26;9(1):175. doi: 10.1038/s41420-023-01474-2.
The global high prevalence of COVID-19 is a major challenge for health professionals and patients. SARS-CoV-2 virus has four structural protein components: the spike protein, envelope protein, membrane protein, and nucleocapsid protein. The SARS-CoV-2 virus mutates predominantly in the spike proteins, whilst the other key viral components usually remain stable. Essentially the pathological functions of the SARS-CoV-2 virus on different cell types are still largely unknown. Previous studies have shown that the human oral cavity can potentially act as reservoir of the SARS-CoV-2 virus. However, the consequence of SARS-CoV-2 viral infection on human oral health has not been systematically examined. COVID-19 can cause severe oral mucosa lesions and is likely to be connected with poor periodontal conditions. Fibroblasts are the major cell type inside periodontal ligament (PDL) and express the SARS-CoV-2 receptor: Angiotensin-converting enzyme 2 (ACE2), whose expression level can increase upon bacterial infection hence potentially provide a direct route of SARS-CoV-2 infection to PDL fibroblasts. In this research, we aimed to study the pathogenicity of SARS-CoV-2 viral components on human fibroblasts. We found that by exposing to SARS-CoV-2, especially to the viral envelope and membrane proteins, the human periodontal fibroblasts could develop fibrotic pathogenic phenotypes, including hyperproliferation that was simultaneously induced with increased apoptosis and senescence. The fibrotic degeneration was mediated by a down-regulation of mitochondrial β-oxidation in the fibroblasts. Fatty acid β-oxidation inhibitor, etomoxir treatment could mirror the same pathological consequence on the cells, similar to SARS-CoV-2 infection. Our results therefore provide novel mechanistic insights into how SARS-CoV-2 infection can affect human periodontal health at the cell and molecular level with potential new therapeutic targets for COVID-19 induced fibrosis.
新型冠状病毒肺炎（COVID-19）在全球的高流行率对医护人员和患者来说是一项重大挑战。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）病毒有四种结构蛋白成分：刺突蛋白、包膜蛋白、膜蛋白和核衣壳蛋白。SARS-CoV-2病毒主要在刺突蛋白中发生突变，而其他关键病毒成分通常保持稳定。本质上，SARS-CoV-2病毒在不同细胞类型上的病理功能仍 largely未知。先前的研究表明，人类口腔可能是SARS-CoV-2病毒的储存库。然而，SARS-CoV-2病毒感染对人类口腔健康的影响尚未得到系统研究。COVID-19可导致严重的口腔黏膜病变，并且可能与不良的牙周状况有关。成纤维细胞是牙周膜（PDL）内的主要细胞类型，并表达SARS-CoV-2受体：血管紧张素转换酶2（ACE2），其表达水平在细菌感染时会升高，因此可能为SARS-CoV-2感染PDL成纤维细胞提供一条直接途径。在本研究中，我们旨在研究SARS-CoV-2病毒成分对人成纤维细胞的致病性。我们发现，通过暴露于SARS-CoV-2，尤其是病毒包膜和膜蛋白，人牙周成纤维细胞可出现纤维化致病表型，包括过度增殖，同时伴有凋亡和衰老增加。纤维化变性是由成纤维细胞中线粒体β-氧化的下调介导的。脂肪酸β-氧化抑制剂依托莫昔治疗可在细胞上模拟与SARS-CoV-2感染相似的病理后果。因此，我们的结果为SARS-CoV-2感染如何在细胞和分子水平上影响人类牙周健康提供了新的机制见解，并为COVID-19诱导的纤维化提供了潜在的新治疗靶点。
