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本帖最后由 顾汉现 于 2022-2-12 19:08 编辑
Nature、Science等：新冠病毒会促进细胞衰老，从而导致长期后遗症的出现
新冠病毒感染细胞后，会诱导产生细胞衰老相关分泌表型（SASP），从而影响附近未感染细胞出现衰老样细胞周期停滞，而且这种影响即使在新冠病毒被清除后仍然持续存在。这提示了我们，新冠病毒感染导致的细胞衰老相关分泌表型（SASP）可能是导致“长期新冠”（Long COVID）的原因。本3篇论文是新冠病毒感染、促细胞衰老、长期后遗症等关联基础医学研究论文。
生物世界
2022/01/29
论文一
论文二
论文三
新冠病毒会促进细胞衰老，从而导致长期后遗症的出现
生物世界
2022/01/29
论文一
论文标题：SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response
作者：Tsuji, Shunya, Minami, Shohei, Hashimoto, Rina, Konishi, Yusuke, Suzuki, Tatsuya, Kondo, Tamae, Sasai, Miwa, Torii, Shiho, Ono, Chikako, Shichinohe, Shintaro, Sato, Shintaro, Wakita, Masahiro, Okumura, Shintaro, Nakano, Sosuke, Matsudaira, Tatsuyuki, Matsumoto, Tomonori, Kawamoto, Shimpei, Yamamoto, Masahiro, Watanabe, Tokiko, Matsuura, Yoshiharu, Takayama, Kazuo, Kobayashi, Takeshi, Okamoto, Toru, Hara, Eiji
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期刊：Nature Aging
发表时间：2022/01/25
数字识别码：10.1038/s43587-022-00170-7
摘要：Reports of post-acute COVID-19 syndrome, in which the inflammatory response persists even after SARS-CoV-2 has disappeared, are increasing1, but the underlying mechanisms of post-acute COVID-19 syndrome remain unknown. Here, we show that SARS-CoV-2-infected cells trigger senescence-like cell-cycle arrest2,3 in neighboring uninfected cells in a paracrine manner via virus-induced cytokine production. In cultured human cells or bronchial organoids, these SASR-CoV-2 infection-induced senescent cells express high levels of a series of inflammatory factors known as senescence-associated secretory phenotypes (SASPs)4 in a sustained manner, even after SARS-CoV-2 is no longer detectable. We also show that the expression of the senescence marker CDKN2A (refs. 5,6) and various SASP factor4 genes is increased in the pulmonary cells of patients with severe post-acute COVID-19 syndrome. Furthermore, we find that mice exposed to a mouse-adapted strain of SARS-CoV-2 exhibit prolonged signs of cellular senescence and SASP in the lung at 14 days after infection when the virus was undetectable, which could be substantially reduced by the administration of senolytic drugs7. The sustained infection-induced paracrine senescence described here may be involved in the long-term inflammation caused by SARS-CoV-2 infection.
https://www.nature.com/articles/s43587-022-00170-7
论文二
论文标题：Senolytics reduce coronavirus-related mortality in old mice
作者：Christina D. Camell , Matthew J. Yousefzadeh , Yi Zhu , Larissa G. P. Langhi Prata , Matthew A. Huggins , Mark Pierson , Lei Zhang , Ryan D. O’Kelly , Tamar Pirtskhalava , Pengcheng Xun , Keisuke Ejima , Ailing Xue , Utkarsh Tripathi , Jair Machado Espindola-Netto , Nino Giorgadze , Elizabeth J. Atkinson , Christina L. Inman , Kurt O. Johnson , Stephanie H. Cholensky , Timothy W. Carlson , Nathan K. LeBrasseur , Sundeep Khosla , M. Gerard O’Sullivan , David B. Allison , Stephen C. Jameson , Alexander Meves , Ming Li , Y. S. Prakash , Sergio E. Chiarella , Sara E. Hamilton , Tamara Tchkonia , Laura J. Niedernhofer , James L. Kirkland , Paul D. Robbins
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期刊：Science
发表时间：2021/07/16
数字识别码：10.1126/science.abe4832
摘要：The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnCs) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 spike protein-1, increasing expression of viral entry proteins and reducing antiviral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2–related mouse β-coronavirus experienced increased senescence and inflammation, with nearly 100% mortality. Targeting SnCs by using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased antiviral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality after viral infection, including that of SARS-CoV-2.
https://www.science.org/doi/10.1126/science.abe4832
论文三
论文标题：Virus-induced senescence is a driver and therapeutic target in COVID-19
作者：Lee, Soyoung, Yu, Yong, Trimpert, Jakob, Benthani, Fahad, Mairhofer, Mario, Richter-Pechanska, Paulina, Wyler, Emanuel, Belenki, Dimitri, Kaltenbrunner, Sabine, Pammer, Maria, Kausche, Lea, Firsching, Theresa C., Dietert, Kristina, Schotsaert, Michael, Martínez-Romero, Carles, Singh, Gagandeep, Kunz, Séverine, Niemeyer, Daniela, Ghanem, Riad, Salzer, Helmut J. F., Paar, Christian, Mülleder, Michael, Uccellini, Melissa, Michaelis, Edward G., Khan, Amjad, Lau, Andrea, Schönlein, Martin, Habringer, Anna, Tomasits, Josef, Adler, Julia M., Kimeswenger, Susanne, Gruber, Achim D., Hoetzenecker, Wolfram, Steinkellner, Herta, Purfürst, Bettina, Motz, Reinhard, Di Pierro, Francesco, Lamprecht, Bernd, Osterrieder, Nikolaus, Landthaler, Markus, Drosten, Christian, García-Sastre, Adolfo, Langer, Rupert, Ralser, Markus, Eils, Roland, Reimann, Maurice, Fan, Dorothy N. Y., Schmitt, Clemens A.
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期刊：Nature
发表时间：2021/09/13
数字识别码：10.1038/s41586-021-03995-1
摘要：Derailed cytokine and immune cell networks account for organ damage and clinical severity of COVID-191–4. Here we show that SARS-CoV-2, like other viruses, evokes cellular senescence as a primary stress response in infected cells. Virus-induced senescence (VIS) is indistinguishable from other forms of cellular senescence and accompanied by a senescence-associated secretory phenotype (SASP), composed of pro-inflammatory cytokines, extracellular matrix-active factors and pro-coagulatory mediators5–7. COVID-19 patients displayed markers of senescence in their airway mucosa in situ and elevated serum levels of SASP factors. Mirroring COVID-19 hallmark features such as macrophage and neutrophil infiltration, endothelial damage and widespread thrombosis in affected lung tissue1,8,9, in vitro assays demonstrated macrophage activation with SASP-reminiscent secretion, complement lysis and SASP-amplifying secondary senescence of endothelial cells, neutrophil extracellular trap (NET) formation as well as activation of platelets and the clotting cascade in response to supernatant of VIS cells, including SARS-CoV-2-induced senescence. Senolytics such as Navitoclax and Dasatinib/Quercetin selectively eliminated VIS cells, mitigated COVID-19-reminiscent lung disease and reduced inflammation in SARS-CoV-2-driven hamster and mouse models. Our findings mark VIS as pathogenic trigger of COVID-19-related cytokine escalation and organ damage, and suggest senolytic targeting of virus-infected cells as a novel treatment option against SARS-CoV-2 and perhaps other viral infections.
https://www.nature.com/articles/s41586-021-03995-1
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所属学科：
病毒学
医学
撰文 | 王聪
编辑 | 王多鱼
排版 | 水成文
自2019年12月新冠大流行以来，全球已有超过2亿人感染新冠肺炎，导致超过500万人死亡。此外，很大一部新冠感染者即使康复后，仍长期存在后遗症，这种情况也被称为“长期新冠”（Long COVID）。因此，还需要更深入的了解新冠病毒感染后的生物学反应，尤其是持续反应。
由于新冠肺炎在老年人中往往更为严重，因此新冠感染与衰老之间的可能存在着重要关联。细胞衰老是一种不可逆的细胞周期状态停滞，可有多种潜在致癌刺激所诱导，被认为是一种肿瘤抑制机制。与凋亡细胞不同，衰老细胞不会立即死亡，而会在全身积聚。重要的是，衰老细胞不仅是不分裂的，它们还会产生一种细胞衰老相关分泌表型（SASP）现象。在这种现象中，衰老细胞会分泌多种促炎因子，例如炎症细胞因子、趋化因子、生长因子和细胞外基质降解酶等等。
因此，虽然细胞衰老的诱导主要作为一种肿瘤抑制，但由于衰老导致的体内衰老细胞的过度积累，会产生细胞衰老相关分泌表型（SASP），从而产生不利影响。而且有研究显示，通过遗传或药理学方法去除衰老细胞可以减缓老年小鼠与衰老相关的炎性疾病的发作。
近日，日本大阪大学的研究团队在 Nature 子刊 Nature Aging 发表了题为：SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response 的研究论文【1】。
该研究表明，新冠病毒感染细胞后，会诱导产生细胞衰老相关分泌表型（SASP），从而影响附近未感染细胞出现衰老样细胞周期停滞，而且这种影响即使在新冠病毒被清除后仍然持续存在。
这提示了我们，新冠病毒感染导致的细胞衰老相关分泌表型（SASP）可能是导致“长期新冠”（Long COVID）的原因。
在此之前，2021年7月16日，美国明尼苏达大学和梅奥医学中心的研究团队在 Science 期刊发表了题为：Senolytics reduce coronavirus-related mortality in old mice 的研究论文【2】。这项研究表明，抗衰老药物Senolytics能够降低老年小鼠与冠状病毒相关的死亡率。
2021年9月13日，德国柏林夏里特医学院的研究人员在 Nature 上发表了题为：Virus-induced senescence is driver and therapeutic target in COVID-19 的研究论文【3】。
这项研究表明，宿主细胞在感染了新冠病毒之后，会唤醒自身的细胞衰老机制作为主要应激反应。基于这一点，研究人员利用针对衰老细胞的Senolytics疗法选择性清除感染了新冠病毒的细胞，从而揭示了一种新的病毒治疗方案。
在这项新研究中，研究团队发现，感染新冠病毒后的细胞会产生细胞衰老相关分泌表型（SASP），并因此在附近细胞中引发衰老样细胞周期停滞。
而在培养的人体细胞或支气管类器官中，这些新冠病毒感染诱导的衰老细胞持续高水平表达一系列炎症因子，也就是所谓的细胞衰老相关分泌表型（SASP），即使在新冠病毒被清除后，这种衰老相关分泌表型也仍然存在。
该研究还发现，许多出现后遗症的新冠康复者的非细胞中的衰老标志物CDKN2A和各种细胞衰老相关分泌表型（SASP）因子的基因表达增加。此外，小鼠实验发现，感染新冠的小鼠模型在感染14天后，表现出细胞衰老和细胞衰老相关分泌表型（SASP）的现象，即使新冠病毒在无法检测到时，这种现象也依然存在，而使用抗衰老药物（例如Senolytics）可以减少细胞衰老和SASP现象。
总的来说，这项研究表明，新冠病毒感染细胞后，会诱导产生细胞衰老相关分泌表型（SASP），从而影响附近未感染细胞出现衰老样细胞周期停滞，而且这种影响即使在新冠病毒被清除后仍然持续存在。这提示了我们，新冠病毒感染导致的细胞衰老相关分泌表型（SASP）可能是导致“长期新冠”（Long COVID）的原因。
更多精彩内容，请关注“生物世界”（ibioworld）
文章标签
SARS-CoV-2
Senescence
Virus–host interactions
Ageing
Virology
衰老
病毒与宿主的相互作用
老化
病毒学
Experimental models of disease
Mechanisms of disease
疾病的实验模型
疾病机制
新冠病毒
https://www.nature.com/articles/s43587-022-00170-7
https://www.science.org/doi/10.1126/science.abe4832
https://www.nature.com/articles/s41586-021-03995-1
https://www.linkresearcher.com/t ... f-a39d-ea9b0e5defe9
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