Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis.
Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis.
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DOI：
10.1183/13993003.02951-2021
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发表时间：
2022-08
期刊：
影响因子：
--
通讯作者：
Gorgoulis VG
中科院分区：
文献类型：
--
作者：
Evangelou K;Veroutis D;Paschalaki K;Foukas PG;Lagopati N;Dimitriou M;Papaspyropoulos A;Konda B;Hazapis O;Polyzou A;Havaki S;Kotsinas A;Kittas C;Tzioufas AG;de Leval L;Vassilakos D;Tsiodras S;Stripp BR;Papantonis A;Blandino G;Karakasiliotis I;Barnes PJ;Gorgoulis VG
严重急性呼吸系统综合征冠状病毒2 （SARS-CoV-2）感染可发展为多系统疾病，并伴有异常炎症反应。细胞衰老促进慢性炎症，称为衰老相关分泌表型（SASP）。我们研究了冠状病毒病2019 （COVID-19）是否与细胞衰老和SASP相关。采用免疫组化方法对11例COVID-19患者和43例年龄匹配且合并症相似的非COVID-19对照组尸检肺组织样本进行了SARS-CoV-2、衰老标志物和关键SASP细胞因子的分析。通过用从COVID-19患者分离的SARS-CoV-2菌株感染上皮细胞Vero-E6和肺泡2型（AT2）细胞的三维肺泡系统，在体外功能重现病毒诱导的衰老。免疫细胞化学和电镜检测主要在AT2细胞中检测到SARS-CoV-2。感染的AT2细胞表达血管紧张素转换酶2，衰老增加（p16INK4A和SenTraGor阳性），白细胞介素(IL)-1β和IL-6表达增加。在体外，SARS-CoV-2感染Vero-E6细胞诱导衰老（SenTraGor）、DNA损伤（γ-H2AX）和细胞因子（IL-1β、IL-6、CXCL8）和载脂蛋白B mrna编辑（APOBEC）酶表达升高。从受感染/衰老的Vero-E6细胞中获得的后代的下一代测序分析显示apobecc介导的SARS-CoV-2突变。在1例COVID-19患者的肺外部位（肾脏和肝脏）确认了sars - cov -2感染的传播和衰老。我们证明，在严重的COVID-19中，被SARS-CoV-2感染的AT2细胞表现出衰老和促炎表型。在体外，SARS-CoV-2感染诱导衰老和炎症。重要的是，受感染的衰老细胞可能是APOBEC酶介导的SARS-CoV-2诱变的一个来源。因此，sars - cov -2诱导的衰老可能是重症COVID-19、疾病持续和突变的重要分子机制。在严重的COVID-19中，被SARS-CoV-2感染的肺泡2型（AT2）细胞表现出衰老并伴有促炎表型，这一分子机制可能在疾病持续（COVID-19急性后后遗症）和突变https://bit.ly/3fnopg9中很重要
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the respiratory system can progress to a multisystemic disease with aberrant inflammatory response. Cellular senescence promotes chronic inflammation, named senescence-associated secretory phenotype (SASP). We investigated whether coronavirus disease 2019 (COVID-19) is associated with cellular senescence and SASP. Autopsy lung tissue samples from 11 COVID-19 patients and 43 age-matched non-COVID-19 controls with similar comorbidities were analysed by immunohistochemistry for SARS-CoV-2, markers of senescence and key SASP cytokines. Virally induced senescence was functionally recapitulated in vitro, by infecting epithelial Vero-E6 cells and a three-dimensional alveosphere system of alveolar type 2 (AT2) cells with SARS-CoV-2 strains isolated from COVID-19 patients. SARS-CoV-2 was detected by immunocytochemistry and electron microscopy predominantly in AT2 cells. Infected AT2 cells expressed angiotensin-converting enzyme 2 and exhibited increased senescence (p16INK4A and SenTraGor positivity) and interleukin (IL)-1β and IL-6 expression. In vitro, infection of Vero-E6 cells with SARS-CoV-2 induced senescence (SenTraGor), DNA damage (γ-H2AX) and increased cytokine (IL-1β, IL-6, CXCL8) and apolipoprotein B mRNA-editing (APOBEC) enzyme expression. Next-generation sequencing analysis of progenies obtained from infected/senescent Vero-E6 cells demonstrated APOBEC-mediated SARS-CoV-2 mutations. Dissemination of the SARS-CoV-2-infection and senescence was confirmed in extrapulmonary sites (kidney and liver) of a COVID-19 patient. We demonstrate that in severe COVID-19, AT2 cells infected by SARS-CoV-2 exhibit senescence and a proinflammatory phenotype. In vitro, SARS-CoV-2 infection induces senescence and inflammation. Importantly, infected senescent cells may act as a source of SARS-CoV-2 mutagenesis mediated by APOBEC enzymes. Therefore, SARS-CoV-2-induced senescence may be an important molecular mechanism of severe COVID-19, disease persistence and mutagenesis. In severe COVID-19, alveolar type 2 (AT2) cells infected by SARS-CoV-2 exhibit senescence accompanied by a proinflammatory phenotype, a molecular mechanism that may be important in persistence of disease (post-acute sequelae of COVID-19) and mutagenesis https://bit.ly/3fnopg9
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影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
DOI：
10.1038/nri3166
发表时间：
2012-03-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1183/13993003.02708-2020
发表时间：
2020-12
期刊：
The European respiratory journal
影响因子：
--
作者：
Kelley WJ;Zemans RL;Goldstein DR
通讯作者：
Goldstein DR
细胞衰老是一种抗病毒防御机制。
影响因子：
4.6
作者：
Baz-Martínez M;Da Silva-Álvarez S;Rodríguez E;Guerra J;El Motiam A;Vidal A;García-Caballero T;González-Barcia M;Sánchez L;Muñoz-Fontela C;Collado M;Rivas C
通讯作者：
Rivas C
影响因子：
82.9
作者：
Del Valle DM;Kim-Schulze S;Huang HH;Beckmann ND;Nirenberg S;Wang B;Lavin Y;Swartz TH;Madduri D;Stock A;Marron TU;Xie H;Patel M;Tuballes K;Van Oekelen O;Rahman A;Kovatch P;Aberg JA;Schadt E;Jagannath S;Mazumdar M;Charney AW;Firpo-Betancourt A;Mendu DR;Jhang J;Reich D;Sigel K;Cordon-Cardo C;Feldmann M;Parekh S;Merad M;Gnjatic S
通讯作者：
Gnjatic S