Cyclosporine A Inhibits Viral Infection and Release as Well as Cytokine Production in Lung Cells by Three SARS-CoV-2 Variants.
Cyclosporine A Inhibits Viral Infection and Release as Well as Cytokine Production in Lung Cells by Three SARS-CoV-2 Variants.
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DOI：
10.1128/spectrum.01504-21
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发表时间：
2022-02-23
影响因子：
3.7
通讯作者：
Daniele T
中科院分区：
文献类型：
--
作者：
Fenizia C;Galbiati S;Vanetti C;Vago R;Clerici M;Tacchetti C;Daniele T
2019年12月，一种新型严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）开始在全球范围内传播，导致2019冠状病毒病（COVID-19）大流行。免疫系统的过度激活被认为是COVID-19患者疾病严重程度和死亡的原因。尽管已经测试了几种方法，但尚未批准任何治疗方案。鉴于环孢菌素A（CsA）是众所周知的发挥强大的抗病毒活性的几种病毒株和抗炎作用，在不同的器官在不同的病理环境中的相关利益，我们测试了它对SARS冠状病毒-2感染的肺细胞的影响。我们发现，在三种SARS-CoV-2变异体感染CaLu 3细胞之前或之后用CsA治疗：（i）减少感染细胞中病毒RNA和蛋白质的表达;（ii）减少感染细胞释放的子代病毒粒子的数量;（iii）抑制病毒触发的细胞因子（包括IL-6，IL-8，IL 1 α和TNF-α）的合成，这些细胞因子参与患者的细胞因子风暴。总之，这些数据为CsA重新定位治疗重度COVID-19患者提供了依据。重要性SARS-CoV-2是最近发现的导致COVID-19大流行的β冠状病毒属成员。重新利用现有药物一直是一种“快速而肮脏”的方法，试图在最初降低受影响患者的死亡率和严重症状，并且仍然是应对COVID-19的不可否认和有价值的方法，因为能够逃避抗体中和的更具“攻击性”/可传播的变体的持续出现和快速扩散对一些抗SARS-CoV-2疫苗的有效性提出了挑战。在这里，我们测试了一种已知的抗病毒和抗炎药物，环孢素A（CsA），发现它在暴露于三种不同的SARS-CoV-2变体时抑制病毒感染和肺细胞释放细胞因子。CsA的主要细胞内靶点亲环素A的敲低不会对病毒感染的药物抑制进行表型复制。总而言之，这些发现为SARS-CoV-2感染的细胞机制提供了新的线索，并为CsA重新定位以治疗严重的COVID-19患者提供了理论基础。
In December 2019, a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started spreading worldwide causing the coronavirus disease 2019 (COVID-19) pandemic. The hyperactivation of the immune system has been proposed to account for disease severity and death in COVID-19 patients. Despite several approaches having been tested, no therapeutic protocol has been approved. Given that Cyclosporine A (CsA) is well-known to exert a strong antiviral activity on several viral strains and an anti-inflammatory role in different organs with relevant benefits in diverse pathological contexts, we tested its effects on SARS-CoV-2 infection of lung cells. We found that treatment with CsA either before or after infection of CaLu3 cells by three SARS-CoV-2 variants: (i) reduces the expression of both viral RNA and proteins in infected cells; (ii) decreases the number of progeny virions released by infected cells; (iii) dampens the virus-triggered synthesis of cytokines (including IL-6, IL-8, IL1α and TNF-α) that are involved in cytokine storm in patients. Altogether, these data provide a rationale for CsA repositioning for the treatment of severe COVID-19 patients. IMPORTANCE SARS-CoV-2 is the most recently identified member of the betacoronavirus genus responsible for the COVID-19 pandemic. Repurposing of available drugs has been a “quick and dirty” approach to try to reduce mortality and severe symptoms in affected patients initially, and can still represent an undeniable and valuable approach to face COVID-19 as the continuous appearance and rapid diffusion of more “aggressive”/transmissible variants, capable of eluding antibody neutralization, challenges the effectiveness of some anti-SARS-CoV-2 vaccines. Here, we tested a known antiviral and anti-inflammatory drug, Cyclosporine A (CsA), and found that it dampens viral infection and cytokine release from lung cells upon exposure to three different SARS-CoV-2 variants. Knock down of the main intracellular target of CsA, Cyclophilin A, does not phenocopy the drug inhibition of viral infection. Altogether, these findings shed new light on the cellular mechanisms of SARS-CoV-2 infection and provide the rationale for CsA repositioning to treat severe COVID-19 patients.
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影响因子：
120.7
作者：
Caricchio, Roberto;Abbate, Antonio;Noviello, Stephanie
通讯作者：
Noviello, Stephanie
影响因子：
8.8
作者：
Dittmar M;Lee JS;Whig K;Segrist E;Li M;Kamalia B;Castellana L;Ayyanathan K;Cardenas-Diaz FL;Morrisey EE;Truitt R;Yang W;Jurado K;Samby K;Ramage H;Schultz DC;Cherry S
通讯作者：
Cherry S
危及生命的Covid-19患者中针对I型IFN的自身抗体。
DOI：
10.1126/science.abd4585
发表时间：
2020-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bastard P;Rosen LB;Zhang Q;Michailidis E;Hoffmann HH;Zhang Y;Dorgham K;Philippot Q;Rosain J;Béziat V;Manry J;Shaw E;Haljasmägi L;Peterson P;Lorenzo L;Bizien L;Trouillet-Assant S;Dobbs K;de Jesus AA;Belot A;Kallaste A;Catherinot E;Tandjaoui-Lambiotte Y;Le Pen J;Kerner G;Bigio B;Seeleuthner Y;Yang R;Bolze A;Spaan AN;Delmonte OM;Abers MS;Aiuti A;Casari G;Lampasona V;Piemonti L;Ciceri F;Bilguvar K;Lifton RP;Vasse M;Smadja DM;Migaud M;Hadjadj J;Terrier B;Duffy D;Quintana-Murci L;van de Beek D;Roussel L;Vinh DC;Tangye SG;Haerynck F;Dalmau D;Martinez-Picado J;Brodin P;Nussenzweig MC;Boisson-Dupuis S;Rodríguez-Gallego C;Vogt G;Mogensen TH;Oler AJ;Gu J;Burbelo PD;Cohen JI;Biondi A;Bettini LR;D'Angio M;Bonfanti P;Rossignol P;Mayaux J;Rieux-Laucat F;Husebye ES;Fusco F;Ursini MV;Imberti L;Sottini A;Paghera S;Quiros-Roldan E;Rossi C;Castagnoli R;Montagna D;Licari A;Marseglia GL;Duval X;Ghosn J;HGID Lab;NIAID-USUHS Immune Response to COVID Group;COVID Clinicians;COVID-STORM Clinicians;Imagine COVID Group;French COVID Cohort Study Group;Milieu Intérieur Consortium;CoV-Contact Cohort;Amsterdam UMC Covid-19 Biobank;COVID Human Genetic Effort;Tsang JS;Goldbach-Mansky R;Kisand K;Lionakis MS;Puel A;Zhang SY;Holland SM;Gorochov G;Jouanguy E;Rice CM;Cobat A;Notarangelo LD;Abel L;Su HC;Casanova JL
通讯作者：
Casanova JL
影响因子：
4.4
作者：
Arora, K;Gwinn, WM;Constant, SL
通讯作者：
Constant, SL
影响因子：
3.8
作者：
de Wilde, Adriaan H.;Zevenhoven-Dobbe, Jessika C.;van Hemert, Martijn J.
通讯作者：
van Hemert, Martijn J.