SARS coronavirus induces apoptosis in Vero E6 Cells

Yan, Huimin; Xiao, Gengfu; Zhang, Jiamin; Hu, Yuanyang; Yuan, Fang; Cole, David K.; Zheng, Chengchao; Gao, George F.

doi:10.1002/jmv.20094

Cited by 96 publications

(101 citation statements)

References 50 publications

(92 reference statements)

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“…Apoptosis can also assist in the dissemination of viral particles and is the cause of tissue damage observed following many viral infections (Lyles, 2000). In SARS patients, apoptosis of cells of the lung epithelium has been observed, suggesting SARS-CoV-induced apoptosis to have a deleterious pathogenic role, leading to severe tissue damage (Yan et al, 2004). There are indications that apoptosis and the antiviral immune response may both contribute to the pathology in SARS patients (Yang et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Padhan

Minakshi

Towheed

et al. 2008

Journal of General Virology

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The molecular mechanisms governing severe acute respiratory syndrome coronavirus-induced pathology are not fully understood. Virus infection and some individual viral proteins, including the 3a protein, induce apoptosis. However, the cellular targets leading to 3a protein-mediated apoptosis have not been fully characterized. This study showed that the 3a protein modulates the mitochondrial death pathway in two possible ways. Activation of caspase-8 through extrinsic signal(s) caused Bid activation. In the intrinsic pathway, there was activation of caspase-9 and cytochrome c release from the mitochondria. This was the result of increased Bax oligomerization and higher levels of p53 in 3a protein-expressing cells, which depended on the activation of p38 MAP kinase (MAPK) in these cells. For p38 activation and apoptosis induction, the 3a cytoplasmic domain was sufficient. In direct Annexin V staining assays, the 3a protein-expressing cells showed increased apoptosis that was attenuated with the p38 MAPK inhibitor SB203580. A block in nuclear translocation of the STAT3 transcription factor in cells expressing the 3a protein was also observed. These results have been used to present a model of 3a-mediated apoptosis. INTRODUCTIONThe aetiological agent for severe acute respiratory syndrome (SARS) was identified as a novel coronavirus (SARS-CoV) (Peiris et al., 2003). SARS-CoV has a polyadenylated, positive-sense RNA genome of approximately 30 kb (Marra et al., 2003). In addition to the prototypic coronavirus genes, the SARS-CoV genome also contains nine unique open reading frames (ORFs) (Marra et al., 2003). Of these, orf3a is the largest and encodes a protein of 274 aa, variously called ORF3A (Ito et al., 2005), X1 (Rota et al., 2003) or U274 (Tan et al., 2004b). The 3a protein has been predicted to contain an N-terminal signal peptide followed by three transmembrane domains and a C-terminal cytoplasmic domain of approximately 150 aa (Zeng et al., 2004).The 3a protein is associated with virus particles produced following infection of Vero E6 or Caco-2 cells (Ito et al., 2005;Shen et al., 2005) and can assemble into virus-like particles when co-expressed with the membrane and envelope proteins in insect cells (Shen et al., 2005). In vitro studies have also shown the 3a protein to interact with the viral envelope, membrane and spike proteins (Tan et al., 2004b;Tan, 2005) and the cellular protein caveolin-1 (Padhan et al., 2007). A deletion of orf3a was shown to reduce virus titres, but not to eliminate virus replication (Yount et al., 2005), and convalescent sera from SARS patients have antibodies to the 3a protein (Tan et al., 2004a), suggesting that it is expressed during virus infection of the host. The 3a protein was shown to upregulate the expression of fibrinogen in A549 lung epithelial cells and to possess an ionchannel activity selective for monovalent cations (Lu et al., 2006). Ectopic expression of the 3a protein has been shown to induce apoptosis in Vero E6 cells through activation of caspase-8, chromatin c...

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Section: Discussionmentioning

confidence: 99%

Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Padhan

Minakshi

Towheed

et al. 2008

Journal of General Virology

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“…This is usually a ciliated respiratory tract epithelial cell in the nasopharynx [12,67]. Thereafter, the mechanisms by which SARS-CoV causes disease can be separated into [68,69], apoptosis [68,70] or cell fusion to form syncytia [71]. Studies in mice have shown that there is a potent CD8 T-cell response with acute MHV infection [72], and that fulminant hepatitis can result from induced transcription of a novel fgl2 prothrombinase gene by the MHV nucleocapsid protein [73].…”

Section: Pathogenesismentioning

confidence: 98%

SARS: clinical presentation, transmission, pathogenesis and treatment options

2006

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SARS (severe acute respiratory syndrome) appeared as the first emerging infectious disease of this century. It is fortunate that the culprit virus can be grown without much difficulty from a commonly used cell line, allowing an unlimited supply of isolates for further molecular studies and leading to the development of sensitive diagnostic assays. How the virus has successfully jumped the species barrier is still a mystery. The superspreading events that occurred within hospital, hotel and high-density housing estate opens a new chapter in the mechanisms and routes of virus transmission. The old practice of quarantine proved to be still useful in controlling the global outbreak. Despite all the available sophisticated tests, alertness with early recognition by healthcare workers and prompt isolation of suspected cases is still the most important step for containing the spread of the infection. Although the rapidly evolving outbreak did not allow the conducting of systematic clinical trails to evaluate treatment options, the accumulated experience on managing SARS patients will improve the clinical outcome should SARS return. Although SARS led to more than 700 deaths worldwide, the lessons learnt have prepared healthcare systems worldwide to face future emerging and re-emerging infections.

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“…Besides lymphopenia, which is caused by the depletion of T lymphocytes by apoptosis, one study also reported apoptosis in the hepatocytes of three SARS patients who had liver impairment (6). Apoptosis was also observed in Vero E6 cells infected by SARS-CoV (31). Overall, these findings indicate that apoptosis plays an important role during SARS-CoV infection.…”

mentioning

confidence: 88%

Overexpression of 7a, a Protein Specifically Encoded by the Severe Acute Respiratory Syndrome Coronavirus, Induces Apoptosis via a Caspase-Dependent Pathway

Tan

Fielding

Goh

et al. 2004

J Virol

199

194

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Besides genes that are homologous to proteins found in other coronaviruses, the severe acute respiratory syndrome coronavirus genome also contains nine other potential open reading frames. Previously, we have characterized the expression and cellular localization of two of these "accessory" viral proteins, 3a (previously termed U274) and 7a (previously termed U122). In this study, we further examined whether they can induce apoptosis, which has been observed clinically. We showed that the overexpression of 7a, but not of 3a or the viral structural proteins, nucleocapsid, membrane, and envelope, induces apoptosis. 7a induces apoptosis via a caspase-dependent pathway and in cell lines derived from different organs, including lung, kidney, and liver.

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SARS coronavirus induces apoptosis in Vero E6 Cells

Cited by 96 publications

References 50 publications

Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

SARS: clinical presentation, transmission, pathogenesis and treatment options

Overexpression of 7a, a Protein Specifically Encoded by the Severe Acute Respiratory Syndrome Coronavirus, Induces Apoptosis via a Caspase-Dependent Pathway

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