Identification of Immunodominant Sites on the Spike Protein of Severe Acute Respiratory Syndrome (SARS) Coronavirus: Implication for Developing SARS Diagnostics and Vaccines

He, Yuxian; Zhou, Yusen; Wu, Hao; Luo, Biao; Chen, Jingming; Li, Wanbo; Jiang, Shibo

doi:10.4049/jimmunol.173.6.4050

Cited by 156 publications

(177 citation statements)

References 36 publications

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“…In addition, MERS-CoV RBD is also a potential candidate for MERS-CoV subunit vaccines. Previous studies have shown that SARS-CoV RBD can elicit robust host immune responses against SARS-CoV infections (40,41). Likewise, the MERS-CoV RBD identified in this study has a well-folded structure and interacts strongly with human DPP4, making it a potential vaccine candidate.…”

Section: Resultsmentioning

confidence: 82%

Crystal Structure of the Receptor-Binding Domain from Newly Emerged Middle East Respiratory Syndrome Coronavirus

Chen

Rajashankar

Yang

et al. 2013

J Virol

115

119

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The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) has infected at least 77 people, with a fatality rate of more than 50%. Alarmingly, the virus demonstrates the capability of human-to-human transmission, raising the possibility of global spread and endangering world health and economy. Here we have identified the receptor-binding domain (RBD) from the MERS-CoV spike protein and determined its crystal structure. This study also presents a structural comparison of MERS-CoV RBD with other coronavirus RBDs, successfully positioning MERS-CoV on the landscape of coronavirus evolution and providing insights into receptor binding by MERS-CoV. Furthermore, we found that MERS-CoV RBD functions as an effective entry inhibitor of MERS-CoV. The identified MERS-CoV RBD may also serve as a potential candidate for MERS-CoV subunit vaccines. Overall, this study enhances our understanding of the evolution of coronavirus RBDs, provides insights into receptor recognition by MERS-CoV, and may help control the transmission of MERS-CoV in humans. Since the summer of 2012, a novel coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), has emerged from the Middle East and spread to parts of Europe. MERS-CoV infection often leads to acute pneumonia and renal failure, and the human fatality rate is more than 50% (1, 2). To date, MERS-CoV has infected at least 77 people and was able to be transmitted from human to human. The genomic sequence of MERS-CoV is closely related to the sequences of certain bat coronaviruses (3-5), raising concerns over persistent bat-to-human cross-species transmission of the virus. The clinical signs and epidemic patterns of MERS-CoV are reminiscent of the severe acute respiratory syndrome coronavirus (SARS-CoV), the etiological agent of the worldwide SARS epidemic in 2002-2003 that infected more than 8,000 people with a ϳ10% fatality rate (6, 7). MERS-CoV poses a significant threat to global health and economy.Coronaviruses are enveloped and positive-stranded RNA viruses and can be divided into three major genera, ␣, ␤, and ␥ (8). They mainly cause respiratory, gastrointestinal, and central nervous system diseases in mammals and birds. Coronaviruses recognize a variety of host receptors. Human NL63 respiratory coronavirus (HCoV-NL63) from ␣-genus and SARS-CoV from ␤-genus both recognize angiotensin-converting enzyme 2 (ACE2) as their host receptor (9, 10). Porcine respiratory coronavirus (PRCV) and some other coronaviruses from ␣-genus recognize aminopeptidase N (APN) (11, 12). Mouse hepatitis coronavirus (MHV) from ␤-genus recognizes carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (13, 14), although certain MHV strains also recognize heparan sulfate (15, 16). Some coronaviruses from each of the three genera recognize sugars (17-20). MERS-CoV belongs to the ␤-genus and uses human dipeptidyl peptidase 4 (DPP4) as its host receptor (21). Receptor recognition is a major determinant of coronavirus host range and tropism.An envelope-anchored trimeric spike p...

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Section: Resultsmentioning

confidence: 82%

Crystal Structure of the Receptor-Binding Domain from Newly Emerged Middle East Respiratory Syndrome Coronavirus

Chen

Rajashankar

Yang

et al. 2013

J Virol

115

119

View full text Add to dashboard Cite

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“…It is possible that the aggravation of liver impairment might be mediated by the enhancing Abs against the S protein. We have recently identified several nonneutralizing immunodominant epitopes located outside of the RBD on the SARS-CoV S protein (40). Another explanation is that the full-length S protein expressed by the DNA vaccines or recombinant viruses may be retained in the endoplasmic reticulum or Golgi after synthesis, thus limiting their ability to induce Ab responses.…”

Section: Discussionmentioning

confidence: 99%

Receptor-Binding Domain of Severe Acute Respiratory Syndrome Coronavirus Spike Protein Contains Multiple Conformation-Dependent Epitopes that Induce Highly Potent Neutralizing Antibodies

Liang

Siddiqui

et al. 2005

The Journal of Immunology

Self Cite

239

300

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The spike (S) protein of severe acute respiratory syndrome associated coronavirus (SARS-CoV) is a major antigenic determinant capable of inducing protective immunity. Recently, a small fragment on the SARS-CoV S protein (residues 318–510) was characterized as a minimal receptor-binding domain (RBD), which mediates virus binding to angiotensin-converting enzyme 2, the functional receptor on susceptible cells. In this study, we demonstrated that a fusion protein containing RBD linked to human IgG1 Fc fragment (designated RBD-Fc) induced high titer of RBD-specific Abs in the immunized mice. The mouse antisera effectively neutralized infection by both SARS-CoV and SARS pseudovirus with mean 50% neutralization titers of 1/15,360 and 1/24,737, respectively. The neutralization determinants on the RBD of S protein were characterized by a panel of 27 mAbs isolated from the immunized mice. Six groups of conformation-dependent epitopes, designated as Conf I–VI, and two adjacent linear epitopes were identified by ELISA and binding competition assays. The Conf IV and Conf V mAbs significantly blocked RBD-Fc binding to angiotensin-converting enzyme 2, suggesting that their epitopes overlap with the receptor-binding sites in the S protein. Most of the mAbs (23 of 25) that recognized the conformational epitopes possessed potent neutralizing activities against SARS pseudovirus with 50% neutralizing dose ranging from 0.005 to 6.569 μg/ml. Therefore, the RBD of SARS S protein contains multiple conformational epitopes capable of inducing potent neutralizing Ab responses, and is an important target site for developing vaccines and immunotherapeutics.

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“…IDS I, II, III, and V reacted with >50% of the convalescent-phase sera from SARS patients, while IDS IV was reactive with >80% of SARS sera, suggesting that IDS IV is the major immunodominant epitope on the S protein (31). Synthetic peptides corresponding to IDS could induce high titers of S protein-specific antibodies, but none of these antibodies possesses neutralizing activity.…”

Section: S Protein-based Vaccinesmentioning

confidence: 99%

SARS Vaccine Development

Jiang

Liu

2005

Emerg. Infect. Dis.

Self Cite

187

173

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Developing effective and safe vaccines is urgently needed to prevent infection by severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV). The inactivated SARS-CoV vaccine may be the first one available for clinical use because it is easy to generate; however, safety is the main concern. The spike (S) protein of SARS-CoV is the major inducer of neutralizing antibodies, and the receptor-binding domain (RBD) in the S1 subunit of S protein contains multiple conformational neutralizing epitopes. This suggests that recombinant proteins containing RBD and vectors encoding the RBD sequence can be used to develop safe and effective SARS vaccines.

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Identification of Immunodominant Sites on the Spike Protein of Severe Acute Respiratory Syndrome (SARS) Coronavirus: Implication for Developing SARS Diagnostics and Vaccines

Cited by 156 publications

References 36 publications

Crystal Structure of the Receptor-Binding Domain from Newly Emerged Middle East Respiratory Syndrome Coronavirus

Crystal Structure of the Receptor-Binding Domain from Newly Emerged Middle East Respiratory Syndrome Coronavirus

Receptor-Binding Domain of Severe Acute Respiratory Syndrome Coronavirus Spike Protein Contains Multiple Conformation-Dependent Epitopes that Induce Highly Potent Neutralizing Antibodies

SARS Vaccine Development

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