17 results on '"Yong Shi"'
Search Results
2. Correction for Zhou et al., 'Neutralization Titers in Vaccinated Patients with SARS-CoV-2 Delta Breakthrough Infections'
- Author
-
Jing Zou, Xuping Xie, Mingru Liu, Pei-Yong Shi, and Ping Ren
- Subjects
Virology ,Microbiology - Published
- 2022
3. Neutralization Titers in Vaccinated Patients with SARS-CoV-2 Delta Breakthrough Infections
- Author
-
Jing Zou, Xuping Xie, Mingru Liu, Pei-Yong Shi, and Ping Ren
- Subjects
Viral Envelope Proteins ,Neutralization Tests ,SARS-CoV-2 ,Virology ,COVID-19 ,Humans ,Antibodies, Viral ,Microbiology ,Antibodies, Neutralizing - Abstract
Given that neutralizing antibodies play a key role in protection of SARS-CoV-2 infection, it is important to define the neutralization levels in vaccinated individuals when they contracted breakthrough infections. In this study, we analyzed the neutralization levels from 64 vaccinated patients on days 0 to 5 before they tested positive for Delta breakthrough infections.
- Published
- 2022
4. Erratum for Vanderheiden et al., 'CCR2 Signaling Restricts SARS-CoV-2 Infection'
- Author
-
Abigail Vanderheiden, Jeronay Thomas, Allison L. Soung, Meredith E. Davis-Gardner, Katharine Floyd, Fengzhi Jin, David A. Cowan, Kathryn Pellegrini, Adrian Creanga, Amarendra Pegu, Alexandrine Derrien-Colemyn, Pei-Yong Shi, Arash Grakoui, Robyn S. Klein, Steven E. Bosinger, Jacob E. Kohlmeier, Vineet D. Menachery, and Mehul S. Suthar
- Subjects
Virology ,Microbiology - Published
- 2022
5. JIB-04 Has Broad-Spectrum Antiviral Activity and Inhibits SARS-CoV-2 Replication and Coronavirus Pathogenesis
- Author
-
Juhee Son, Shimeng Huang, Qiru Zeng, Traci L. Bricker, James Brett Case, Jinzhu Zhou, Ruochen Zang, Zhuoming Liu, Xinjian Chang, Tamarand L. Darling, Jian Xu, Houda H. Harastani, Lu Chen, Maria Florencia Gomez Castro, Yongxiang Zhao, Hinissan P. Kohio, Gaopeng Hou, Baochao Fan, Beibei Niu, Rongli Guo, Paul W. Rothlauf, Adam L. Bailey, Xin Wang, Pei-Yong Shi, Elisabeth D. Martinez, Steven L. Brody, Sean P. J. Whelan, Michael S. Diamond, Adrianus C. M. Boon, Bin Li, and Siyuan Ding
- Subjects
SARS-CoV-2 ,viruses ,coronavirus ,virus diseases ,RNA ,Biology ,medicine.disease_cause ,Microbiology ,Virology ,Virus ,In vitro ,law.invention ,chemistry.chemical_compound ,chemistry ,law ,In vivo ,JIB-04 ,antiviral agents ,Recombinant DNA ,medicine ,Vero cell ,DNA ,Coronavirus ,Research Article - Abstract
Pathogenic coronaviruses represent a major threat to global public health. Here, using a recombinant reporter virus-based compound screening approach, we identified several small-molecule inhibitors that potently block the replication of the newly emerged severe acute respiratory syndrome virus 2 (SARS-CoV-2). Among them, JIB-04 inhibited SARS-CoV-2 replication in Vero E6 cells with an EC50 of 695 nM, with a specificity index of greater than 1,000. JIB-04 showed in vitro antiviral activity in multiple cell types against several DNA and RNA viruses, including porcine coronavirus transmissible gastroenteritis virus. In an in vivo porcine model of coronavirus infection, administration of JIB-04 reduced virus infection and associated tissue pathology, which resulted in improved weight gain and survival. These results highlight the potential utility of JIB-04 as an antiviral agent against SARS-CoV-2 and other viral pathogens.
- Published
- 2022
6. CCR2 Signaling Restricts SARS-CoV-2 Infection
- Author
-
Steven E. Bosinger, Fengzhi Jin, Pei Yong Shi, Jacob E. Kohlmeier, Jeronay Thomas, Vineet D. Menachery, Abigail Vanderheiden, Robyn S. Klein, David A Cowan, Kathryn L. Pellegrini, Meredith E. Davis-Gardner, Arash Grakoui, Allison Soung, Katharine Floyd, and Mehul S. Suthar
- Subjects
Receptors, CCR2 ,medicine.medical_treatment ,viruses ,mouse model ,Pneumonia, Viral ,Inflammation ,Biology ,Virus Replication ,Microbiology ,Proinflammatory cytokine ,Mice ,Virology ,medicine ,Animals ,Lung ,innate immunity ,Innate immune system ,SARS-CoV-2 ,Respiratory disease ,lung inflammation ,COVID-19 ,Viral Load ,respiratory system ,medicine.disease ,Immunity, Innate ,QR1-502 ,respiratory tract diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,Cytokine ,medicine.anatomical_structure ,Immunology ,Cytokines ,Female ,medicine.symptom ,monocytes ,Viral load ,Respiratory tract ,Signal Transduction ,Research Article - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a historic pandemic of respiratory disease (coronavirus disease 2019 [COVID-19]), and current evidence suggests that severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here, we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2 signaling restricts the viral burden in the lung. We find that a recently developed mouse-adapted SARS-CoV-2 (MA-SARS-CoV-2) strain as well as the emerging B.1.351 variant trigger an inflammatory response in the lung characterized by the expression of proinflammatory cytokines and interferon-stimulated genes. Using intravital antibody labeling, we demonstrate that MA-SARS-CoV-2 infection leads to increases in circulating monocytes and an influx of CD45+ cells into the lung parenchyma that is dominated by monocyte-derived cells. Single-cell RNA sequencing (scRNA-Seq) analysis of lung homogenates identified a hyperinflammatory monocyte profile. We utilize this model to demonstrate that mechanistically, CCR2 signaling promotes the infiltration of classical monocytes into the lung and the expansion of monocyte-derived cells. Parenchymal monocyte-derived cells appear to play a protective role against MA-SARS-CoV-2, as mice lacking CCR2 showed higher viral loads in the lungs, increased lung viral dissemination, and elevated inflammatory cytokine responses. These studies have identified a potential CCR2-monocyte axis that is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection. IMPORTANCE SARS-CoV-2 has caused a historic pandemic of respiratory disease (COVID-19), and current evidence suggests that severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here, we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2-dependent infiltration of monocytes restricts the viral burden in the lung. We find that SARS-CoV-2 triggers an inflammatory response in the lung characterized by the expression of proinflammatory cytokines and interferon-stimulated genes. Using RNA sequencing and flow cytometry approaches, we demonstrate that SARS-CoV-2 infection leads to increases in circulating monocytes and an influx of CD45+ cells into the lung parenchyma that is dominated by monocyte-derived cells. Mechanistically, CCR2 signaling promoted the infiltration of classical monocytes into the lung and the expansion of monocyte-derived cells. Parenchymal monocyte-derived cells appear to play a protective role against MA-SARS-CoV-2, as mice lacking CCR2 showed higher viral loads in the lungs, increased lung viral dissemination, and elevated inflammatory cytokine responses. These studies have identified that the CCR2 pathway is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection.
- Published
- 2021
7. Zika Virus NS2A-Mediated Virion Assembly
- Author
-
Jing Zou, Xinwen Chen, Xuping Xie, Pei Yong Shi, Xianwen Zhang, Vsevolod L. Popov, Hongjie Xia, and Linfen Huang
- Subjects
Untranslated region ,Molecular Biology and Physiology ,Immunoprecipitation ,viruses ,Genome, Viral ,Biology ,Viral Nonstructural Proteins ,Virus Replication ,Microbiology ,Virus ,03 medical and health sciences ,Viral Proteins ,Zika ,Viral Envelope Proteins ,Pregnancy ,Virology ,Humans ,Nucleocapsid ,030304 developmental biology ,0303 health sciences ,NS3 ,Zika Virus Infection ,Flavivirus ,Virus Assembly ,030302 biochemistry & molecular biology ,Serine Endopeptidases ,virus diseases ,RNA ,Zika Virus ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,QR1-502 ,3. Good health ,Cell biology ,Capsid ,Virion assembly ,Mutation ,RNA, Viral ,Female ,Research Article ,Peptide Hydrolases - Abstract
ZIKV is a recently emerged mosquito-borne flavivirus that can cause devastating congenital Zika syndrome in pregnant women and Guillain-Barré syndrome in adults. The molecular mechanism of ZIKV virion assembly is largely unknown. Here, we report that ZIKV NS2A plays a central role in recruiting viral RNA, structural protein prM/E, and viral NS2B/NS3 protease to the virion assembly site and orchestrating virion morphogenesis. One mutation that impairs these interactions does not significantly affect viral RNA replication but selectively abolishes virion assembly, demonstrating the specific role of these interactions in virus morphogenesis. We also show that the 3ʹ UTR of ZIKV RNA may serve as a “recruitment signal” through binding to NS2A to enter the virion assembly site. Following a coordinated cleavage of C-prM-E at the virion assembly site, NS2A may present the viral RNA to C protein for nucleocapsid formation followed by envelopment with prM/E proteins. The results have provided new insights into flavivirus virion assembly., The flavivirus virion consists of an envelope outer layer, formed by envelope (E) and membrane (M) proteins on a lipid bilayer, and an internal core, formed by capsid (C) protein and genomic RNA. The molecular mechanism of flavivirus assembly is not well understood. Here, we show that Zika virus (ZIKV) NS2A protein recruits genomic RNA, the structural protein prM/E complex, and the NS2B/NS3 protease complex to the virion assembly site and orchestrates virus morphogenesis. Coimmunoprecipitation analysis showed that ZIKV NS2A binds to prM, E, NS2B, and NS3 (but not C, NS4B, or NS5) in a viral RNA-independent manner, whereas prM/E complex does not interact with NS2B/NS3 complex. Remarkably, a single-amino-acid mutation (E103A) of NS2A impairs its binding to prM/E and NS2B/NS3 and abolishes virus production, demonstrating the indispensable role of NS2A/prM/E and NS2A/NS2B/NS3 interactions in virion assembly. In addition, RNA-protein pulldown analysis identified a stem-loop RNA from the 3ʹ untranslated region (UTR) of the viral genome as an “RNA recruitment signal” for ZIKV assembly. The 3ʹ UTR RNA binds to a cytoplasmic loop of NS2A protein. Mutations of two positively charged residues (R96A and R102A) from the cytoplasmic loop reduce NS2A binding to viral RNA, leading to a complete loss of virion assembly. Collectively, our results support a virion assembly model in which NS2A recruits viral NS2B/NS3 protease and structural C-prM-E polyprotein to the virion assembly site; once the C-prM-E polyprotein has been processed, NS2A presents viral RNA to the structural proteins for virion assembly.
- Published
- 2019
8. Axl Promotes Zika Virus Entry and Modulates the Antiviral State of Human Sertoli Cells
- Author
-
Saguna Verma, Xuping Xie, Nima Pourhabibi Zarandi, Pei Yong Shi, Hooman Sadri-Ardekani, Coleman Baker, Boonyanudh Jiyarom, and Daniel P. Strange
- Subjects
Male ,Axl receptor tyrosine kinase ,Cell type ,endocrine system ,Sexual transmission ,testes ,Biology ,virus entry ,Microbiology ,Receptor tyrosine kinase ,Host-Microbe Biology ,03 medical and health sciences ,Immune system ,Interferon ,Viral entry ,Virology ,Proto-Oncogene Proteins ,medicine ,Humans ,Cells, Cultured ,030304 developmental biology ,Disease Resistance ,0303 health sciences ,Sertoli Cells ,AXL receptor tyrosine kinase ,GAS6 ,Zika Virus Infection ,030302 biochemistry & molecular biology ,Receptor Protein-Tyrosine Kinases ,Zika Virus ,Virus Internalization ,QR1-502 ,3. Good health ,Host-Pathogen Interactions ,biology.protein ,interferon signaling ,testicular organoids ,medicine.drug ,Research Article - Abstract
Recent Zika virus (ZIKV) outbreaks have identified sexual transmission as a new route of disease spread not reported for other flaviviruses. ZIKV crosses the blood-testis barrier and establishes infection in seminiferous tubules, the site for spermatozoa development. Currently, there are no therapies to treat ZIKV infection, and the immune mechanisms underlying testicular persistence are unclear. We found that multiple human testicular cell types, except Leydig cells, support ZIKV infection. Axl receptor, which plays a pivotal role in maintaining the immunosuppressive milieu of the testis, is highly expressed in Sertoli cells and augments ZIKV infection by promoting virus entry and negatively regulating the antiviral state. By using testicular organoids, we further describe the antiviral role of Axl inhibition. The significance of our research lies in defining cross talk between Axl and type I interferon signaling as an essential mechanism of immune control that can inform therapeutic efforts to clear ZIKV from the testis., Zika virus (ZIKV) is unique among mosquito-borne flaviviruses in its ability to be sexually transmitted. Persistent ZIKV infection in the testes, which are immune privileged organs, long after peripheral clearance suggests involvement of immunosuppressive pathways; however, the underlying mechanisms remain undetermined. We recently demonstrated that ZIKV infects human Sertoli cells (SC), the major cell type of the seminiferous epithelium responsible for maintaining the immune privileged compartment of seminiferous tubules. Recent reports have identified the TAM (Tyro3, Axl, Mer) receptor tyrosine kinase Axl as an entry receptor and/or immune modulator for ZIKV in a cell type-specific manner. Interestingly, the seminiferous epithelium exhibits high basal expression of the Axl receptor where it is involved in clearance of apoptotic germ cells and immunosuppression. Here, we show that Axl was highly expressed in SC compared to Leydig cells (LC) that correlated with robust ZIKV infection of SC, but not LC. Further, neutralization of Axl receptor and its ligand Gas6 strongly attenuated virus entry in SC. However, inhibition of Axl kinase did not affect ZIKV entry but instead led to decreased protein levels of suppressor of cytokine signaling 1 (SOCS1) and SOCS3, increased expression of interferon-stimulated genes (ISGs), and reduced ZIKV replication. Similarly, treatment of multicellular human testicular organoids with an Axl kinase inhibitor attenuated ZIKV replication and increased ISG expression. Together, our data demonstrate that Axl promotes ZIKV entry and negatively regulates the antiviral state of SC to augment ZIKV infection of the testes and provides new insights into testis antiviral immunity and ZIKV persistence.
- Published
- 2019
9. Erratum for Chen et al., 'Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine Candidate'
- Author
-
Pei Yong Shi, Jianghong Man, Jin Wu, Chao Shan, Xiaofeng Li, Tongyan Zhao, Feng Ma, Cheng-Feng Qin, Dapei Li, Yan Wu, Qi Chen, Qing Ye, Xuping Xie, Chunfeng Li, Haitao Wu, Qian Zhu, Xiaoling Qin, and Xiaoyan Zhan
- Subjects
Mice, Nude ,Apoptosis ,Vaccines, Attenuated ,Microbiology ,Zika virus ,Mice ,03 medical and health sciences ,Virology ,Chlorocebus aethiops ,Animals ,Humans ,Medicine ,Vero Cells ,030304 developmental biology ,Inflammation ,Oncolytic Virotherapy ,Mice, Inbred BALB C ,0303 health sciences ,biology ,Brain Neoplasms ,030306 microbiology ,business.industry ,Published Erratum ,Zika Virus ,biology.organism_classification ,medicine.disease ,Xenograft Model Antitumor Assays ,QR1-502 ,Mice, Inbred C57BL ,Oncolytic Viruses ,Viral Tropism ,Neoplastic Stem Cells ,Female ,Erratum ,Glioblastoma ,business - Abstract
Glioblastoma (GBM) is the deadliest type of brain tumor, and glioma stem cells (GSCs) contribute to tumor recurrence and therapeutic resistance. Thus, an oncolytic virus targeting GSCs may be useful for improving GBM treatment. Because Zika virus (ZIKV) has an oncolytic tropism for infecting GSCs, we investigated the safety and efficacy of a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a GSC-derived orthotopic model. Intracerebral injection of ZIKV-LAV into mice caused no neurological symptoms or behavioral abnormalities. The neurovirulence of ZIKV-LAV was more attenuated than that of the licensed Japanese encephalitis virus LAV 14-14-2, underlining the superior safety of ZIKV-LAV for potential GBM treatment. Importantly, ZIKV-LAV significantly reduced intracerebral tumor growth and prolonged animal survival by selectively killing GSCs within the tumor. Mechanistically, ZIKV infection elicited antiviral immunity, inflammation, and GSC apoptosis. Together, these results further support the clinical development of ZIKV-LAV for GBM therapy.
- Published
- 2019
10. Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine Candidate
- Author
-
Xiaoling Qin, Haitao Wu, Pei Yong Shi, Jianghong Man, Cheng-Feng Qin, Qing Ye, Qi Chen, Qian Zhu, Xiaoyan Zhan, Tongyang Zhao, Dapei Li, Chao Shan, Jin Wu, Feng Ma, Yan Wu, Xiaofeng Li, Xuping Xie, and Chunfeng Li
- Subjects
0301 basic medicine ,endocrine system ,medicine.medical_treatment ,Brain tumor ,Microbiology ,Virus ,Zika virus ,03 medical and health sciences ,Virology ,Glioma ,vaccine ,Medicine ,anticancer therapy ,Tropism ,Chemotherapy ,biology ,business.industry ,glioblastoma ,medicine.disease ,biology.organism_classification ,QR1-502 ,Oncolytic virus ,030104 developmental biology ,Cancer research ,Stem cell ,business - Abstract
Glioblastoma (GBM) is the deadliest type of brain tumor, and glioma stem cells (GSCs) contribute to tumor recurrence and therapeutic resistance. Thus, an oncolytic virus targeting GSCs may be useful for improving GBM treatment. Because Zika virus (ZIKV) has an oncolytic tropism for infecting GSCs, we investigated the safety and efficacy of a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a GSC-derived orthotopic model. Intracerebral injection of ZIKV-LAV into mice caused no neurological symptoms or behavioral abnormalities. The neurovirulence of ZIKV-LAV was more attenuated than that of the licensed Japanese encephalitis virus LAV 14-14-2, underlining the superior safety of ZIKV-LAV for potential GBM treatment. Importantly, ZIKV-LAV significantly reduced intracerebral tumor growth and prolonged animal survival by selectively killing GSCs within the tumor. Mechanistically, ZIKV infection elicited antiviral immunity, inflammation, and GSC apoptosis. Together, these results further support the clinical development of ZIKV-LAV for GBM therapy. IMPORTANCE Glioblastoma (GBM), the deadliest type of brain tumor, is currently incurable because of its high recurrence rate after traditional treatments, including surgery to remove the main part of the tumor and radiation and chemotherapy to target residual tumor cells. These treatments fail mainly due to the presence of a cell subpopulation called glioma stem cells (GSCs), which are resistant to radiation and chemotherapy and capable of self-renewal and tumorigenicity. Because Zika virus (ZIKV) has an oncolytic tropism for infecting GSCs, we tested a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a human GSC-derived orthotopic model. Our results showed that ZIKV-LAV retained good efficacy against glioblastoma by selectively killing GSCs within the tumor. In addition, ZIKV-LAV exhibited an excellent safety profile upon intracerebral injection into the treated animals. The good balance between the safety of ZIKV-LAV and its efficacy against human GSCs suggests that it is a potential candidate for combination with the current treatment regimen for GBM therapy.
- Published
- 2018
11. CCR2 Signaling Restricts SARS-CoV-2 Infection
- Author
-
Abigail Vanderheiden, Jeronay Thomas, Allison L. Soung, Meredith E. Davis-Gardner, Katharine Floyd, Fengzhi Jin, David A. Cowan, Kathryn Pellegrini, Adrian Creanga, Amarendra Pegu, Alexandrine Derrien-Colemyn, Pei-Yong Shi, Arash Grakoui, Robyn S. Klein, Steven E. Bosinger, Jacob E. Kohlmeier, Vineet D. Menachery, and Mehul S. Suthar
- Subjects
lung inflammation ,monocytes ,SARS-CoV-2 ,innate immunity ,mouse model ,Microbiology ,QR1-502 - Abstract
ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a historic pandemic of respiratory disease (coronavirus disease 2019 [COVID-19]), and current evidence suggests that severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here, we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2 signaling restricts the viral burden in the lung. We find that a recently developed mouse-adapted SARS-CoV-2 (MA-SARS-CoV-2) strain as well as the emerging B.1.351 variant trigger an inflammatory response in the lung characterized by the expression of proinflammatory cytokines and interferon-stimulated genes. Using intravital antibody labeling, we demonstrate that MA-SARS-CoV-2 infection leads to increases in circulating monocytes and an influx of CD45+ cells into the lung parenchyma that is dominated by monocyte-derived cells. Single-cell RNA sequencing (scRNA-Seq) analysis of lung homogenates identified a hyperinflammatory monocyte profile. We utilize this model to demonstrate that mechanistically, CCR2 signaling promotes the infiltration of classical monocytes into the lung and the expansion of monocyte-derived cells. Parenchymal monocyte-derived cells appear to play a protective role against MA-SARS-CoV-2, as mice lacking CCR2 showed higher viral loads in the lungs, increased lung viral dissemination, and elevated inflammatory cytokine responses. These studies have identified a potential CCR2-monocyte axis that is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection. IMPORTANCE SARS-CoV-2 has caused a historic pandemic of respiratory disease (COVID-19), and current evidence suggests that severe disease is associated with dysregulated immunity within the respiratory tract. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here, we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2-dependent infiltration of monocytes restricts the viral burden in the lung. We find that SARS-CoV-2 triggers an inflammatory response in the lung characterized by the expression of proinflammatory cytokines and interferon-stimulated genes. Using RNA sequencing and flow cytometry approaches, we demonstrate that SARS-CoV-2 infection leads to increases in circulating monocytes and an influx of CD45+ cells into the lung parenchyma that is dominated by monocyte-derived cells. Mechanistically, CCR2 signaling promoted the infiltration of classical monocytes into the lung and the expansion of monocyte-derived cells. Parenchymal monocyte-derived cells appear to play a protective role against MA-SARS-CoV-2, as mice lacking CCR2 showed higher viral loads in the lungs, increased lung viral dissemination, and elevated inflammatory cytokine responses. These studies have identified that the CCR2 pathway is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection.
- Published
- 2021
- Full Text
- View/download PDF
12. Inhibition of Coronavirus Entry In Vitro and Ex Vivo by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain
- Author
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Victor K. Outlaw, Francesca T. Bovier, Megan C. Mears, Maria N. Cajimat, Yun Zhu, Michelle J. Lin, Amin Addetia, Nicole A. P. Lieberman, Vikas Peddu, Xuping Xie, Pei-Yong Shi, Alexander L. Greninger, Samuel H. Gellman, Dennis A. Bente, Anne Moscona, and Matteo Porotto
- Subjects
SARS-CoV-2 ,spike protein ,fusion inhibitor ,lipopeptide ,Microbiology ,QR1-502 - Abstract
ABSTRACT The emergence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of the 2019 coronavirus disease (COVID-19), has erupted into a global pandemic that has led to tens of millions of infections and hundreds of thousands of deaths worldwide. The development of therapeutics to treat infection or as prophylactics to halt viral transmission and spread is urgently needed. SARS-CoV-2 relies on structural rearrangements within a spike (S) glycoprotein to mediate fusion of the viral and host cell membranes. Here, we describe the development of a lipopeptide that is derived from the C-terminal heptad repeat (HRC) domain of SARS-CoV-2 S that potently inhibits infection by SARS-CoV-2. The lipopeptide inhibits cell-cell fusion mediated by SARS-CoV-2 S and blocks infection by live SARS-CoV-2 in Vero E6 cell monolayers more effectively than previously described lipopeptides. The SARS-CoV-2 lipopeptide exhibits broad-spectrum activity by inhibiting cell-cell fusion mediated by SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) and blocking infection by live MERS-CoV in cell monolayers. We also show that the SARS-CoV-2 HRC-derived lipopeptide potently blocks the spread of SARS-CoV-2 in human airway epithelial (HAE) cultures, an ex vivo model designed to mimic respiratory viral propagation in humans. While viral spread of SARS-CoV-2 infection was widespread in untreated airways, those treated with SARS-CoV-2 HRC lipopeptide showed no detectable evidence of viral spread. These data provide a framework for the development of peptide therapeutics for the treatment of or prophylaxis against SARS-CoV-2 as well as other coronaviruses. IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, continues to spread globally, placing strain on health care systems and resulting in rapidly increasing numbers of cases and mortalities. Despite the growing need for medical intervention, no FDA-approved vaccines are yet available, and treatment has been limited to supportive therapy for the alleviation of symptoms. Entry inhibitors could fill the important role of preventing initial infection and preventing spread. Here, we describe the design, synthesis, and evaluation of a lipopeptide that is derived from the HRC domain of the SARS-CoV-2 S glycoprotein that potently inhibits fusion mediated by SARS-CoV-2 S glycoprotein and blocks infection by live SARS-CoV-2 in both cell monolayers (in vitro) and human airway tissues (ex vivo). Our results highlight the SARS-CoV-2 HRC-derived lipopeptide as a promising therapeutic candidate for SARS-CoV-2 infections.
- Published
- 2020
- Full Text
- View/download PDF
13. Zika Virus NS2A-Mediated Virion Assembly
- Author
-
Xianwen Zhang, Xuping Xie, Hongjie Xia, Jing Zou, Linfen Huang, Vsevolod L. Popov, Xinwen Chen, and Pei-Yong Shi
- Subjects
Zika ,flavivirus ,virus assembly ,Microbiology ,QR1-502 - Abstract
ABSTRACT The flavivirus virion consists of an envelope outer layer, formed by envelope (E) and membrane (M) proteins on a lipid bilayer, and an internal core, formed by capsid (C) protein and genomic RNA. The molecular mechanism of flavivirus assembly is not well understood. Here, we show that Zika virus (ZIKV) NS2A protein recruits genomic RNA, the structural protein prM/E complex, and the NS2B/NS3 protease complex to the virion assembly site and orchestrates virus morphogenesis. Coimmunoprecipitation analysis showed that ZIKV NS2A binds to prM, E, NS2B, and NS3 (but not C, NS4B, or NS5) in a viral RNA-independent manner, whereas prM/E complex does not interact with NS2B/NS3 complex. Remarkably, a single-amino-acid mutation (E103A) of NS2A impairs its binding to prM/E and NS2B/NS3 and abolishes virus production, demonstrating the indispensable role of NS2A/prM/E and NS2A/NS2B/NS3 interactions in virion assembly. In addition, RNA-protein pulldown analysis identified a stem-loop RNA from the 3ʹ untranslated region (UTR) of the viral genome as an “RNA recruitment signal” for ZIKV assembly. The 3ʹ UTR RNA binds to a cytoplasmic loop of NS2A protein. Mutations of two positively charged residues (R96A and R102A) from the cytoplasmic loop reduce NS2A binding to viral RNA, leading to a complete loss of virion assembly. Collectively, our results support a virion assembly model in which NS2A recruits viral NS2B/NS3 protease and structural C-prM-E polyprotein to the virion assembly site; once the C-prM-E polyprotein has been processed, NS2A presents viral RNA to the structural proteins for virion assembly. IMPORTANCE ZIKV is a recently emerged mosquito-borne flavivirus that can cause devastating congenital Zika syndrome in pregnant women and Guillain-Barré syndrome in adults. The molecular mechanism of ZIKV virion assembly is largely unknown. Here, we report that ZIKV NS2A plays a central role in recruiting viral RNA, structural protein prM/E, and viral NS2B/NS3 protease to the virion assembly site and orchestrating virion morphogenesis. One mutation that impairs these interactions does not significantly affect viral RNA replication but selectively abolishes virion assembly, demonstrating the specific role of these interactions in virus morphogenesis. We also show that the 3ʹ UTR of ZIKV RNA may serve as a “recruitment signal” through binding to NS2A to enter the virion assembly site. Following a coordinated cleavage of C-prM-E at the virion assembly site, NS2A may present the viral RNA to C protein for nucleocapsid formation followed by envelopment with prM/E proteins. The results have provided new insights into flavivirus virion assembly.
- Published
- 2019
- Full Text
- View/download PDF
14. Axl Promotes Zika Virus Entry and Modulates the Antiviral State of Human Sertoli Cells
- Author
-
Daniel P. Strange, Boonyanudh Jiyarom, Nima Pourhabibi Zarandi, Xuping Xie, Coleman Baker, Hooman Sadri-Ardekani, Pei-Yong Shi, and Saguna Verma
- Subjects
Axl receptor tyrosine kinase ,Sertoli cells ,Zika virus ,interferon signaling ,testes ,testicular organoids ,Microbiology ,QR1-502 - Abstract
ABSTRACT Zika virus (ZIKV) is unique among mosquito-borne flaviviruses in its ability to be sexually transmitted. Persistent ZIKV infection in the testes, which are immune privileged organs, long after peripheral clearance suggests involvement of immunosuppressive pathways; however, the underlying mechanisms remain undetermined. We recently demonstrated that ZIKV infects human Sertoli cells (SC), the major cell type of the seminiferous epithelium responsible for maintaining the immune privileged compartment of seminiferous tubules. Recent reports have identified the TAM (Tyro3, Axl, Mer) receptor tyrosine kinase Axl as an entry receptor and/or immune modulator for ZIKV in a cell type-specific manner. Interestingly, the seminiferous epithelium exhibits high basal expression of the Axl receptor where it is involved in clearance of apoptotic germ cells and immunosuppression. Here, we show that Axl was highly expressed in SC compared to Leydig cells (LC) that correlated with robust ZIKV infection of SC, but not LC. Further, neutralization of Axl receptor and its ligand Gas6 strongly attenuated virus entry in SC. However, inhibition of Axl kinase did not affect ZIKV entry but instead led to decreased protein levels of suppressor of cytokine signaling 1 (SOCS1) and SOCS3, increased expression of interferon-stimulated genes (ISGs), and reduced ZIKV replication. Similarly, treatment of multicellular human testicular organoids with an Axl kinase inhibitor attenuated ZIKV replication and increased ISG expression. Together, our data demonstrate that Axl promotes ZIKV entry and negatively regulates the antiviral state of SC to augment ZIKV infection of the testes and provides new insights into testis antiviral immunity and ZIKV persistence. IMPORTANCE Recent Zika virus (ZIKV) outbreaks have identified sexual transmission as a new route of disease spread not reported for other flaviviruses. ZIKV crosses the blood-testis barrier and establishes infection in seminiferous tubules, the site for spermatozoa development. Currently, there are no therapies to treat ZIKV infection, and the immune mechanisms underlying testicular persistence are unclear. We found that multiple human testicular cell types, except Leydig cells, support ZIKV infection. Axl receptor, which plays a pivotal role in maintaining the immunosuppressive milieu of the testis, is highly expressed in Sertoli cells and augments ZIKV infection by promoting virus entry and negatively regulating the antiviral state. By using testicular organoids, we further describe the antiviral role of Axl inhibition. The significance of our research lies in defining cross talk between Axl and type I interferon signaling as an essential mechanism of immune control that can inform therapeutic efforts to clear ZIKV from the testis.
- Published
- 2019
- Full Text
- View/download PDF
15. Erratum for Chen et al., 'Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine Candidate'
- Author
-
Qi Chen, Jin Wu, Qing Ye, Feng Ma, Qian Zhu, Yan Wu, Chao Shan, Xuping Xie, Dapei Li, Xiaoyan Zhan, Chunfeng Li, Xiao-Feng Li, Xiaoling Qin, Tongyan Zhao, Haitao Wu, Pei-Yong Shi, Jianghong Man, and Cheng-Feng Qin
- Subjects
Microbiology ,QR1-502 - Published
- 2019
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16. Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine Candidate
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Qi Chen, Jin Wu, Qing Ye, Feng Ma, Qian Zhu, Yan Wu, Chao Shan, Xuping Xie, Dapei Li, Xiaoyan Zhan, Chunfeng Li, Xiao-Feng Li, Xiaoling Qin, Tongyan Zhao, Haitao Wu, Pei-Yong Shi, Jianghong Man, and Cheng-Feng Qin
- Subjects
Zika virus ,anticancer therapy ,glioblastoma ,vaccine ,Microbiology ,QR1-502 - Abstract
ABSTRACT Glioblastoma (GBM) is the deadliest type of brain tumor, and glioma stem cells (GSCs) contribute to tumor recurrence and therapeutic resistance. Thus, an oncolytic virus targeting GSCs may be useful for improving GBM treatment. Because Zika virus (ZIKV) has an oncolytic tropism for infecting GSCs, we investigated the safety and efficacy of a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a GSC-derived orthotopic model. Intracerebral injection of ZIKV-LAV into mice caused no neurological symptoms or behavioral abnormalities. The neurovirulence of ZIKV-LAV was more attenuated than that of the licensed Japanese encephalitis virus LAV 14-14-2, underlining the superior safety of ZIKV-LAV for potential GBM treatment. Importantly, ZIKV-LAV significantly reduced intracerebral tumor growth and prolonged animal survival by selectively killing GSCs within the tumor. Mechanistically, ZIKV infection elicited antiviral immunity, inflammation, and GSC apoptosis. Together, these results further support the clinical development of ZIKV-LAV for GBM therapy. IMPORTANCE Glioblastoma (GBM), the deadliest type of brain tumor, is currently incurable because of its high recurrence rate after traditional treatments, including surgery to remove the main part of the tumor and radiation and chemotherapy to target residual tumor cells. These treatments fail mainly due to the presence of a cell subpopulation called glioma stem cells (GSCs), which are resistant to radiation and chemotherapy and capable of self-renewal and tumorigenicity. Because Zika virus (ZIKV) has an oncolytic tropism for infecting GSCs, we tested a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a human GSC-derived orthotopic model. Our results showed that ZIKV-LAV retained good efficacy against glioblastoma by selectively killing GSCs within the tumor. In addition, ZIKV-LAV exhibited an excellent safety profile upon intracerebral injection into the treated animals. The good balance between the safety of ZIKV-LAV and its efficacy against human GSCs suggests that it is a potential candidate for combination with the current treatment regimen for GBM therapy.
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- 2018
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17. Understanding Zika Virus Stability and Developing a Chimeric Vaccine through Functional Analysis
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Xuping Xie, Yujiao Yang, Antonio E. Muruato, Jing Zou, Chao Shan, Bruno T. D. Nunes, Daniele B. A. Medeiros, Pedro F. C. Vasconcelos, Scott C. Weaver, Shannan L. Rossi, and Pei-Yong Shi
- Subjects
Microbiology ,QR1-502 - Abstract
ABSTRACT Compared with other flaviviruses, Zika virus (ZIKV) is uniquely associated with congenital diseases in pregnant women. One recent study reported that (i) ZIKV has higher thermostability than dengue virus (DENV [a flavivirus closely related to ZIKV]), which might contribute to the disease outcome; (ii) the higher thermostability of ZIKV could arise from an extended loop structure in domain III of the viral envelope (E) protein and an extra hydrogen-bond interaction between E molecules (V. A. Kostyuchenko, E. X. Y. Lim, S. Zhang, G. Fibriansah, T.-S. Ng, J. S. G. Ooi, J. Shi, and S.-M. Lok, Nature 533:425–428, 2016, https://doi.org/10.1038/nature17994 ). Here we report the functional analysis of the structural information in the context of complete ZIKV and DENV-2 virions. Swapping the prM-E genes between ZIKV and DENV-2 switched the thermostability of the chimeric viruses, identifying the prM-E proteins as the major determinants for virion thermostability. Shortening the extended loop of the E protein by 1 amino acid was lethal for ZIKV assembly/release. Mutations (Q350I and T351V) that abolished the extra hydrogen-bond interaction between the E proteins did not reduce ZIKV thermostability, indicating that the extra interaction does not increase the thermostability. Interestingly, mutant T351V was attenuated in A129 mice defective in type I interferon receptors, even though the virus retained the wild-type thermostability. Furthermore, we found that a chimeric ZIKV with the DENV-2 prM-E and a chimeric DENV-2 with the ZIKV prM-E were highly attenuated in A129 mice; these chimeric viruses were highly immunogenic and protective against DENV-2 and ZIKV challenge, respectively. These results indicate the potential of these chimeric viruses for vaccine development. IMPORTANCE Analysis of a recently observed high-resolution structure of ZIKV led to a hypothesis that its unusual stability may contribute to the associated, unique disease outcomes. Here we performed a functional analysis to demonstrate that viral prM-E genes are the main determinants for the high stability of ZIKV. The extra hydrogen-bond interaction (observed in the high-resolution structure) between ZIKV E proteins did not enhance virion stability, whereas the extended loop of E protein (CD loop in domain III) was essential for ZIKV assembly. More importantly, we found that a chimeric ZIKV with DENV-2 prM-E genes and a chimeric DENV-2 with ZIKV prM-E genes were highly attenuated in A129 mice. Mice immunized with these chimeric viruses generated robust neutralizing antibody responses and were fully protected from DENV-2 and ZIKV challenge, respectively, indicating that these chimeric viruses could be further developed as vaccine candidates.
- Published
- 2017
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