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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-337032

ABSTRACT

ABSTRACT Recent studies found that Omicron variant escapes vaccine-elicited immunity. Interestingly, potent cross-clade pan-sarbecovirus neutralizing antibodies were found in survivors of the infection by SARS-CoV-1 after BNT162b2 mRNA vaccination ( N Engl J Med. 2021 Oct 7;385(15):1401-1406 ). These pan-sarbecovirus neutralizing antibodies were observed to efficiently neutralize the infection driven by the S protein from both SARS-CoV and multiple SARS-CoV-2 variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), and B.1.617.2 (Delta). However, whether these cross-reactive antibodies could neutralize the Omicron variant is still unknown. Based on the data collected from a cohort of SARS-CoV-1 survivors received 3-dose of immunization, our studies reported herein showed that a high level of neutralizing antibodies against both SARS-CoV-1 and SARS-CoV-2 were elicited by a 3rd-dose of booster vaccination of protein subunit vaccine ZF2001. However, a dramatically reduced neutralization of SARS-CoV-2 Omicron Variant (B.1.1.529) is observed in sera from these SARS-CoV-1 survivors received 3-dose of Vaccination. Our results indicates that the rapid development of pan-variant adapted vaccines is warranted.

2.
J Mol Biol ; 434(6): 167438, 2022 03 30.
Article in English | MEDLINE | ID: covidwho-1851578

ABSTRACT

Recognition of viral infections by various pattern recognition receptors (PRRs) activates an inflammatory cytokine response that inhibits viral replication and orchestrates the activation of adaptive immune responses to control the viral infection. The broadly active innate immune response puts a strong selective pressure on viruses and drives the selection of variants with increased capabilities to subvert the induction and function of antiviral cytokines. This revolutionary process dynamically shapes the host ranges, cell tropism and pathogenesis of viruses. Recent studies on the innate immune responses to the infection of human coronaviruses (HCoV), particularly SARS-CoV-2, revealed that HCoV infections can be sensed by endosomal toll-like receptors and/or cytoplasmic RIG-I-like receptors in various cell types. However, the profiles of inflammatory cytokines and transcriptome response induced by a specific HCoV are usually cell type specific and determined by the virus-specific mechanisms of subverting the induction and function of interferons and inflammatory cytokines as well as the genetic trait of the host genes of innate immune pathways. We review herein the recent literatures on the innate immune responses and their roles in the pathogenesis of HCoV infections with emphasis on the pathobiological roles and therapeutic effects of type I interferons in HCoV infections and their antiviral mechanisms. The knowledge on the mechanism of innate immune control of HCoV infections and viral evasions should facilitate the development of therapeutics for induction of immune resolution of HCoV infections and vaccines for efficient control of COVID-19 pandemics and other HCoV infections.


Subject(s)
Antiviral Agents , Coronavirus Infections , Coronavirus , Drug Development , Immune Evasion , Interferon Type I , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/prevention & control , Coronavirus/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/virology , Humans , Immunity, Innate , Interferon Type I/immunology , Interferon Type I/therapeutic use , SARS-CoV-2/immunology
3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335277

ABSTRACT

The Omicron variant of SARS-COV-2 (GISAID GRA clade [B.1.1.529, BA.1 and BA.2]) is now the single dominant Variant of Concern (VOC). The high number of mutations in the Omicron Spike (S) protein promotes humoral immunological escape. Although a third homologous boost with S, derived from the ancestral strain, was able to increase neutralizing antibody titers and breadth including to Omicron, the magnitude of virus neutralization could benefit from further optimization. Moreover, combining SARS-COV-2 strains as additional valences may address the current antigenicity range occupied by VOCs. Using Trimer-Tag™ platform we have previously demonstrated phase 3 efficacy and safety of a prototypic vaccine SCB-2019 in the SPECTRA trial and have submitted applications for licensure. Here, we successfully generated a bivalent vaccine candidate including both Ancestor and Omicron variant S-proteins. Preclinical studies demonstrate this SARS-CoV-2 bivalent S-Trimer subunit vaccine elicits high titers of neutralizing antibodies against all VOCs, with markedly enhanced Omicron specific neutralizing antibody responses.

4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-324219

ABSTRACT

Background: Molecular imaging specifically detecting SARS-CoV-2 in live subjects may aid theranostics for Coronavirus Disease 2019 (COVID-19). Herein, we developed novel molecular probes, Cy5-EK1 and [64 Cu]-NOTA-EK1, based on 36-mer EK1 peptide derived from the S2 subunit of spike (S) protein of SARS-CoV-2, an element of the six-helix bundle of S-protein for virus entry in vivoMethods: Enzyme-linked immunosorbent assay (ELISA) and immunostaining were performed to evaluate the potency of binding between these probes and recombinant full-length S-protein in vitro. HEK293 cells expressing S-protein of SARS-CoV-2 tumor-bearing mouse models were established to test the imaging target engagement in vivo.Findings: The potency of binding between NOTA-EK1 and S-protein was very strong, for which K d was 3.56 ± 0.38 nM and IC50 was 15.7 ± 0.6 nM. The uptake of [64Cu]-NOTA-EK1 in S-protein-positive tumors was greatly increased as early as 1 h post-injection and maintained at a high level until 24 h, while no signal was observed for S-protein-negative tumors. These differences were further confirmed by ex vivo imaging from both fluorescence and PET post-imaging studies. Immunofluorescent staining confirmed the colocalization of Cy5-EK1 with cell surface S-protein of SARS-CoV-2 in S-protein-positive HEK293 cells.Interpretation: Cy5-EK1 and [ 64Cu]-NOTA-EK1 could be used as specific molecular imaging probes for tracking SARS-CoV-2, which may have potential for the imaging and quantification of COVID-19 in a clinical context.Funding: This work was financially supported by the National Key R&D Program of China (2018YFC0910600).Declaration of Interest: None to declare. Ethical Approval: All animal experiments were carried out in accordance with the Institutional Ethical Guidelines for Animal Experiments of the Fifth Affiliated Hospital of Sun Yat-sen University(approval number: 00065).

5.
Viruses ; 13(10)2021 10 01.
Article in English | MEDLINE | ID: covidwho-1444334

ABSTRACT

Coronaviruses (CoVs) are a group of enveloped positive-sense RNA viruses and can cause deadly diseases in animals and humans. Cell entry is the first and essential step of successful virus infection and can be divided into two ongoing steps: cell binding and membrane fusion. Over the past two decades, stimulated by the global outbreak of SARS-CoV and pandemic of SARS-CoV-2, numerous efforts have been made in the CoV research. As a result, significant progress has been achieved in our understanding of the cell entry process. Here, we review the current knowledge of this essential process, including the viral and host components involved in cell binding and membrane fusion, molecular mechanisms of their interactions, and the sites of virus entry. We highlight the recent findings of host restriction factors that inhibit CoVs entry. This knowledge not only enhances our understanding of the cell entry process, pathogenesis, tissue tropism, host range, and interspecies-transmission of CoVs but also provides a theoretical basis to design effective preventive and therapeutic strategies to control CoVs infection.


Subject(s)
Coronavirus Infections/pathology , Coronavirus/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Attachment , Virus Internalization , Animals , Cats/virology , Cattle/virology , Chickens/virology , Coronavirus/genetics , Dogs/virology , Livestock/virology , Membrane Fusion/physiology , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/genetics , Swine/virology , Viral Tropism/physiology
6.
Nat Commun ; 12(1): 1346, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1111984

ABSTRACT

SARS-CoV-2 is the underlying cause for the COVID-19 pandemic. Like most enveloped RNA viruses, SARS-CoV-2 uses a homotrimeric surface antigen to gain entry into host cells. Here we describe S-Trimer, a native-like trimeric subunit vaccine candidate for COVID-19 based on Trimer-Tag technology. Immunization of S-Trimer with either AS03 (oil-in-water emulsion) or CpG 1018 (TLR9 agonist) plus alum adjuvants induced high-level of neutralizing antibodies and Th1-biased cellular immune responses in animal models. Moreover, rhesus macaques immunized with adjuvanted S-Trimer were protected from SARS-CoV-2 challenge compared to vehicle controls, based on clinical observations and reduction of viral loads in lungs. Trimer-Tag may be an important platform technology for scalable production and rapid development of safe and effective subunit vaccines against current and future emerging RNA viruses.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/immunology , COVID-19/prevention & control , SARS-CoV-2/pathogenicity , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Blotting, Western , COVID-19/therapy , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunity, Cellular/physiology , Immunization, Passive , Immunohistochemistry , Macaca mulatta , Mice , Mice, Inbred BALB C , Microscopy, Electron , SARS-CoV-2/immunology
7.
J Virol ; 94(18)2020 08 31.
Article in English | MEDLINE | ID: covidwho-803471

ABSTRACT

The COVID-19 pandemic has caused an unprecedented global public health and economic crisis. The origin and emergence of its causal agent, SARS-CoV-2, in the human population remains mysterious, although bat and pangolin were proposed to be the natural reservoirs. Strikingly, unlike the SARS-CoV-2-like coronaviruses (CoVs) identified in bats and pangolins, SARS-CoV-2 harbors a polybasic furin cleavage site in its spike (S) glycoprotein. SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as its receptor to infect cells. Receptor recognition by the S protein is the major determinant of host range, tissue tropism, and pathogenesis of coronaviruses. In an effort to search for the potential intermediate or amplifying animal hosts of SARS-CoV-2, we examined receptor activity of ACE2 from 14 mammal species and found that ACE2s from multiple species can support the infectious entry of lentiviral particles pseudotyped with the wild-type or furin cleavage site-deficient S protein of SARS-CoV-2. ACE2 of human/rhesus monkey and rat/mouse exhibited the highest and lowest receptor activities, respectively. Among the remaining species, ACE2s from rabbit and pangolin strongly bound to the S1 subunit of SARS-CoV-2 S protein and efficiently supported the pseudotyped virus infection. These findings have important implications for understanding potential natural reservoirs, zoonotic transmission, human-to-animal transmission, and use of animal models.IMPORTANCE SARS-CoV-2 uses human ACE2 as a primary receptor for host cell entry. Viral entry mediated by the interaction of ACE2 with spike protein largely determines host range and is the major constraint to interspecies transmission. We examined the receptor activity of 14 ACE2 orthologs and found that wild-type and mutant SARS-CoV-2 lacking the furin cleavage site in S protein could utilize ACE2 from a broad range of animal species to enter host cells. These results have important implications in the natural hosts, interspecies transmission, animal models, and molecular basis of receptor binding for SARS-CoV-2.


Subject(s)
Animal Diseases/metabolism , Animal Diseases/virology , Betacoronavirus/physiology , Coronavirus Infections/veterinary , Pandemics/veterinary , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/veterinary , Receptors, Virus/metabolism , Amino Acid Sequence , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/classification , COVID-19 , Cell Line , Host Specificity , Humans , Models, Molecular , Mutation , Peptidyl-Dipeptidase A/chemistry , Phylogeny , Protein Binding , Protein Domains , Proteolysis , Receptors, Virus/chemistry , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship , Viral Tropism , Virus Internalization
8.
Emerg Microbes Infect ; 9(1): 1567-1579, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-707709

ABSTRACT

Diverse SARS-like coronaviruses (SL-CoVs) have been identified from bats and other animal species. Like SARS-CoV, some bat SL-CoVs, such as WIV1, also use angiotensin converting enzyme 2 (ACE2) from human and bat as entry receptor. However, whether these viruses can also use the ACE2 of other animal species as their receptor remains to be determined. We report herein that WIV1 has a broader tropism to ACE2 orthologs than SARS-CoV isolate Tor2. Among the 9 ACE2 orthologs examined, human ACE2 exhibited the highest efficiency to mediate the infection of WIV1 pseudotyped virus. Our findings thus imply that WIV1 has the potential to infect a wide range of wild animals and may directly jump to humans. We also showed that cell entry of WIV1 could be restricted by interferon-induced transmembrane proteins (IFITMs). However, WIV1 could exploit the airway protease TMPRSS2 to partially evade the IFITM3 restriction. Interestingly, we also found that amphotericin B could enhance the infectious entry of SARS-CoVs and SL-CoVs by evading IFITM3-mediated restriction. Collectively, our findings further underscore the risk of exposure to animal SL-CoVs and highlight the vulnerability of patients who take amphotericin B to infection by SL-CoVs, including the most recently emerging (SARS-CoV-2).


Subject(s)
Betacoronavirus/physiology , Chiroptera/virology , Membrane Proteins/metabolism , Peptidyl-Dipeptidase A/metabolism , RNA-Binding Proteins/metabolism , Receptors, Virus/metabolism , Serine Endopeptidases/metabolism , Virus Internalization , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/classification , HEK293 Cells , Humans , Rats , Receptors, Coronavirus , SARS Virus/physiology , Viverridae
9.
J Virol ; 94(18)2020 08 31.
Article in English | MEDLINE | ID: covidwho-639615

ABSTRACT

C3A is a subclone of the human hepatoblastoma HepG2 cell line with strong contact inhibition of growth. We fortuitously found that C3A was more susceptible to human coronavirus HCoV-OC43 infection than HepG2, which was attributed to the increased efficiency of virus entry into C3A cells. In an effort to search for the host cellular protein(s) mediating the differential susceptibility of the two cell lines to HCoV-OC43 infection, we found that ArfGAP with dual pleckstrin homology (PH) domains 2 (ADAP2), gamma-interferon-inducible lysosome/endosome-localized thiolreductase (GILT), and lymphocyte antigen 6 family member E (LY6E), the three cellular proteins identified to function in interference with virus entry, were expressed at significantly higher levels in HepG2 cells. Functional analyses revealed that ectopic expression of LY6E, but not GILT or ADAP2, in HEK 293 cells inhibited the entry of HCoV-O43. While overexpression of LY6E in C3A and A549 cells efficiently inhibited the infection of HCoV-OC43, knockdown of LY6E expression in HepG2 significantly increased its susceptibility to HCoV-OC43 infection. Moreover, we found that LY6E also efficiently restricted the entry mediated by the envelope spike proteins of other human coronaviruses, including the currently pandemic SARS-CoV-2. Interestingly, overexpression of serine protease TMPRSS2 or amphotericin treatment significantly neutralized the IFN-inducible transmembrane 3 (IFITM3) restriction of human coronavirus (CoV) entry, but did not compromise the effect of LY6E on the entry of human coronaviruses. The work reported herein thus demonstrates that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis via a mechanism distinct from other factors that modulate CoV entry.IMPORTANCE Virus entry into host cells is one of the key determinants of host range and cell tropism and is subjected to the control of host innate and adaptive immune responses. In the last decade, several interferon-inducible cellular proteins, including IFITMs, GILT, ADAP2, 25CH, and LY6E, had been identified to modulate the infectious entry of a variety of viruses. Particularly, LY6E was recently identified as a host factor that facilitates the entry of several human-pathogenic viruses, including human immunodeficiency virus, influenza A virus, and yellow fever virus. Identification of LY6E as a potent restriction factor of coronaviruses expands the biological function of LY6E and sheds new light on the immunopathogenesis of human coronavirus infection.


Subject(s)
Antigens, Surface/metabolism , Betacoronavirus/physiology , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Coronavirus/physiology , Host-Pathogen Interactions , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Virus Internalization , Amino Acid Sequence , Amphotericin B/pharmacology , Betacoronavirus/drug effects , COVID-19 , Cell Line , Coronavirus/drug effects , Coronavirus Infections/epidemiology , Disease Susceptibility , Evolution, Molecular , GPI-Linked Proteins/metabolism , Humans , Pandemics , Pneumonia, Viral/epidemiology , Protein Sorting Signals , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
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