Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 88
Filter
2.
Proc Natl Acad Sci U S A ; 118(50)2021 12 14.
Article in English | MEDLINE | ID: covidwho-1555255

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), binds to host receptor angiotensin-converting enzyme 2 (ACE2) through its spike (S) glycoprotein, which mediates membrane fusion and viral entry. However, the expression of ACE2 is extremely low in a variety of human tissues, especially in the airways. Thus, other coreceptors and/or cofactors on the surface of host cells may contribute to SARS-CoV-2 infection. Here, we identified nonmuscle myosin heavy chain IIA (MYH9) as an important host factor for SARS-CoV-2 infection of human pulmonary cells by using APEX2 proximity-labeling techniques. Genetic ablation of MYH9 significantly reduced SARS-CoV-2 pseudovirus infection in wild type (WT) A549 and Calu-3 cells, and overexpression of MYH9 enhanced the pseudovirus infection in WT A549 and H1299 cells. MYH9 was colocalized with the SARS-CoV-2 S and directly interacted with SARS-CoV-2 S through the S2 subunit and S1-NTD (N-terminal domain) by its C-terminal domain (designated as PRA). Further experiments suggested that endosomal or myosin inhibitors effectively block the viral entry of SARS-CoV-2 into PRA-A549 cells, while transmembrane protease serine 2 (TMPRSS2) and cathepsin B and L (CatB/L) inhibitors do not, indicating that MYH9 promotes SARS-CoV-2 endocytosis and bypasses TMPRSS2 and CatB/L pathway. Finally, we demonstrated that loss of MYH9 reduces authentic SARS-CoV-2 infection in Calu-3, ACE2-A549, and ACE2-H1299 cells. Together, our results suggest that MYH9 is a candidate host factor for SARS-CoV-2, which mediates the virus entering host cells by endocytosis in an ACE2-dependent manner, and may serve as a potential target for future clinical intervention strategies.


Subject(s)
COVID-19/virology , Myosin Heavy Chains/metabolism , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/metabolism , Cell Line , Cell Membrane/metabolism , Humans , Lung/metabolism , Middle East Respiratory Syndrome Coronavirus/physiology , Myosin Heavy Chains/chemistry , Myosin Heavy Chains/genetics , Protein Binding , Protein Domains , SARS Virus/physiology , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
3.
J Immunol Methods ; 500: 113197, 2022 01.
Article in English | MEDLINE | ID: covidwho-1536657

ABSTRACT

Since the first detection of a novel Coronavirus (SARS-CoV-2) in December 2019 in Wuhan (China), it has become crucial to assess and quantize the human humoral immune response after SARS-CoV-2 natural infection and/or vaccination. Having well standardized and reliable serological assays able to accurately measure the total IgG antibodies response as well as the neutralization dynamics, play a pivotal role for the evaluation of "second" and "third" vaccines generation and in monitoring the effect in case of reinfection in the human population caused by the original strains or new SARS-CoV-2 variants. In the present study we reported that both symptomatic convalescent and vaccinated donors showed the presence of different levels of neutralizing antibodies. In addition, vaccinated subjects presented high levels of anti-S antibodies, whereas the complete absence of anti-N antibodies, whereas convalescent patients presented high levels of both anti-S and anti-N antibodies. The evaluation of the correlation between SARS-CoV-2 neutralizing and binding antibodies in convalescent and vaccinated subjects revealed that the IgG anti-S log-values were significantly higher in the vaccinated group respect to convalescent subjects. In addition, the level of binding antibodies recognizing the S protein shows a positive linear regression when compared to neutralizing titres in both the two groups evaluated.


Subject(s)
COVID-19 Serological Testing/methods , COVID-19 Vaccines/immunology , COVID-19/immunology , SARS Virus/physiology , SARS-CoV-2/genetics , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/metabolism , Antibodies, Viral/immunology , Antibodies, Viral/metabolism , COVID-19/diagnosis , Convalescence , Humans , Immunization, Secondary , Protein Binding , Vaccination
4.
Immunity ; 54(12): 2908-2921.e6, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1521063

ABSTRACT

Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Second-generation vaccines will need to elicit neutralizing antibodies against sites that are evolutionarily conserved across the sarbecovirus subgenus. Here, we immunized mice containing a human antibody repertoire with diverse sarbecovirus receptor-binding domains (RBDs) to identify antibodies targeting conserved sites of vulnerability. Antibodies with broad reactivity against diverse clade B RBDs targeting the conserved class 4 epitope, with recurring IGHV/IGKV pairs, were readily elicited but were non-neutralizing. However, rare class 4 antibodies binding this conserved RBD supersite showed potent neutralization of SARS-CoV-2 and all variants of concern. Structural analysis revealed that the neutralizing ability of cross-reactive antibodies was reserved only for those with an elongated CDRH3 that extends the antiparallel beta-sheet RBD core and orients the antibody light chain to obstruct ACE2-RBD interactions. These results identify a structurally defined pathway for vaccine strategies eliciting escape-resistant SARS-CoV-2 neutralizing antibodies.


Subject(s)
Betacoronavirus/physiology , COVID-19 Vaccines/immunology , Coronavirus Infections/immunology , SARS Virus/physiology , Spike Glycoprotein, Coronavirus/metabolism , Animals , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Conserved Sequence/genetics , Evolution, Molecular , Humans , Immunization , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Protein Binding , Protein Domains/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
5.
J Biol Chem ; 297(6): 101399, 2021 12.
Article in English | MEDLINE | ID: covidwho-1509947

ABSTRACT

The nonstructural protein 1 (nsp1) of severe acute respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus 2 is a critical viral protein that suppresses host gene expression by blocking the assembly of the ribosome on host mRNAs. To understand the mechanism of inhibition of host gene expression, we sought to identify cellular proteins that interact with nsp1. Using proximity-dependent biotinylation followed by proteomic analyses of biotinylated proteins, here we captured multiple dynamic interactions of nsp1 with host cell proteins. In addition to ribosomal proteins, we identified several pre-mRNA processing proteins that interact with nsp1, including splicing factors and transcription termination proteins, as well as exosome, and stress granule (SG)-associated proteins. We found that the interactions with transcription termination factors are primarily governed by the C-terminal region of nsp1 and are disrupted by the mutation of amino acids K164 and H165 that are essential for its host shutoff function. We further show that nsp1 interacts with Ras GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) and colocalizes with G3BP1 in SGs under sodium arsenite-induced stress. Finally, we observe that the presence of nsp1 disrupts the maturation of SGs over a long period. Isolation of SG core at different times shows a gradual loss of G3BP1 in the presence of nsp1.


Subject(s)
COVID-19/metabolism , RNA-Dependent RNA Polymerase/metabolism , SARS Virus/metabolism , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome/metabolism , Viral Nonstructural Proteins/metabolism , Biotinylation , COVID-19/virology , HEK293 Cells , Host-Pathogen Interactions , Humans , Proteomics , Ribosomal Proteins/metabolism , SARS Virus/physiology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/virology , /metabolism
6.
Viruses ; 13(11)2021 10 29.
Article in English | MEDLINE | ID: covidwho-1488763

ABSTRACT

In the last two decades, several coronavirus (CoV) interspecies jumping events have occurred between bats and other animals/humans, leading to major epidemics/pandemics and high fatalities. The SARS epidemic in 2002/2003 had a ~10% fatality. The discovery of SARS-related CoVs in horseshoe bats and civets and genomic studies have confirmed bat-to-civet-to-human transmission. The MERS epidemic that emerged in 2012 had a ~35% mortality, with dromedaries as the reservoir. Although CoVs with the same genome organization (e.g., Tylonycteris BatCoV HKU4 and Pipistrellus BatCoV HKU5) were also detected in bats, there is still a phylogenetic gap between these bat CoVs and MERS-CoV. In 2016, 10 years after the discovery of Rhinolophus BatCoV HKU2 in Chinese horseshoe bats, fatal swine disease outbreaks caused by this virus were reported in southern China. In late 2019, an outbreak of pneumonia emerged in Wuhan, China, and rapidly spread globally, leading to >4,000,000 fatalities so far. Although the genome of SARS-CoV-2 is highly similar to that of SARS-CoV, patient zero and the original source of the pandemic are still unknown. To protect humans from future public health threats, measures should be taken to monitor and reduce the chance of interspecies jumping events, either occurring naturally or through recombineering experiments.


Subject(s)
COVID-19/virology , Chiroptera/virology , Coronavirus Infections/virology , Coronavirus/physiology , Host Adaptation , Severe Acute Respiratory Syndrome/virology , Alphacoronavirus/genetics , Alphacoronavirus/physiology , Animals , COVID-19/transmission , Coronavirus/genetics , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Coronavirus Infections/veterinary , Host Specificity , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/physiology , SARS Virus/genetics , SARS Virus/physiology , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/transmission , Severe Acute Respiratory Syndrome/veterinary
8.
Microbes Infect ; 22(4-5): 226-229, 2020.
Article in English | MEDLINE | ID: covidwho-1386324

ABSTRACT

During virus infection, host toll-like receptors (TLRs) can recognize different pathogen-associated molecular patterns and trigger the innate immune response. TLR7/8 can identify the single-stranded RNA (ssRNA) of the virus. This study aimed to search ssRNA sequences recognized by TLR7/8 from the SARS-CoV-2, SARS-CoV, and MERS-CoV whole genomes by a bioinformatic technique. The immunoinformatic approach showed that the SARS-CoV-2 genome has more ssRNA fragments that could be recognized by TLR7/8 than the SARS-CoV genome. These findings suggest innate immune hyperactivation by SARS-CoV-2. This activity is possibly able to provoke a robust proinflammatory response via TLR7/8 recognition and cause acute lung injury.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Middle East Respiratory Syndrome Coronavirus/physiology , Pneumonia, Viral/virology , SARS Virus/physiology , Toll-Like Receptor 7/physiology , Toll-Like Receptor 8/physiology , COVID-19 , Computational Biology , Genome, Viral , Humans , Immunity, Innate , Pandemics , SARS-CoV-2 , Virus Attachment
9.
Cell ; 181(5): 969-977, 2020 05 28.
Article in English | MEDLINE | ID: covidwho-1385208

ABSTRACT

SARS-CoV-2 infection is mild in the majority of individuals but progresses into severe pneumonia in a small proportion of patients. The increased susceptibility to severe disease in the elderly and individuals with co-morbidities argues for an initial defect in anti-viral host defense mechanisms. Long-term boosting of innate immune responses, also termed "trained immunity," by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells. We propose that induction of trained immunity by whole-microorganism vaccines may represent an important tool for reducing susceptibility to and severity of SARS-CoV-2.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/immunology , Immunity, Innate , Immunomodulation , Pneumonia, Viral/immunology , SARS Virus/physiology , Animals , BCG Vaccine/immunology , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Coronavirus Infections/transmission , Humans , Immunity, Innate/drug effects , Lung/immunology , Lung/pathology , Lymphopenia/pathology , Middle East Respiratory Syndrome Coronavirus/physiology , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/transmission , SARS-CoV-2 , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/pathology , Virus Replication
10.
Viruses ; 13(8)2021 08 23.
Article in English | MEDLINE | ID: covidwho-1367925

ABSTRACT

An escalating pandemic of the novel SARS-CoV-2 virus is impacting global health, and effective antivirals are needed. Umifenovir (Arbidol) is an indole-derivative molecule, licensed in Russia and China for prophylaxis and treatment of influenza and other respiratory viral infections. It has been shown that umifenovir has broad spectrum activity against different viruses. We evaluated the sensitivity of different coronaviruses, including the novel SARS-CoV-2 virus, to umifenovir using in vitro assays. Using a plaque assay, we revealed an antiviral effect of umifenovir against seasonal HCoV-229E and HCoV-OC43 coronaviruses in Vero E6 cells, with estimated 50% effective concentrations (EC50) of 10.0 ± 0.5 µM and 9.0 ± 0.4 µM, respectively. Umifenovir at 90 µM significantly suppressed plaque formation in CMK-AH-1 cells infected with SARS-CoV. Umifenovir also inhibited the replication of SARS-CoV-2 virus, with EC50 values ranging from 15.37 ± 3.6 to 28.0 ± 1.0 µM. In addition, 21-36 µM of umifenovir significantly suppressed SARS-CoV-2 virus titers (≥2 log TCID50/mL) in the first 24 h after infection. Repurposing of antiviral drugs is very helpful in fighting COVID-19. A safe, pan-antiviral drug such as umifenovir could be extremely beneficial in combating the early stages of a viral pandemic.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 229E, Human/drug effects , Coronavirus OC43, Human/drug effects , Indoles/pharmacology , SARS Virus/drug effects , SARS-CoV-2/drug effects , Animals , Antiviral Agents/administration & dosage , Cell Survival/drug effects , Chlorocebus aethiops , Coronavirus 229E, Human/physiology , Coronavirus OC43, Human/physiology , Cytopathogenic Effect, Viral/drug effects , Humans , Indoles/administration & dosage , Microbial Sensitivity Tests , SARS Virus/physiology , SARS-CoV-2/physiology , Vero Cells , Viral Load/drug effects , Viral Plaque Assay , Virus Replication/drug effects
11.
Viruses ; 13(8)2021 08 18.
Article in English | MEDLINE | ID: covidwho-1360825

ABSTRACT

Recent outbreaks of zoonotic coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have caused tremendous casualties and great economic shock. Although some repurposed drugs have shown potential therapeutic efficacy in clinical trials, specific therapeutic agents targeting coronaviruses have not yet been developed. During coronavirus replication, a replicase gene cluster, including RNA-dependent RNA polymerase (RdRp), is alternatively translated via a process called -1 programmed ribosomal frameshift (-1 PRF) by an RNA pseudoknot structure encoded in viral RNAs. The coronavirus frameshifting has been identified previously as a target for antiviral therapy. In this study, the frameshifting efficiencies of MERS-CoV, SARS-CoV and SARS-CoV-2 were determined using an in vitro -1 PRF assay system. Our group has searched approximately 9689 small molecules to identify potential -1 PRF inhibitors. Herein, we found that a novel compound, 2-(5-acetylthiophen-2yl)furo[2,3-b]quinoline (KCB261770), inhibits the frameshifting of MERS-CoV and effectively suppresses viral propagation in MERS-CoV-infected cells. The inhibitory effects of 87 derivatives of furo[2,3-b]quinolines were also examined showing less prominent inhibitory effect when compared to compound KCB261770. We demonstrated that KCB261770 inhibits the frameshifting without suppressing cap-dependent translation. Furthermore, this compound was able to inhibit the frameshifting, to some extent, of SARS-CoV and SARS-CoV-2. Therefore, the novel compound 2-(5-acetylthiophen-2yl)furo[2,3-b]quinoline may serve as a promising drug candidate to interfere with pan-coronavirus frameshifting.


Subject(s)
Antiviral Agents/pharmacology , Frameshifting, Ribosomal/drug effects , Middle East Respiratory Syndrome Coronavirus/drug effects , Quinolines/pharmacology , SARS Virus/drug effects , SARS-CoV-2/drug effects , A549 Cells , Animals , Cell Line , Frameshifting, Ribosomal/physiology , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/physiology , SARS Virus/genetics , SARS Virus/physiology , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Small Molecule Libraries , Viral Zoonoses/virology , Virus Replication/drug effects
13.
Am J Chin Med ; 48(7): 1539-1552, 2020.
Article in English | MEDLINE | ID: covidwho-1327716

ABSTRACT

The SARS-CoV-2 outbreak in 2019 highlighted the fact that no specific medications providing effective treatment have been identified and approved. We explored the possibilities for COVID-19 by systematically reviewing evidence on the efficacy and safety of glycyrrhizin preparations for SARS and MERS. Electronic databases were systematically searched from inception to February 2020 for eligible studies that evaluated the efficacy and safety of glycyrrhizin preparations for SARS and MERS. A quantitative analysis or descriptive analysis was applied. Five retrospective cohort studies were included, and NOS scores ranged from 5-7 points. The clinical symptoms of dry cough, chest distress and dyspnoea improved quickly, and elevated serum levels of aminotransferase decreased after compound glycyrrhizin treatment. The SARS-CoV antibody appeared earlier in the treated group than in the control group ([Formula: see text][Formula: see text]d). Compared to that with conventional medications, the average period from peak to 50% improvement of lesions, in terms of X-ray manifestations, was shorter with compound glycyrrhizin treatment ([Formula: see text]2.1[Formula: see text]d), and treatment reduced the dosage ([Formula: see text][Formula: see text]mg/d) and duration of the corticosteroids used, without other serious adverse reactions. Based on the available evidence regarding glycyrrhizin preparations for treating SARS and MERS, we infer that compound glycyrrhizin could be an optional therapeutic strategy for SARS-CoV-2 infections, especially those complicated with liver damage. Further research using well-designed randomized clinical trials (RCTs) is warranted to determine the dosage and duration of use of compound glycyrrhizin and to monitor its specific adverse effects.


Subject(s)
COVID-19/drug therapy , Coronavirus Infections/drug therapy , Glycyrrhizic Acid/therapeutic use , Middle East Respiratory Syndrome Coronavirus/drug effects , SARS Virus/drug effects , SARS-CoV-2/drug effects , Severe Acute Respiratory Syndrome/drug therapy , Anti-Inflammatory Agents/therapeutic use , COVID-19/epidemiology , COVID-19/virology , Coronavirus Infections/virology , Humans , Middle East Respiratory Syndrome Coronavirus/physiology , Pandemics , SARS Virus/physiology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/virology , Treatment Outcome
14.
Viruses ; 13(8)2021 07 27.
Article in English | MEDLINE | ID: covidwho-1325793

ABSTRACT

Over the past 18 years, three highly pathogenic human (h) coronaviruses (CoVs) have caused severe outbreaks, the most recent causative agent, SARS-CoV-2, being the first to cause a pandemic. Although much progress has been made since the COVID-19 pandemic started, much about SARS-CoV-2 and its disease, COVID-19, is still poorly understood. The highly pathogenic hCoVs differ in some respects, but also share some similarities in clinical presentation, the risk factors associated with severe disease, and the characteristic immunopathology associated with the progression to severe disease. This review aims to highlight these overlapping aspects of the highly pathogenic hCoVs-SARS-CoV, MERS-CoV, and SARS-CoV-2-briefly discussing the importance of an appropriately regulated immune response; how the immune response to these highly pathogenic hCoVs might be dysregulated through interferon (IFN) inhibition, antibody-dependent enhancement (ADE), and long non-coding RNA (lncRNA); and how these could link to the ensuing cytokine storm. The treatment approaches to highly pathogenic hCoV infections are discussed and it is suggested that a greater focus be placed on T-cell vaccines that elicit a cell-mediated immune response, using rapamycin as a potential agent to improve vaccine responses in the elderly and obese, and the potential of stapled peptides as antiviral agents.


Subject(s)
COVID-19/immunology , Coronavirus Infections/immunology , Severe Acute Respiratory Syndrome/immunology , Animals , COVID-19/epidemiology , COVID-19/virology , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Cytokines/immunology , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/physiology , Pandemics , SARS Virus/genetics , SARS Virus/physiology , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/virology
15.
PLoS Pathog ; 17(7): e1009715, 2021 07.
Article in English | MEDLINE | ID: covidwho-1315897

ABSTRACT

SARS-CoV and SARS-CoV-2 encode spike proteins that bind human ACE2 on the cell surface to enter target cells during infection. A small fraction of humans encode variants of ACE2, thus altering the biochemical properties at the protein interaction interface. These and other ACE2 coding mutants can reveal how the spike proteins of each virus may differentially engage the ACE2 protein surface during infection. We created an engineered HEK 293T cell line for facile stable transgenic modification, and expressed the major human ACE2 allele or 28 of its missense mutants, 24 of which are possible through single nucleotide changes from the human reference sequence. Infection with SARS-CoV or SARS-CoV-2 spike pseudotyped lentiviruses revealed that high ACE2 cell-surface expression could mask the effects of impaired binding during infection. Drastically reducing ACE2 cell surface expression revealed a range of infection efficiencies across the panel of mutants. Our infection results revealed a non-linear relationship between soluble SARS-CoV-2 RBD binding to ACE2 and pseudovirus infection, supporting a major role for binding avidity during entry. While ACE2 mutants D355N, R357A, and R357T abrogated entry by both SARS-CoV and SARS-CoV-2 spike proteins, the Y41A mutant inhibited SARS-CoV entry much more than SARS-CoV-2, suggesting differential utilization of the ACE2 side-chains within the largely overlapping interaction surfaces utilized by the two CoV spike proteins. These effects correlated well with cytopathic effects observed during SARS-CoV-2 replication in ACE2-mutant cells. The panel of ACE2 mutants also revealed altered ACE2 surface dependencies by the N501Y spike variant, including a near-complete utilization of the K353D ACE2 variant, despite decreased infection mediated by the parental SARS-CoV-2 spike. Our results clarify the relationship between ACE2 abundance, binding, and infection, for various SARS-like coronavirus spike proteins and their mutants, and inform our understanding for how changes to ACE2 sequence may correspond with different susceptibilities to infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/etiology , SARS Virus/physiology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/etiology , Spike Glycoprotein, Coronavirus/physiology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/virology , HEK293 Cells , Humans , Mutation, Missense , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/virology
16.
Arch Pathol Lab Med ; 145(10): 1194-1211, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1299680

ABSTRACT

CONTEXT.­: The purpose of this review was to compare 3 coronavirus diseases, including severe acute respiratory syndrome, Middle East respiratory syndrome, and COVID-19 caused by SARS-CoV, MERS-CoV, and SARS-CoV-2 viruses, respectively. OBJECTIVE.­: To cover the following topics: clinical considerations, viral characteristics, pathology, immune response, pathogenesis, and the prognosis associated with each coronavirus disease in humans. DATA SOURCES.­: Clinically, flu-like symptoms are usual at the time of presentation for all 3 diseases, but these vary from asymptomatic to severe multisystem involvement. The pathology associated with symptomatic severe acute respiratory syndrome and COVID-19 has been well described, the most prominent of which is diffuse alveolar damage. The immune response to each of these viruses is highly complex and includes both humoral and cellular components that can have a significant impact on prognosis. In severe cases of COVID-19, a dysregulated innate host immune system can initiate a hyperinflammatory syndrome dominated by endothelial dysfunction that can lead to a hypercoagulable state with microthrombi, resulting in a systemic microvascular and macrovascular disease. CONCLUSIONS.­: The severe acute respiratory syndrome and Middle East respiratory syndrome epidemics have been limited, involving approximately 8000 and 2500 individuals, respectively. In contrast, COVID-19 has resulted in a worldwide pandemic with more than 177 million cases and 3.9 million deaths as of June 15, 2021, and fatality rates ranging from less than 0.1% to approximately 10% depending upon the country. Ending on a positive note, the development of a number of vaccines, at least 6 of which now are in clinical use, should mitigate and eventually control the devastating COVID-19 pandemic.


Subject(s)
COVID-19/immunology , Coronavirus Infections/immunology , Immune System/immunology , Severe Acute Respiratory Syndrome/immunology , Betacoronavirus/immunology , Betacoronavirus/physiology , COVID-19/epidemiology , COVID-19/virology , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Humans , Pandemics/prevention & control , Prognosis , SARS Virus/immunology , SARS Virus/physiology , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/virology
17.
Science ; 373(6558): 991-998, 2021 08 27.
Article in English | MEDLINE | ID: covidwho-1295160

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and SARS-CoV-2 in 2019 highlights the need to develop universal vaccination strategies against the broader Sarbecovirus subgenus. Using chimeric spike designs, we demonstrate protection against challenge from SARS-CoV, SARS-CoV-2, SARS-CoV-2 B.1.351, bat CoV (Bt-CoV) RsSHC014, and a heterologous Bt-CoV WIV-1 in vulnerable aged mice. Chimeric spike messenger RNAs (mRNAs) induced high levels of broadly protective neutralizing antibodies against high-risk Sarbecoviruses. By contrast, SARS-CoV-2 mRNA vaccination not only showed a marked reduction in neutralizing titers against heterologous Sarbecoviruses, but SARS-CoV and WIV-1 challenge in mice resulted in breakthrough infections. Chimeric spike mRNA vaccines efficiently neutralized D614G, mink cluster five, and the UK B.1.1.7 and South African B.1.351 variants of concern. Thus, multiplexed-chimeric spikes can prevent SARS-like zoonotic coronavirus infections with pandemic potential.


Subject(s)
Betacoronavirus/immunology , COVID-19 Vaccines/immunology , Coronavirus Infections/prevention & control , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/immunology , Viral Vaccines/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Betacoronavirus/physiology , COVID-19/prevention & control , Coronavirus Infections/immunology , Cross Protection , Cytokines/blood , Female , Immunity, Heterologous , Immunogenicity, Vaccine , Liposomes , Lung/pathology , Lung/virology , Mice , Mice, Inbred BALB C , Nanoparticles , Protein Domains , Recombinant Fusion Proteins , SARS Virus/immunology , SARS Virus/physiology , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/prevention & control , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Virus Replication
18.
Cells ; 10(7)2021 06 28.
Article in English | MEDLINE | ID: covidwho-1288809

ABSTRACT

Betacoronaviruses, responsible for the "Severe Acute Respiratory Syndrome" (SARS) and the "Middle East Respiratory Syndrome" (MERS), use the spikes protruding from the virion envelope to attach and subsequently infect the host cells. The coronavirus spike (S) proteins contain receptor binding domains (RBD), allowing the specific recognition of either the dipeptidyl peptidase CD23 (MERS-CoV) or the angiotensin-converting enzyme ACE2 (SARS-Cov, SARS-CoV-2) host cell receptors. The heavily glycosylated S protein includes both complex and high-mannose type N-glycans that are well exposed at the surface of the spikes. A detailed analysis of the carbohydrate-binding specificity of mannose-binding lectins from plants, algae, fungi, and bacteria, revealed that, depending on their origin, they preferentially recognize either complex type N-glycans, or high-mannose type N-glycans. Since both complex and high-mannose glycans substantially decorate the S proteins, mannose-specific lectins are potentially useful glycan probes for targeting the SARS-CoV, MERS-CoV, and SARS-CoV-2 virions. Mannose-binding legume lectins, like pea lectin, and monocot mannose-binding lectins, like snowdrop lectin or the algal lectin griffithsin, which specifically recognize complex N-glycans and high-mannose glycans, respectively, are particularly adapted for targeting coronaviruses. The biomedical prospects of targeting coronaviruses with mannose-specific lectins are wide-ranging including detection, immobilization, prevention, and control of coronavirus infection.


Subject(s)
Lectins/pharmacology , Middle East Respiratory Syndrome Coronavirus/metabolism , SARS Virus/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , COVID-19/drug therapy , COVID-19/virology , Cyanobacteria/chemistry , Drug Delivery Systems/methods , Fungi/chemistry , Humans , Lectins/isolation & purification , Lectins/therapeutic use , Middle East Respiratory Syndrome Coronavirus/physiology , Plants/chemistry , Protein Binding , SARS Virus/physiology , SARS-CoV-2/physiology , Species Specificity , Virus Internalization/drug effects
19.
PLoS One ; 16(5): e0251913, 2021.
Article in English | MEDLINE | ID: covidwho-1232467

ABSTRACT

Last decade has witnessed three major pandemics caused by SARS-CoV, SARS-CoV-2 and MERS-CoV that belong to Coronavirus family. Currently, there are no effective therapies available for corona virus infections. Since the three viruses belong to the same family and share many common features, we can theoretically design a drug that can be effective on all the three of them. In this study, using computational approach, we designed a peptide (Peptide 7) that can bind to the Receptor Binding Domain (RBD) of SARS-CoV, SARS-CoV-2 and MERS-CoV thereby preventing the entry of the viruses into the host cell. The peptide inhibitor was designed as a consensus peptide from three different peptides that might individually bind to the RBD of the three viruses. Docking studies and molecular dynamic simulations using Peptide 7 has shown that it binds with higher affinity than the native receptors of the RBD and forms a stable complex thereby preventing further viral-receptor interaction and inhibiting their cellular entry. This effective binding is observed for the three RBDs, despite the Peptide 7 interactions being slightly different. Hence; this peptide inhibitor can be used as a potential candidate for the development of peptide based anti-viral therapy against Corona viruses.


Subject(s)
Middle East Respiratory Syndrome Coronavirus/physiology , Peptides/pharmacology , SARS Virus/physiology , SARS-CoV-2/physiology , Virus Internalization/drug effects , Amino Acid Sequence , Binding Sites , Humans , Hydrogen Bonding , Middle East Respiratory Syndrome Coronavirus/metabolism , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptides/chemistry , Peptides/metabolism , Protein Binding , Receptors, Virus/chemistry , Receptors, Virus/metabolism , SARS Virus/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
20.
Cladistics ; 37(5): 461-488, 2021 10.
Article in English | MEDLINE | ID: covidwho-1201590

ABSTRACT

The severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in humans in 2002. Despite reports showing Chiroptera as the original animal reservoir of SARS-CoV, many argue that Carnivora-hosted viruses are the most likely origin. The emergence of the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 also involves Chiroptera-hosted lineages. However, factors such as the lack of comprehensive phylogenies hamper our understanding of host shifts once MERS-CoV emerged in humans and Artiodactyla. Since 2019, the origin of SARS-CoV-2, causative agent of coronavirus disease 2019 (COVID-19), added to this episodic history of zoonotic transmission events. Here we introduce a phylogenetic analysis of 2006 unique and complete genomes of different lineages of Orthocoronavirinae. We used gene annotations to align orthologous sequences for total evidence analysis under the parsimony optimality criterion. Deltacoronavirus and Gammacoronavirus were set as outgroups to understand spillovers of Alphacoronavirus and Betacoronavirus among ten orders of animals. We corroborated that Chiroptera-hosted viruses are the sister group of SARS-CoV, SARS-CoV-2 and MERS-related viruses. Other zoonotic events were qualified and quantified to provide a comprehensive picture of the risk of coronavirus emergence among humans. Finally, we used a 250 SARS-CoV-2 genomes dataset to elucidate the phylogenetic relationship between SARS-CoV-2 and Chiroptera-hosted coronaviruses.


Subject(s)
Chiroptera/virology , Host-Pathogen Interactions/physiology , Middle East Respiratory Syndrome Coronavirus/physiology , Phylogeny , SARS Virus/physiology , SARS-CoV-2/physiology , Animals , Genome, Viral , Humans , Likelihood Functions , Pangolins/virology , Recombination, Genetic/genetics , Spike Glycoprotein, Coronavirus/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL