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2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-315229

ABSTRACT

Background: To investigate the long-term effects of SARS-CoV-1 on patients’ lung and immune systems 15 years post-infection. Methods: : We enrolled 58 health care workers with confirmed SARS in Peking University People’s Hospital in 2003. We evaluated lung damage by mMRC score, pulmonary function tests, and chest CT. Immune function was assessed by their serum levels of globin, complete components, and peripheral T cell subsets. ELISA was used to detect SARS-CoV-specific IgG antibodies in sera. Results: : After 15 years of disease onset, 19 (36.5%), 8 (34.6%), and 19 (36.5%) subjects had impaired DL(CO), RV, and FEF 25-75 , respectively. 17 (30.4%) subjects had an mMRC score ≥ 2. Fourteen (25.5%) cases had residual CT abnormalities. T regulatory cells were a bit higher in the SARS survivors. IgG antibodies against SARS S-RBD protein and N protein were detected in 11 (18.97%) and 12 (20.69%) subjects, respectively. Subgroup analysis revealed that small airway dysfunction and CT abnormalities were more common in the severe group than in the non-severe group (57.1% vs 22.6%, 54.5% vs 6.1%, respectively, p < 0.05). Conclusions: : SARS-CoV-1 could cause permanent damage to the lung, which requires early pulmonary rehabilitation. The long-lived immune memory response against coronavirus requires further studies to assess the potential benefit. Trail registration: ClinicalTrials.gov, NCT03443102. Registered prospectively on 22/02/2018.

3.
Medicine (Baltimore) ; 100(47): e27950, 2021 Nov 24.
Article in English | MEDLINE | ID: covidwho-1604259

ABSTRACT

ABSTRACT: During the coronavirus disease 2019 (COVID-19) pandemic, convenient accessibility and rapid publication of studies related to the ongoing pandemic prompted shorter preparation time for studies. Whether the methodological quality and reporting characteristics of published systematic reviews (SRs)/meta-analyses are affected during the specific pandemic condition is yet to be clarified. This study aimed to evaluate the epidemiology, methodological quality, and reporting characteristics of published SRs/meta-analyses related to COVID-19.The Ovid Medline, Ovid Embase, Cochrane Library, and Web of Science electronic databases were searched to identify published SRs/meta-analyses related to the COVID-19 pandemic. Study screening, data extraction, and methodology quality assessment were performed independently by 2 authors. The methodology quality of included SRs/meta-analyses was evaluated using revised version of a measurement tool to assess SRs, and the reporting characteristics were assessed based on the preferred reporting items for SRs and meta-analyses guidelines.A total of 47 SRs/meta-analyses were included with a low to critically low methodological quality. The median number of days from the date of literature retrieval to the date that the study was first available online was 21 days; due to the limited time, only 7 studies had study protocols, and the studies focused on a wide range of COVID-19 topics. The rate of compliance to the preferred reporting items for SRs and meta-analyses checklists of reporting characteristics ranged from 14.9% to 100%. The rate of compliance to the items of protocol and registration, detailed search strategy, and assessment of publication bias was less than 50%.SRs/meta-analyses on COVID-19 were poorly conducted and reported, and thus, need to be substantially improved.


Subject(s)
COVID-19 , Meta-Analysis as Topic , Periodicals as Topic/standards , Publishing/standards , Systematic Reviews as Topic , Cross-Sectional Studies , Humans , Pandemics , Quality Control , SARS-CoV-2
4.
BMC Infect Dis ; 21(1): 1183, 2021 Nov 24.
Article in English | MEDLINE | ID: covidwho-1606168

ABSTRACT

BACKGROUND: We investigate the long-term effects of SARS-CoV on patients' lung and immune systems 15 years post-infection. SARS-CoV-2 pandemic is ongoing however, another genetically related beta-coronavirus SARS-CoV caused an epidemic in 2003-2004. METHODS: We enrolled 58 healthcare workers from Peking University People's Hospital who were infected with SARS-CoV in 2003. We evaluated lung damage by mMRC score, pulmonary function tests, and chest CT. Immune function was assessed by their serum levels of globin, complete components, and peripheral T cell subsets. ELISA was used to detect SARS-CoV-specific IgG antibodies in sera. RESULTS: After 15 years of disease onset, 19 (36.5%), 8 (34.6%), and 19 (36.5%) subjects had impaired DL (CO), RV, and FEF25-75, respectively. 17 (30.4%) subjects had an mMRC score ≥ 2. Fourteen (25.5%) cases had residual CT abnormalities. T regulatory cells were a bit higher in the SARS survivors. IgG antibodies against SARS S-RBD protein and N protein were detected in 11 (18.97%) and 12 (20.69%) subjects, respectively. Subgroup analysis revealed that small airway dysfunction and CT abnormalities were more common in the severe group than in the non-severe group (57.1% vs 22.6%, 54.5% vs 6.1%, respectively, p < 0.05). CONCLUSIONS: SARS-CoV could cause permanent damage to the lung, which requires early pulmonary rehabilitation. The long-lived immune memory response against coronavirus requires further studies to assess the potential benefit. Trial registration ClinicalTrials.gov, NCT03443102. Registered prospectively on 25 January 2018.


Subject(s)
Antibodies, Viral , COVID-19 , Humans , Lung , Pandemics , SARS-CoV-2
5.
J Gen Virol ; 102(10)2021 10.
Article in English | MEDLINE | ID: covidwho-1490495

ABSTRACT

The highly pathogenic Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a severe respiratory virus. Recent reports indicate additional central nervous system (CNS) involvement. In this study, human DPP4 transgenic mice were infected with MERS-CoV, and viral antigens were first detected in the midbrain-hindbrain 4 days post-infection, suggesting the virus may enter the brainstem via peripheral nerves. Neurons and astrocytes throughout the brain were infected, followed by damage of the blood brain barrier (BBB), as well as microglial activation and inflammatory cell infiltration, which may be caused by complement activation based on the observation of deposition of complement activation product C3 and high expression of C3a receptor (C3aR) and C5a receptor (C5aR1) in neurons and glial cells. It may be concluded that these effects were mediated by complement activation in the brain, because of their reduction resulted from the treatment with mouse C5aR1-specific mAb. Such mAb significantly reduced nucleoprotein expression, suppressed microglial activation and decreased activation of caspase-3 in neurons and p38 phosphorylation in the brain. Collectively, these results suggest that MERS-CoV infection of CNS triggers complement activation, leading to inflammation-mediated damage of brain tissue, and regulating of complement activation could be a promising intervention and adjunctive treatment for CNS injury by MERS-CoV and other coronaviruses.


Subject(s)
Brain/pathology , Complement System Proteins/immunology , Coronavirus Infections/pathology , Dipeptidyl Peptidase 4/genetics , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Animals , Blood-Brain Barrier/immunology , Blood-Brain Barrier/pathology , Brain/blood supply , Brain/immunology , Brain/virology , Complement Activation/drug effects , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Models, Animal , Humans , Inflammation , Mice , Mice, Transgenic , Microglia/immunology , Microglia/pathology
6.
Nat Commun ; 12(1): 5654, 2021 09 27.
Article in English | MEDLINE | ID: covidwho-1440471

ABSTRACT

There is an urgent need for animal models to study SARS-CoV-2 pathogenicity. Here, we generate and characterize a novel mouse-adapted SARS-CoV-2 strain, MASCp36, that causes severe respiratory symptoms, and mortality. Our model exhibits age- and gender-related mortality akin to severe COVID-19. Deep sequencing identified three amino acid substitutions, N501Y, Q493H, and K417N, at the receptor binding domain (RBD) of MASCp36, during in vivo passaging. All three RBD mutations significantly enhance binding affinity to its endogenous receptor, ACE2. Cryo-electron microscopy analysis of human ACE2 (hACE2), or mouse ACE2 (mACE2), in complex with the RBD of MASCp36, at 3.1 to 3.7 Å resolution, reveals the molecular basis for the receptor-binding switch. N501Y and Q493H enhance the binding affinity to hACE2, whereas triple mutations at N501Y/Q493H/K417N decrease affinity and reduce infectivity of MASCp36. Our study provides a platform for studying SARS-CoV-2 pathogenesis, and unveils the molecular mechanism for its rapid adaptation and evolution.


Subject(s)
COVID-19/diagnosis , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/metabolism , Animals , Binding Sites/genetics , COVID-19/mortality , COVID-19/virology , Disease Models, Animal , Female , Humans , Male , Mice , Protein Binding/genetics , Protein Domains/genetics , SARS-CoV-2/genetics , Severity of Illness Index , Spike Glycoprotein, Coronavirus/genetics
7.
Virol Sin ; 36(6): 1484-1491, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1359969

ABSTRACT

The sudden emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) has caused global panic in 2003, and the risk of SARS-CoV outbreak still exists. However, no specific antiviral drug or vaccine is available; thus, the development of therapeutic antibodies against SARS-CoV is needed. In this study, a nanobody phage-displayed library was constructed from peripheral blood mononuclear cells of alpacas immunized with the recombinant receptor-binding domain (RBD) of SARS-CoV. Four positive clones were selected after four rounds of bio-panning and subjected to recombinant expression in E. coli. Further biological identification demonstrated that one of the nanobodies, S14, showed high affinity to SARS-CoV RBD and potent neutralization activity at the picomole level against SARS-CoV pseudovirus. A competitive inhibition assay showed that S14 blocked the binding of SARS-CoV RBD to either soluble or cell-expressed angiotensin-converting enzyme 2 (ACE2). In summary, we developed a novel nanobody targeting SARS-CoV RBD, which might be useful for the development of therapeutics against SARS.


Subject(s)
COVID-19 , SARS Virus , Antibodies, Neutralizing , Antibodies, Viral/metabolism , Escherichia coli/metabolism , Humans , Leukocytes, Mononuclear/metabolism , Protein Binding , SARS Virus/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
8.
J Virol ; 94(5)2020 02 14.
Article in English | MEDLINE | ID: covidwho-908

ABSTRACT

Antibody-dependent enhancement (ADE) of viral entry has been a major concern for epidemiology, vaccine development, and antibody-based drug therapy. However, the molecular mechanism behind ADE is still elusive. Coronavirus spike protein mediates viral entry into cells by first binding to a receptor on the host cell surface and then fusing viral and host membranes. In this study, we investigated how a neutralizing monoclonal antibody (MAb), which targets the receptor-binding domain (RBD) of Middle East respiratory syndrome (MERS) coronavirus spike, mediates viral entry using pseudovirus entry and biochemical assays. Our results showed that MAb binds to the virus surface spike, allowing it to undergo conformational changes and become prone to proteolytic activation. Meanwhile, MAb binds to cell surface IgG Fc receptor, guiding viral entry through canonical viral-receptor-dependent pathways. Our data suggest that the antibody/Fc-receptor complex functionally mimics viral receptor in mediating viral entry. Moreover, we characterized MAb dosages in viral-receptor-dependent, Fc-receptor-dependent, and both-receptors-dependent viral entry pathways, delineating guidelines on MAb usages in treating viral infections. Our study reveals a novel molecular mechanism for antibody-enhanced viral entry and can guide future vaccination and antiviral strategies.IMPORTANCE Antibody-dependent enhancement (ADE) of viral entry has been observed for many viruses. It was shown that antibodies target one serotype of viruses but only subneutralize another, leading to ADE of the latter viruses. Here we identify a novel mechanism for ADE: a neutralizing antibody binds to the surface spike protein of coronaviruses like a viral receptor, triggers a conformational change of the spike, and mediates viral entry into IgG Fc receptor-expressing cells through canonical viral-receptor-dependent pathways. We further evaluated how antibody dosages impacted viral entry into cells expressing viral receptor, Fc receptor, or both receptors. This study reveals complex roles of antibodies in viral entry and can guide future vaccine design and antibody-based drug therapy.


Subject(s)
Antibodies, Viral/immunology , Antibody-Dependent Enhancement , Middle East Respiratory Syndrome Coronavirus/immunology , Middle East Respiratory Syndrome Coronavirus/physiology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Cell Line , Dipeptidyl Peptidase 4/metabolism , Humans , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fab Fragments/metabolism , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Peptide Hydrolases/metabolism , Proprotein Convertases/antagonists & inhibitors , Proprotein Convertases/metabolism , Protein Conformation , Protein Domains , Protein Multimerization , Receptors, Fc/metabolism , Receptors, IgG/immunology , Receptors, IgG/metabolism , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Trypsin/metabolism
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