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1.
Science ; 371(6530): 735-741, 2021 02 12.
Article in English | MEDLINE | ID: covidwho-1066809

ABSTRACT

Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-related emergent zoonotic coronaviruses is urgently needed. We made homotypic nanoparticles displaying the receptor binding domain (RBD) of SARS-CoV-2 or co-displaying SARS-CoV-2 RBD along with RBDs from animal betacoronaviruses that represent threats to humans (mosaic nanoparticles with four to eight distinct RBDs). Mice immunized with RBD nanoparticles, but not soluble antigen, elicited cross-reactive binding and neutralization responses. Mosaic RBD nanoparticles elicited antibodies with superior cross-reactive recognition of heterologous RBDs relative to sera from immunizations with homotypic SARS-CoV-2-RBD nanoparticles or COVID-19 convalescent human plasmas. Moreover, after priming, sera from mosaic RBD-immunized mice neutralized heterologous pseudotyped coronaviruses as well as or better than sera from homotypic SARS-CoV-2-RBD nanoparticle immunizations, demonstrating no loss of immunogenicity against particular RBDs resulting from co-display. A single immunization with mosaic RBD nanoparticles provides a potential strategy to simultaneously protect against SARS-CoV-2 and emerging zoonotic coronaviruses.


Subject(s)
Antibodies, Viral/immunology , Betacoronavirus/immunology , Nanoparticles , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Coronavirus Infections/immunology , Cross Reactions , Enzyme-Linked Immunosorbent Assay , Female , Immune Sera/immunology , Immunization , Immunoglobulin G/blood , Immunoglobulin G/immunology , Mice , Mice, Inbred BALB C , Neutralization Tests , Protein Domains , Receptors, Antigen, B-Cell/immunology , Spike Glycoprotein, Coronavirus/chemistry , /virology
2.
Int J Mol Sci ; 22(3)2021 Jan 28.
Article in English | MEDLINE | ID: covidwho-1055069

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel epidemic strain of Betacoronavirus that is responsible for the current viral pandemic, coronavirus disease 2019 (COVID-19), a global health crisis. Other epidemic Betacoronaviruses include the 2003 SARS-CoV-1 and the 2009 Middle East Respiratory Syndrome Coronavirus (MERS-CoV), the genomes of which, particularly that of SARS-CoV-1, are similar to that of the 2019 SARS-CoV-2. In this extensive review, we document the most recent information on Coronavirus proteins, with emphasis on the membrane proteins in the Coronaviridae family. We include information on their structures, functions, and participation in pathogenesis. While the shared proteins among the different coronaviruses may vary in structure and function, they all seem to be multifunctional, a common theme interconnecting these viruses. Many transmembrane proteins encoded within the SARS-CoV-2 genome play important roles in the infection cycle while others have functions yet to be understood. We compare the various structural and nonstructural proteins within the Coronaviridae family to elucidate potential overlaps and parallels in function, focusing primarily on the transmembrane proteins and their influences on host membrane arrangements, secretory pathways, cellular growth inhibition, cell death and immune responses during the viral replication cycle. We also offer bioinformatic analyses of potential viroporin activities of the membrane proteins and their sequence similarities to the Envelope (E) protein. In the last major part of the review, we discuss complement, stimulation of inflammation, and immune evasion/suppression that leads to CoV-derived severe disease and mortality. The overall pathogenesis and disease progression of CoVs is put into perspective by indicating several stages in the resulting infection process in which both host and antiviral therapies could be targeted to block the viral cycle. Lastly, we discuss the development of adaptive immunity against various structural proteins, indicating specific vulnerable regions in the proteins. We discuss current CoV vaccine development approaches with purified proteins, attenuated viruses and DNA vaccines.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/metabolism , Viral Matrix Proteins/metabolism , Animals , Betacoronavirus/genetics , Betacoronavirus/immunology , /metabolism , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Genome, Viral , Host-Pathogen Interactions , Humans , Immune Evasion , Protein Interaction Maps , /immunology , Viral Matrix Proteins/genetics , Viral Matrix Proteins/immunology , Virus Internalization , Virus Replication
3.
Science ; 371(6531): 823-829, 2021 02 19.
Article in English | MEDLINE | ID: covidwho-1048643

ABSTRACT

The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope that overlaps the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate against clade 1 sarbecoviruses.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Viral/immunology , Betacoronavirus/immunology , Broadly Neutralizing Antibodies/immunology , Spike Glycoprotein, Coronavirus/immunology , /metabolism , Animals , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/metabolism , Antibodies, Viral/genetics , Antibodies, Viral/metabolism , Antibody Affinity , Binding Sites , Binding Sites, Antibody , Broadly Neutralizing Antibodies/genetics , Broadly Neutralizing Antibodies/metabolism , /therapy , Cell Surface Display Techniques , Directed Molecular Evolution , Epitopes/immunology , Humans , Immunization, Passive , Immunoglobulin Fc Fragments/immunology , Mice, Inbred BALB C , Protein Domains , Protein Engineering , SARS Virus/immunology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/prevention & control , Severe Acute Respiratory Syndrome/therapy , Spike Glycoprotein, Coronavirus/metabolism
4.
J Exp Med ; 218(3)2021 03 01.
Article in English | MEDLINE | ID: covidwho-1044017

ABSTRACT

SARS-CoV-2, the causative agent of COVID-19, has been responsible for over 42 million infections and 1 million deaths since its emergence in December 2019. There are few therapeutic options and no approved vaccines. Here, we examine the properties of highly potent human monoclonal antibodies (hu-mAbs) in a Syrian hamster model of SARS-CoV-2 and in a mouse-adapted model of SARS-CoV-2 infection (SARS-CoV-2 MA). Antibody combinations were effective for prevention and in therapy when administered early. However, in vitro antibody neutralization potency did not uniformly correlate with in vivo protection, and some hu-mAbs were more protective in combination in vivo. Analysis of antibody Fc regions revealed that binding to activating Fc receptors contributes to optimal protection against SARS-CoV-2 MA. The data indicate that intact effector function can affect hu-mAb protective activity and that in vivo testing is required to establish optimal hu-mAb combinations for COVID-19 prevention.


Subject(s)
Antibodies, Monoclonal, Murine-Derived , Antibodies, Neutralizing , Antibodies, Viral , Betacoronavirus/immunology , Coronavirus Infections , Pandemics , Pneumonia, Viral , Animals , Antibodies, Monoclonal, Murine-Derived/immunology , Antibodies, Monoclonal, Murine-Derived/pharmacology , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/pharmacology , Antibodies, Viral/immunology , Antibodies, Viral/pharmacology , Cell Line , Coronavirus Infections/immunology , Coronavirus Infections/therapy , Female , Humans , Mesocricetus , Mice , Mice, Inbred BALB C , Pneumonia, Viral/immunology , Pneumonia, Viral/therapy
5.
Cell ; 182(4): 828-842.e16, 2020 08 20.
Article in English | MEDLINE | ID: covidwho-1027977

ABSTRACT

Neutralizing antibody responses to coronaviruses mainly target the receptor-binding domain (RBD) of the trimeric spike. Here, we characterized polyclonal immunoglobulin Gs (IgGs) and Fabs from COVID-19 convalescent individuals for recognition of coronavirus spikes. Plasma IgGs differed in their focus on RBD epitopes, recognition of alpha- and beta-coronaviruses, and contributions of avidity to increased binding/neutralization of IgGs over Fabs. Using electron microscopy, we examined specificities of polyclonal plasma Fabs, revealing recognition of both S1A and RBD epitopes on SARS-CoV-2 spike. Moreover, a 3.4 Å cryo-electron microscopy (cryo-EM) structure of a neutralizing monoclonal Fab-spike complex revealed an epitope that blocks ACE2 receptor binding. Modeling based on these structures suggested different potentials for inter-spike crosslinking by IgGs on viruses, and characterized IgGs would not be affected by identified SARS-CoV-2 spike mutations. Overall, our studies structurally define a recurrent anti-SARS-CoV-2 antibody class derived from VH3-53/VH3-66 and similarity to a SARS-CoV VH3-30 antibody, providing criteria for evaluating vaccine-elicited antibodies.


Subject(s)
Antibodies, Neutralizing/chemistry , Betacoronavirus/chemistry , Coronavirus Infections/immunology , Immunoglobulin Fab Fragments/chemistry , Immunoglobulin G/chemistry , Pneumonia, Viral/immunology , Spike Glycoprotein, Coronavirus/chemistry , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/immunology , Antibodies, Viral/isolation & purification , Betacoronavirus/immunology , Coronavirus Infections/blood , Coronavirus Infections/therapy , Cross Reactions , Cryoelectron Microscopy , Epitope Mapping , Epitopes , Humans , Immunization, Passive , Immunoglobulin Fab Fragments/blood , Immunoglobulin Fab Fragments/isolation & purification , Immunoglobulin Fab Fragments/ultrastructure , Immunoglobulin G/blood , Immunoglobulin G/isolation & purification , Immunoglobulin G/ultrastructure , Middle East Respiratory Syndrome Coronavirus/chemistry , Middle East Respiratory Syndrome Coronavirus/immunology , Models, Molecular , Pandemics , Pneumonia, Viral/blood , SARS Virus/chemistry , SARS Virus/immunology , Spike Glycoprotein, Coronavirus/immunology
15.
Int J Mol Sci ; 21(21)2020 Oct 30.
Article in English | MEDLINE | ID: covidwho-983342

ABSTRACT

The 2019 novel coronavirus [2019-nCoV], which started to spread from December 2019 onwards, caused a global pandemic. Besides being responsible for the severe acute respiratory syndrome 2 [SARS-CoV-2], the virus can affect other organs causing various symptoms. A close relationship between SARS-CoV-2 and the cardiovascular system has been shown, demonstrating an epidemiological linkage between SARS-CoV-2 and cardiac injury. There are emerging data regarding possible direct myocardial damage by 2019-nCoV. In this review, the most important available evidences will be discussed to clarify the precise mechanisms of cardiovascular injury in SARS-CoV-2 patients, even if further researches are needed.


Subject(s)
Cardiovascular Diseases/etiology , Coronavirus Infections/complications , Pneumonia, Viral/complications , Animals , Betacoronavirus/immunology , Cardiovascular Diseases/epidemiology , Coronavirus Infections/immunology , Humans , Pandemics , Pneumonia, Viral/immunology
16.
EBioMedicine ; 61: 103069, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-983306

ABSTRACT

BACKGROUND: Italy was the first western country to experience a large Coronavirus Disease 2019 (COVID-19) outbreak and the province of Bergamo experienced one of the deadliest COVID-19 outbreaks in the world. Following the peak of the epidemic in mid-March, the curve has slowly fallen thanks to the strict lockdown imposed by the Italian government on 9th March 2020. METHODS: We performed a cross-sectional study to assess the prevalence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in 423 workers in Bergamo province who returned to the workplace after the end of the Italian lockdown on 5th May 2020. To this end, we performed an enzyme-linked immunosorbent assay (ELISA) to detect the humoral response against SARS-CoV-2 and a nasopharyngeal swab to assess the presence of SARS-CoV-2 RNA by real-time reverse transcription polymerase chain reaction (rRT-PCR). As a secondary aim of the study, we validated a lateral flow immunochromatography assay (LFIA) for the detection of anti-SARS-CoV-2 antibodies. FINDINGS: ELISA identified 38.5% positive subjects, of whom 51.5% were positive for both IgG and IgM, 47.3% were positive only for IgG, but only 1.2% were positive for IgM alone. Only 23 (5.4%) participants tested positive for SARS-CoV-2 by rRT-PCR, although with high cycle thresholds (between 34 and 39), indicating a very low residual viral load that was not able to infect cultured cells. All these rRT-PCR positive subjects had already experienced seroconversion. When the ELISA was used as the comparator, the estimated specificity and sensitivity of the rapid LFIA for IgG were 98% and 92%, respectively. INTERPRETATION: the prevalence of SARS-CoV-2 infection in the province of Bergamo reached 38.5%, significantly higher than has been reported for most other regions worldwide. Few nasopharyngeal swabs tested positive in fully recovered subjects, though with a very low SARS-CoV-2 viral load, with implications for infectivity and discharge policies for positive individuals in the post-pandemic period. The rapid LFIA used in this study is a valuable tool for rapid serologic surveillance of COVID-19 for population studies. FUNDING: The study was supported by Regione Lombardia, Milano Serravalle - Milano Tangenziali S.p.A., Brembo S.p.A, and by MEI System.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/genetics , Betacoronavirus/immunology , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , RNA, Viral/metabolism , Adult , Betacoronavirus/isolation & purification , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Cross-Sectional Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Italy/epidemiology , Male , Middle Aged , Nasopharynx/virology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , RNA, Viral/genetics , Real-Time Polymerase Chain Reaction , Viral Load
17.
Viruses ; 12(10)2020 10 10.
Article in English | MEDLINE | ID: covidwho-983008

ABSTRACT

Herd immunity is the most critical and essential prophylactic intervention that delivers protection against infectious diseases at both the individual and community level. This process of natural vaccination is immensely pertinent to the current context of a pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection around the globe. The conventional idea of herd immunity is based on efficient transmission of pathogens and developing natural immunity within a population. This is entirely encouraging while fighting against any disease in pandemic circumstances. A spatial community is occupied by people having variable resistance capacity against a pathogen. Protection efficacy against once very common diseases like smallpox, poliovirus or measles has been possible only because of either natural vaccination through contagious infections or expanded immunization programs among communities. This has led to achieving herd immunity in some cohorts. The microbiome plays an essential role in developing the body's immune cells for the emerging competent vaccination process, ensuring herd immunity. Frequency of interaction among microbiota, metabolic nutrients and individual immunity preserve the degree of vaccine effectiveness against several pathogens. Microbiome symbiosis regulates pathogen transmissibility and the success of vaccination among different age groups. Imbalance of nutrients perturbs microbiota and abrogates immunity. Thus, a particular population can become vulnerable to the infection. Intestinal dysbiosis leads to environmental enteropathy (EE). As a consequence, the generation of herd immunity can either be delayed or not start in a particular cohort. Moreover, disparities of the protective response of many vaccines in developing countries outside of developed countries are due to inconsistencies of healthy microbiota among the individuals. We suggested that pan-India poliovirus vaccination program, capable of inducing herd immunity among communities for the last 30 years, may also influence the inception of natural course of heterologous immunity against SARS-CoV-2 infection. Nonetheless, this anamnestic recall is somewhat counterintuitive, as antibody generation against original antigens of SARS-CoV-2 will be subdued due to original antigenic sin.


Subject(s)
Immunity, Herd , Microbiota , Virus Diseases/immunology , Virus Diseases/microbiology , Betacoronavirus/immunology , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/microbiology , Coronavirus Infections/transmission , Dysbiosis/immunology , Humans , Immunity, Heterologous , Immunity, Innate , Microbiota/immunology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/microbiology , Pneumonia, Viral/transmission , Vaccination , Virus Diseases/epidemiology , Virus Diseases/transmission
18.
Zool Res ; 41(6): 621-631, 2020 11 18.
Article in English | MEDLINE | ID: covidwho-982982

ABSTRACT

Understanding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clarifying antiviral immunity in hosts are critical aspects for the development of vaccines and antivirals. Mice are frequently used to generate animal models of infectious diseases due to their convenience and ability to undergo genetic manipulation. However, normal adult mice are not susceptible to SARS-CoV-2. Here, we developed a viral receptor (human angiotensin-converting enzyme 2, hACE2) pulmonary transfection mouse model to establish SARS-CoV-2 infection rapidly in the mouse lung. Based on the model, the virus successfully infected the mouse lung 2 days after transfection. Viral RNA/protein, innate immune cell infiltration, inflammatory cytokine expression, and pathological changes in the infected lungs were observed after infection. Further studies indicated that neutrophils were the first and most abundant leukocytes to infiltrate the infected lungs after viral infection. In addition, using infected CXCL5-knockout mice, chemokine CXCL5 was responsible for neutrophil recruitment. CXCL5 knockout decreased lung inflammation without diminishing viral clearance, suggesting a potential target for controlling pneumonia.


Subject(s)
Betacoronavirus/immunology , Chemokine CXCL5/immunology , Coronavirus Infections/immunology , Immunity, Innate/immunology , Neutrophils/immunology , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/immunology , Animals , Betacoronavirus/genetics , Betacoronavirus/physiology , Cell Line , Chemokine CXCL5/genetics , Chemokine CXCL5/metabolism , Coronavirus Infections/genetics , Coronavirus Infections/virology , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Humans , Male , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Neutrophils/metabolism , Neutrophils/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/genetics , Pneumonia, Viral/virology
19.
J Med Internet Res ; 22(10): e19152, 2020 10 30.
Article in English | MEDLINE | ID: covidwho-982931

ABSTRACT

BACKGROUND: Real-time polymerase chain reaction (RT-PCR) testing for the identification of viral nucleic acid is the current standard for the diagnosis of SARS-CoV-2 infection, but technical issues limit its utilization for large-scale screening. Serological immunoglobulin M (IgM)/IgG testing has been proposed as a useful tool for detecting SARS-CoV-2 exposure. OBJECTIVE: The objective of our study was to compare the results of the rapid serological VivaDiag test for SARS-CoV-2-related IgM/IgG detection with those of the standard RT-PCR laboratory test for identifying SARS-CoV-2 nucleic acid. METHODS: We simultaneously performed both serological and molecular tests with a consecutive series of 191 symptomatic patients. The results provided by a new rapid serological colorimetric test for analyzing IgM/IgG expression were compared with those of RT-PCR testing for SARS-CoV-2 detection. RESULTS: Of the 191 subjects, 70 (36.6%) tested positive for SARS-CoV-2 based on RT-PCR results, while 34 (17.3%) tested positive based on serological IgM/IgG expression. Additionally, 13 (6.8%) subjects tested positive based on serological test results, but also tested negative based on RT-PCR results. The rapid serological test had a sensitivity of 30% and a specificity of 89% compared to the standard RT-PCR assay. Interestingly, the performance of both assays improved 8 days after symptom appearance. After 10 days had passed since symptom appearance, the predictive value of the rapid serological test was higher than that of the standard molecular assay (proportion of positive results: 40% vs 20%). Multivariate analysis showed that age >58 years (P<.01) and period of >15 days after symptom onset (P<.02) were significant and independent factors associated with serological test positivity. CONCLUSIONS: The rapid serological test analyzed in this study seems limited in terms of usefulness when diagnosing SARS-CoV-2 infection. However, it may be useful for providing relevant information on people's immunoreaction to COVID-19 exposure.


Subject(s)
Betacoronavirus/immunology , Betacoronavirus/isolation & purification , Clinical Laboratory Techniques/methods , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Real-Time Polymerase Chain Reaction/methods , Serologic Tests/methods , Betacoronavirus/genetics , Coronavirus Infections/immunology , Female , Humans , Immunoglobulin G/analysis , Immunoglobulin G/immunology , Immunoglobulin M/analysis , Immunoglobulin M/immunology , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology , Sensitivity and Specificity
20.
Medicina (Kaunas) ; 56(10)2020 Oct 05.
Article in English | MEDLINE | ID: covidwho-982923

ABSTRACT

The clinical spectrum of novel coronavirus infection appears to be wide, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia, with respiratory failure and even death. Autoantibodies, especially antiphospholipid antibodies, can occur in severe infections. Other autoantibodies are seldom reported. Here, a 60-year-old female patient without dry-mouth symptoms detected positive for anti-60 kDa SSA/Ro antibodies on day 43 after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To investigate this unique clinical case of SARS-CoV-2 infection, immunological characteristics of this case were detected by using flow cytometry and were compared to the other three groups of patients-health subjects, 2019 novel coronavirus disease (COVID-19) recovery patients, and Sjögren's syndrome (SS) patients. Monitoring the autoantibody level and the development of subsequently related autoimmune diseases are warranted after SARS-CoV-2 infection.


Subject(s)
Antibodies, Antinuclear/immunology , Antibodies, Viral/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Immunophenotyping , Pneumonia, Viral/immunology , Female , Flow Cytometry , Humans , Middle Aged , Pandemics , Sjogren's Syndrome
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