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1.
Clin J Am Soc Nephrol ; 16(11): 1755-1765, 2021 11.
Article in English | MEDLINE | ID: covidwho-1526737

ABSTRACT

Despite evidence of multiorgan tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with coronavirus disease 2019 (COVID-19), direct viral kidney invasion has been difficult to demonstrate. The question of whether SARS-CoV2 can directly infect the kidney is relevant to the understanding of pathogenesis of AKI and collapsing glomerulopathy in patients with COVID-19. Methodologies to document SARS-CoV-2 infection that have been used include immunohistochemistry, immunofluorescence, RT-PCR, in situ hybridization, and electron microscopy. In our review of studies to date, we found that SARS-CoV-2 in the kidneys of patients with COVID-19 was detected in 18 of 94 (19%) by immunohistochemistry, 71 of 144 (49%) by RT-PCR, and 11 of 84 (13%) by in situ hybridization. In a smaller number of patients with COVID-19 examined by immunofluorescence, SARS-CoV-2 was detected in 10 of 13 (77%). In total, in kidneys from 102 of 235 patients (43%), the presence of SARS-CoV-2 was suggested by at least one of the methods used. Despite these positive findings, caution is needed because many other studies have been negative for SARS-CoV-2 and it should be noted that when detected, it was only in kidneys obtained at autopsy. There is a clear need for studies from kidney biopsies, including those performed at early stages of the COVID-19-associated kidney disease. Development of tests to detect kidney viral infection in urine samples would be more practical as a noninvasive way to evaluate SARS-CoV-2 infection during the evolution of COVID-19-associated kidney disease.


Subject(s)
COVID-19/virology , Kidney Diseases/virology , Kidney/virology , SARS-CoV-2/pathogenicity , Animals , Biopsy , COVID-19/complications , COVID-19/diagnosis , COVID-19/mortality , COVID-19 Testing , Host-Pathogen Interactions , Humans , Kidney Diseases/diagnosis , Kidney Diseases/mortality , Predictive Value of Tests , Prognosis , Risk Assessment , Risk Factors
3.
Microbiol Spectr ; 9(2): e0135221, 2021 10 31.
Article in English | MEDLINE | ID: covidwho-1526454

ABSTRACT

The emerging new lineages of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have marked a new phase of coronavirus disease 2019 (COVID-19). Understanding the recognition mechanisms of potent neutralizing monoclonal antibodies (NAbs) against the spike protein is pivotal for developing new vaccines and antibody drugs. Here, we isolated several monoclonal antibodies (MAbs) against the SARS-CoV-2 spike protein receptor-binding domain (S-RBD) from the B cell receptor repertoires of a SARS-CoV-2 convalescent. Among these MAbs, the antibody nCoV617 demonstrates the most potent neutralizing activity against authentic SARS-CoV-2 infection, as well as prophylactic and therapeutic efficacies against the human angiotensin-converting enzyme 2 (ACE2) transgenic mouse model in vivo. The crystal structure of S-RBD in complex with nCoV617 reveals that nCoV617 mainly binds to the back of the "ridge" of RBD and shares limited binding residues with ACE2. Under the background of the S-trimer model, it potentially binds to both "up" and "down" conformations of S-RBD. In vitro mutagenesis assays show that mutant residues found in the emerging new lineage B.1.1.7 of SARS-CoV-2 do not affect nCoV617 binding to the S-RBD. These results provide a new human-sourced neutralizing antibody against the S-RBD and assist vaccine development. IMPORTANCE COVID-19 is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The COVID-19 pandemic has posed a serious threat to global health and the economy, so it is necessary to find safe and effective antibody drugs and treatments. The receptor-binding domain (RBD) in the SARS-CoV-2 spike protein is responsible for binding to the angiotensin-converting enzyme 2 (ACE2) receptor. It contains a variety of dominant neutralizing epitopes and is an important antigen for the development of new coronavirus antibodies. The significance of our research lies in the determination of new epitopes, the discovery of antibodies against RBD, and the evaluation of the antibodies' neutralizing effect. The identified antibodies here may be drug candidates for the development of clinical interventions for SARS-CoV-2.


Subject(s)
Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , COVID-19/therapy , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/metabolism , Antibodies, Viral/immunology , Antibodies, Viral/metabolism , Binding Sites/immunology , COVID-19 Vaccines/immunology , Crystallography, X-Ray , Disease Models, Animal , Female , Humans , Immunization, Passive/methods , Immunoglobulin G/blood , Mice , Mice, Inbred C57BL , Mice, Transgenic , Protein Interaction Domains and Motifs/immunology , Viral Load/drug effects
4.
J Infect Dis ; 224(3): 415-419, 2021 08 02.
Article in English | MEDLINE | ID: covidwho-1526165

ABSTRACT

Mutagenic ribonucleosides can act as broad-based antiviral agents. They are metabolized to the active ribonucleoside triphosphate form and concentrate in genomes of RNA viruses during viral replication. ß-d-N4-hydroxycytidine (NHC, initial metabolite of molnupiravir) is >100-fold more active than ribavirin or favipiravir against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with antiviral activity correlated to the level of mutagenesis in virion RNA. However, NHC also displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate highly active mutagenic ribonucleosides may hold risk for the host.


Subject(s)
Antiviral Agents/pharmacology , Cytidine/analogs & derivatives , Mutagens/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/adverse effects , CHO Cells/drug effects , Cells, Cultured , Cricetulus , Cytidine/adverse effects , Cytidine/pharmacology , Dose-Response Relationship, Drug , Mutagenesis/drug effects , Mutagens/adverse effects , SARS-CoV-2/genetics , Virus Replication/drug effects
5.
Cardiovasc Res ; 117(9): 2045-2053, 2021 07 27.
Article in English | MEDLINE | ID: covidwho-1526155

ABSTRACT

Although coronavirus disease 2019 seems to be the leading topic in research number of outstanding studies have been published in the field of aorta and peripheral vascular diseases likely affecting our clinical practice in the near future. This review article highlights key research on vascular diseases published in 2020. Some studies have shed light in the pathophysiology of aortic aneurysm and dissection suggesting a potential role for kinase inhibitors as new therapeutic options. A first proteogenomic study on fibromuscular dysplasia (FMD) revealed a promising novel disease gene and provided proof-of-concept for a protein/lipid-based FMD blood test. The role of NADPH oxidases in vascular physiology, and particularly endothelial cell differentiation, is highlighted with potential for cell therapy development. Imaging of vulnerable plaque has been an intense field of research. Features of plaque vulnerability on magnetic resonance imaging as an under-recognized cause of stroke are discussed. Major clinical trials on lower extremity peripheral artery disease have shown added benefit of dual antithrombotic (aspirin plus rivaroxaban) treatment.


Subject(s)
Aortic Diseases , Biomedical Research/trends , Peripheral Vascular Diseases , Animals , Aortic Diseases/diagnosis , Aortic Diseases/epidemiology , Aortic Diseases/genetics , Aortic Diseases/therapy , COVID-19 , Clinical Trials as Topic , Diffusion of Innovation , Humans , Peripheral Vascular Diseases/diagnosis , Peripheral Vascular Diseases/epidemiology , Peripheral Vascular Diseases/genetics , Peripheral Vascular Diseases/therapy , Prognosis
6.
Sci Total Environ ; 800: 149578, 2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1525945

ABSTRACT

In the current pandemic of COVID-19, sewage surveillance of SARS-CoV-2 genome has been used to complement viral epidemiology in different countries. The aim of this work was to introduce and evaluate this wastewater-based tool in the metropolitan region of Buenos Aires, Argentina. As a pilot study, surveillance of SARS-CoV-2 in wastewater from three districts of this area was performed for more than nine months from June 2020 to April 2021. Viruses present in the samples were concentrated using polyethylene glycol precipitation and quantified using RT-qPCR CDC N1 assay. Virus recovery for SARS-CoV-2 and a potential surrogate, bovine coronavirus Mebus strain, that shares the Betacoronavirus genus and structural characteristics with SARS-CoV-2, were evaluated after concentration and detection procedures. Recovery of both viruses did not differ significantly, with a median for SARS-CoV-2 and BCoV of 0.085 (95% CI: 0.021-0.179) and 0.262 (95% CI: 1.18 × 10-5-0.564) respectively. The concentration of SARS-CoV-2 genome in wastewater ranged from 10 -1 to 10 3 cg/ml, depending on the wastewater treatment plant, type of collection site, viral recovery of the concentration method and the epidemiological situation of the outbreaks. Significant correlations were observed between SARS-CoV-2 concentration in wastewater and reported clinical cases, reinforcing the utility of this approach to monitor the epidemiological status of populations.


Subject(s)
COVID-19 , Waste Water , Animals , Argentina/epidemiology , Cattle , Humans , Pilot Projects , SARS-CoV-2
7.
Biomed J ; 44(4): 504-507, 2021 08.
Article in English | MEDLINE | ID: covidwho-1525701

ABSTRACT

COVID-19, an infectious disease caused by a novel coronavirus (SARS-CoV-2) has emerged as global pandemic. Here, we described the changes in microbiota of upper respiratory tract by analyzing the publically available RNA sequencing data of SARS-CoV-2-infected ferrets. The bacterial dysbiosis due to SARS-CoV-2 was largely inversely proportional to the dysbiosis caused by influenza-A virus. The bacterial taxa which are defined as healthy ecostate were significantly reduced during SARS-CoV-2 infection. Altogether, this preliminary study provides a new insight on the possible role of bacterial communities of upper respiratory tract in determining the immunity, susceptibility, and mortality for COVID-19.


Subject(s)
COVID-19 , Microbiota , Animals , Dysbiosis , Ferrets , Humans , Microbiota/genetics , RNA , Respiratory System , SARS-CoV-2 , Sequence Analysis, RNA
8.
Theranostics ; 11(14): 7005-7017, 2021.
Article in English | MEDLINE | ID: covidwho-1524524

ABSTRACT

The tumor suppressor protein p53 remains in a wild type but inactive form in ~50% of all human cancers. Thus, activating it becomes an attractive approach for targeted cancer therapies. In this regard, our lab has previously discovered a small molecule, Inauhzin (INZ), as a potent p53 activator with no genotoxicity. Method: To improve its efficacy and bioavailability, here we employed nanoparticle encapsulation, making INZ-C, an analog of INZ, to nanoparticle-encapsulated INZ-C (n-INZ-C). Results: This approach significantly improved p53 activation and inhibition of lung and colorectal cancer cell growth by n-INZ-C in vitro and in vivo while it displayed a minimal effect on normal human Wi38 and mouse MEF cells. The improved activity was further corroborated with the enhanced cellular uptake observed in cancer cells and minimal cellular uptake observed in normal cells. In vivo pharmacokinetic evaluation of these nanoparticles showed that the nanoparticle encapsulation prolongates the half-life of INZ-C from 2.5 h to 5 h in mice. Conclusions: These results demonstrate that we have established a nanoparticle system that could enhance the bioavailability and efficacy of INZ-C as a potential anti-cancer therapeutic.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Indoles/pharmacology , Lung Neoplasms/drug therapy , Nanoparticles/chemistry , Phenothiazines/pharmacology , Tumor Suppressor Protein p53/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Biological Availability , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Indoles/therapeutic use , Mice , Mice, Inbred C57BL , Microscopy, Electron, Transmission , Nanoparticles/toxicity , Nanoparticles/ultrastructure , Phenothiazines/chemistry , Phenothiazines/pharmacokinetics , Phenothiazines/therapeutic use , Spectroscopy, Fourier Transform Infrared , Tumor Suppressor Protein p53/genetics , Xenograft Model Antitumor Assays
9.
Viruses ; 13(8)2021 08 23.
Article in English | MEDLINE | ID: covidwho-1524167

ABSTRACT

The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread despite the global efforts taken to control it. The 3C-like protease (3CLpro), the major protease of SARS-CoV-2, is one of the most interesting targets for antiviral drug development because it is highly conserved among SARS-CoVs and plays an important role in viral replication. Herein, we developed high throughput screening for SARS-CoV-2 3CLpro inhibitor based on AlphaScreen. We screened 91 natural product compounds and found that all-trans retinoic acid (ATRA), an FDA-approved drug, inhibited 3CLpro activity. The 3CLpro inhibitory effect of ATRA was confirmed in vitro by both immunoblotting and AlphaScreen with a 50% inhibition concentration (IC50) of 24.7 ± 1.65 µM. ATRA inhibited the replication of SARS-CoV-2 in VeroE6/TMPRSS2 and Calu-3 cells, with IC50 = 2.69 ± 0.09 µM in the former and 0.82 ± 0.01 µM in the latter. Further, we showed the anti-SARS-CoV-2 effect of ATRA on the currently circulating variants of concern (VOC); alpha, beta, gamma, and delta. These results suggest that ATRA may be considered as a potential therapeutic agent against SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , SARS-CoV-2/drug effects , Tretinoin/pharmacology , Animals , Cell Line, Tumor , Chlorocebus aethiops , Cysteine Proteinase Inhibitors/pharmacology , DEAD Box Protein 58/metabolism , High-Throughput Screening Assays , Humans , Receptors, Immunologic/metabolism , SARS-CoV-2/enzymology , SARS-CoV-2/physiology , Vero Cells , Virus Replication/drug effects
10.
Parasit Vectors ; 14(1): 282, 2021 May 26.
Article in English | MEDLINE | ID: covidwho-1523322

ABSTRACT

Trichinellosis is a foodborne disease caused by several Trichinella species around the world. In Chile, the domestic cycle was fairly well-studied in previous decades, but has been neglected in recent years. The aims of this study were to analyze, geographically, the incidence of trichinellosis in Chile to assess the relative risk and to analyze the incidence rate fluctuation in the last decades. Using temporal data spanning 1964-2019, as well as geographical data from 2010 to 2019, the time series of cases was analyzed with ARIMA models to explore trends and periodicity. The Dickey-Fuller test was used to study trends, and the Portmanteau test was used to study white noise in the model residuals. The Besag-York-Mollie (BYM) model was used to create Bayesian maps of the level of risk relative to that expected by the overall population. The association of the relative risk with the number of farmed swine was assessed with Spearman's correlation. The number of annual cases varied between 5 and 220 (mean: 65.13); the annual rate of reported cases varied between 0.03 and 1.9 cases per 105 inhabitants (mean: 0.53). The cases of trichinellosis in Chile showed a downward trend that has become more evident since the 1980s. No periodicities were detected via the autocorrelation function. Communes (the smallest geographical administrative subdivision) with high incidence rates and high relative risk were mostly observed in the Araucanía region. The relative risk of the commune was significantly associated with the number of farmed pigs and boar (Sus scrofa Linnaeus, 1758). The results allowed us to state that trichinellosis is not a (re)emerging disease in Chile, but the severe economic poverty rate of the Mapuche Indigenous peoples and the high number of backyard and free-ranging pigs seem to be associated with the high risk of trichinellosis in the Araucanía region.


Subject(s)
Swine Diseases/epidemiology , Trichinellosis/epidemiology , Animals , Bayes Theorem , Chile/epidemiology , Disease Outbreaks , Geographic Mapping , History, 20th Century , History, 21st Century , Incidence , Risk Assessment , Swine , Trichinella , Trichinellosis/history
11.
Genome ; 64(4): v-vii, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1523064
12.
mBio ; 12(2)2021 03 30.
Article in English | MEDLINE | ID: covidwho-1522913

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged virus that causes coronavirus infectious disease 2019 (COVID-19). SARS-CoV-2 spike protein, like SARS-CoV-1, uses the angiotensin converting enzyme 2 (ACE2) as a cellular receptor to initiate infection. Compounds that interfere with the SARS-CoV-2 spike protein receptor binding domain protein (RBD)-ACE2 receptor interaction may function as entry inhibitors. Here, we used a dual strategy of molecular docking and surface plasmon resonance (SPR) screening of compound libraries to identify those that bind to human ACE2 or the SARS-CoV-2 spike protein receptor binding domain (RBD). Molecular modeling screening interrogated 57,641 compounds and focused on the region of ACE2 that is engaged by RBD of the SARS-CoV-2 spike glycoprotein and vice versa. SPR screening used immobilized human ACE2 and SARS-CoV-2 Spike protein to evaluate the binding of these proteins to a library of 3,141 compounds. These combined screens identified compounds from these libraries that bind at KD (equilibrium dissociation constant) <3 µM affinity to their respective targets, 17 for ACE2 and 6 for SARS-CoV-2 RBD. Twelve ACE2 binders and six of the RBD binders compete with the RBD-ACE2 interaction in an SPR-based competition assay. These compounds included registered drugs and dyes used in biomedical applications. A Vero-E6 cell-based SARS-CoV-2 infection assay was used to evaluate infection blockade by candidate entry inhibitors. Three compounds demonstrated dose-dependent antiviral in vitro potency-Evans blue, sodium lifitegrast, and lumacaftor. This study has identified potential drugs for repurposing as SARS-CoV-2 entry inhibitors or as chemical scaffolds for drug development.IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, has caused more than 60 million cases worldwide with almost 1.5 million deaths as of November 2020. Repurposing existing drugs is the most rapid path to clinical intervention for emerging diseases. Using an in silico screen of 57,641 compounds and a biophysical screen of 3,141 compounds, we identified 22 compounds that bound to either the angiotensin converting enzyme 2 (ACE2) and/or the SARS-CoV-2 spike protein receptor binding domain (SARS-CoV-2 spike protein RBD). Nine of these drugs were identified by both screening methods. Three of the identified compounds, Evans blue, sodium lifitegrast, and lumacaftor, were found to inhibit viral replication in a Vero-E6 cell-based SARS-CoV-2 infection assay and may have utility as repurposed therapeutics. All 22 identified compounds provide scaffolds for the development of new chemical entities for the treatment of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , Spike Glycoprotein, Coronavirus/metabolism , Virus Attachment/drug effects , Virus Replication/drug effects , Aminopyridines/pharmacology , Animals , Benzodioxoles/pharmacology , Cell Line , Chlorocebus aethiops , Drug Evaluation, Preclinical , Drug Repositioning , Evans Blue/pharmacology , Humans , Molecular Docking Simulation , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacology , Protein Binding/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Sulfones/pharmacology , Surface Plasmon Resonance , Vero Cells
13.
Front Public Health ; 9: 751103, 2021.
Article in English | MEDLINE | ID: covidwho-1518576

ABSTRACT

The COVID-19 pandemic, which has ravaged the world, has led to a rethinking of the relationship between humans and nature and the clichés of the economic-centered model. Thus, the ecological economy has been reviewed, especially from an ethical worldview. This paper uses statistical methods to retrieve and categorize 3,646 wildlife crime cases for analysis and quantitative research. It adopts legal and ethical perspectives to analyze the subject and the subjective, incidence, and sentencing factors of wildlife crimes and uses the ecological economic ethical model to measure wildlife crimes. We argue that the existing judicial system fails to answer the difficulties of the economic ethics of wildlife crimes. It is recommended that ecological and economic ethical awareness be internalized. We suggest calling for comprehensive legislation on wildlife crimes from the perspective of ecological economic ethics to effectively prevent and reduce wildlife crime and eventually promote public health.


Subject(s)
Animals, Wild , COVID-19 , Animals , China/epidemiology , Crime , Humans , Pandemics , SARS-CoV-2
14.
Front Immunol ; 12: 770066, 2021.
Article in English | MEDLINE | ID: covidwho-1518490

ABSTRACT

Acute inflammation is a critical host defense response during viral infection. When dysregulated, inflammation drives immunopathology and tissue damage. Excessive, damaging inflammation is a hallmark of both pandemic influenza A virus (IAV) infections and Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infections. Chronic, low-grade inflammation is also a feature of obesity. In recent years, obesity has been recognized as a growing pandemic with significant mortality and associated costs. Obesity is also an independent risk factor for increased disease severity and death during both IAV and SARS-CoV-2 infection. This review focuses on the effect of obesity on the inflammatory response in the context of viral respiratory infections and how this leads to increased viral pathology. Here, we will review the fundamentals of inflammation, how it is initiated in IAV and SARS-CoV-2 infection and its link to disease severity. We will examine how obesity drives chronic inflammation and trained immunity and how these impact the immune response to IAV and SARS-CoV-2. Finally, we review both medical and non-medical interventions for obesity, how they impact on the inflammatory response and how they could be used to prevent disease severity in obese patients. As projections of global obesity numbers show no sign of slowing down, future pandemic preparedness will require us to consider the metabolic health of the population. Furthermore, if weight-loss alone is insufficient to reduce the risk of increased respiratory virus-related mortality, closer attention must be paid to a patient's history of health, and new therapeutic options identified.


Subject(s)
COVID-19/immunology , Inflammation/immunology , Influenza A virus , Influenza, Human/immunology , Obesity/immunology , SARS-CoV-2 , Animals , Humans , Severity of Illness Index
15.
Front Immunol ; 12: 741218, 2021.
Article in English | MEDLINE | ID: covidwho-1518486

ABSTRACT

The global outbreak of the SARS-Cov-2 virus in 2020 has killed millions of people worldwide and forced large parts of the world into lockdowns. While multiple vaccine programs are starting to immunize the global population, there is no direct cure for COVID-19, the disease caused by the SARS-Cov-2 infection. A common symptom in patients is a decrease in T cells, called lymphopenia. It is as of yet unclear what the exact role of T cells are in the immune response to COVID-19. The research so far has mainly focused on the involvement of classical αß T cells. However, another subset of T cells called γδ T cells could have an important role to play. As part of the innate immune system, γδ T cells respond to inflammation and stressed or infected cells. The γδ T cell subset appears to be particularly affected by lymphopenia in COVID-19 patients and commonly express activation and exhaustion markers. Particularly in children, this subset of T cells seems to be most affected. This is interesting and relevant because γδ T cells are more prominent and active in early life. Their specific involvement in this group of patients could indicate a significant role for γδ T cells in this disease. Furthermore, they seem to be involved in other viral infections and were able to kill SARS infected cells in vitro. γδ T cells can take up, process and present antigens from microbes and human cells. As e.g. tumour-associated antigens are presented by MHC on γδ T cells to classical T-cells, we argue here that it stands to reason that also viral antigens, such as SARS-Cov-2-derived peptides, can be presented in the same way. γδ T cells are already used for medical purposes in oncology and have potential in cancer therapy. As γδ T cells are not necessarily able to distinguish between a transformed and a virally infected cell it could therefore be of great interest to investigate further the relationship between COVID-19 and γδ T cells.


Subject(s)
COVID-19/immunology , Intraepithelial Lymphocytes/immunology , SARS-CoV-2 , Animals , Cytokine Release Syndrome/immunology , Humans , Neoplasms/immunology , Pulmonary Fibrosis/immunology
16.
J Vet Med Sci ; 83(11): 1722-1725, 2021 Nov 16.
Article in English | MEDLINE | ID: covidwho-1518345

ABSTRACT

We investigated the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among dogs in the Tokyo area via enzyme-linked immunosorbent assay (ELISA) using the spike protein as the target antigen. Plasma samples from 494 household dogs and blood-donor dogs were tested from July 2020 to January 2021. Of these samples, three showed optical densities that were higher than the mean plus two standard deviations of the mean of the negative-control optical densities (ODs). Of these three samples, only the sample with the highest OD by ELISA was confirmed positive by virus neutralization testing. The positive dog presented no SARS-CoV-2-related symptoms. The positivity rate of SARS-CoV-2 infections among dogs in the Tokyo area was approximately 0.2%.


Subject(s)
COVID-19 , Dog Diseases , Animals , Antibodies, Viral , COVID-19/veterinary , Dog Diseases/epidemiology , Dogs , Enzyme-Linked Immunosorbent Assay/veterinary , Japan/epidemiology , SARS-CoV-2 , Seroepidemiologic Studies , Spike Glycoprotein, Coronavirus
18.
Cell Rep ; 37(3): 109869, 2021 10 19.
Article in English | MEDLINE | ID: covidwho-1517084

ABSTRACT

The dramatically expanding coronavirus disease 2019 (COVID-19) needs multiple effective countermeasures. Neutralizing nanobodies (Nbs) are a potential therapeutic strategy for treating COVID-19. Here, we characterize several receptor binding domain (RBD)-specific Nbs isolated from an Nb library derived from an alpaca immunized with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S); among them, three Nbs exhibit picomolar potency against SARS-CoV-2 live virus, pseudotyped viruses, and circulating SARS-CoV-2 variants. To improve their efficacy, various configurations of Nbs are engineered. Nb15-NbH-Nb15, a trimer constituted of three Nbs, is constructed to be bispecific for human serum albumin (HSA) and RBD of SARS-CoV-2. Nb15-NbH-Nb15 exhibits single-digit ng/ml neutralization potency against the wild-type and Delta variants of SARS-CoV-2 with a long half-life in vivo. In addition, we show that intranasal administration of Nb15-NbH-Nb15 provides effective protection for both prophylactic and therapeutic purposes against SARS-CoV-2 infection in transgenic hACE2 mice. Nb15-NbH-Nb15 is a potential candidate for both the prevention and treatment of SARS-CoV-2 through respiratory administration.


Subject(s)
Administration, Intranasal , Angiotensin-Converting Enzyme 2/immunology , Antibodies, Bispecific/immunology , COVID-19/immunology , SARS-CoV-2 , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Neutralizing , Antibodies, Viral/immunology , Camelids, New World , Epitopes/chemistry , Female , Humans , Kinetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neutralization Tests , Protein Binding , Protein Domains , Protein Engineering/methods , Serum Albumin, Human/chemistry , Single-Domain Antibodies , Spike Glycoprotein, Coronavirus/immunology
19.
Cell Rep ; 37(3): 109838, 2021 10 19.
Article in English | MEDLINE | ID: covidwho-1517083

ABSTRACT

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads, variants with enhanced virulence and transmissibility have emerged. Although in vitro systems allow rapid characterization, they do not fully recapitulate the dynamic interaction of virions and neutralizing antibodies in the airway. Here, we demonstrate that the N501Y variant permits respiratory infection in unmodified mice. We utilize N501Y to survey in vivo pseudovirus infection dynamics and susceptibility to reinfection with the L452R (Los Angeles), K417N + E484K (South Africa), and L452R + K417N + E484Q (India) variants. Human coronavirus disease 2019 (COVID-19)+ or vaccinated antibody isotypes, titers, variant receptor binding domain (RBD) binding, and neutralization potential are studied, revealing numerous significant correlations. Immune escape of the K417N + E484K variant is observed because infection can be appreciated in the nasopharynx, but not lungs, of mice transferred with low-antibody-tier plasma. Conversely, near-complete protection is observed in animals receiving high-antibody-tier plasma, a phenomenon that can only be appreciated in vivo.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/therapy , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Cell Line , Cricetinae , Genetic Variation , HEK293 Cells , Humans , Immune System , Immunization, Passive/methods , In Vitro Techniques , Mice , Mutation , Nasopharynx/virology , Protein Binding , Recombinant Proteins/metabolism , Spike Glycoprotein, Coronavirus/genetics
20.
Comp Med ; 71(5): 359-368, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1515728

ABSTRACT

The significant advances made by the global scientific community during the COVID-19 pandemic, exemplified by the development of multiple SARS-CoV-2 vaccines in less than 1 y, were made possible in part because of animal research. Historically, animals have been used to study the characterization, treatment, and prevention of most of the major infectious disease outbreaks that humans have faced. From the advent of modern 'germ theory' prior to the 1918 Spanish Flu pandemic through the more recent Ebola and Zika virus outbreaks, research that uses animals has revealed or supported key discoveries in disease pathogenesis and therapy development, helping to save lives during crises. Here we summarize the role of animal research in past pandemic and epidemic response efforts, as well as current and future considerations for animal research in the context of infectious disease research.


Subject(s)
Animal Experimentation , COVID-19 , Influenza Pandemic, 1918-1919 , Zika Virus Infection , Zika Virus , Animals , COVID-19 Vaccines , History, 20th Century , Humans , Pandemics/prevention & control , SARS-CoV-2
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