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1.
Nat Commun ; 12(1): 7345, 2021 12 20.
Article in English | MEDLINE | ID: covidwho-1585860

ABSTRACT

The emergence of SARS-CoV-2 Kappa and Beta variants with enhanced transmissibility and resistance to neutralizing antibodies has created new challenges for the control of the ongoing COVID-19 pandemic. Understanding the structural nature of Kappa and Beta spike (S) proteins and their association with ACE2 is of significant importance. Here we present two cryo-EM structures for each of the Kappa and Beta spikes in the open and open-prone transition states. Compared with wild-type (WT) or G614 spikes, the two variant spikes appear more untwisted/open especially for Beta, and display a considerable population shift towards the open state as well as more pronounced conformational dynamics. Moreover, we capture four conformational states of the S-trimer/ACE2 complex for each of the two variants, revealing an enlarged conformational landscape for the Kappa and Beta S-ACE2 complexes and pronounced population shift towards the three RBDs up conformation. These results implicate that the mutations in Kappa and Beta may modify the kinetics of receptor binding and viral fusion to improve virus fitness. Combined with biochemical analysis, our structural study shows that the two variants are enabled to efficiently interact with ACE2 receptor despite their sensitive ACE2 binding surface is modified to escape recognition by some potent neutralizing MAbs. Our findings shed new light on the pathogenicity and immune evasion mechanism of the Beta and Kappa variants.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Cryoelectron Microscopy , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Antibodies, Neutralizing/immunology , Binding Sites , COVID-19 , Humans , Kinetics , Molecular Conformation , Mutation , Protein Binding
2.
Emerg Microbes Infect ; : 1-51, 2021 Dec 29.
Article in English | MEDLINE | ID: covidwho-1585238

ABSTRACT

The emergence of multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of currently approved vaccines and authorized therapeutic monoclonal antibodies (MAbs). It is hence important to continue searching for SARS-CoV-2 broadly neutralizing MAbs and defining their epitopes. Here, we isolate 9 neutralizing mouse MAbs raised against the spike protein of a SARS-CoV-2 prototype strain and evaluate their neutralizing potency towards a panel of variants, including B.1.1.7, B.1.351, B.1.617.1, and B.1.617.2. By using a combination of biochemical, virological, and cryo-EM structural analyses, we identify three types of cross-variant neutralizing MAbs, represented by S5D2, S5G2, and S3H3, respectively, and further define their epitopes. S5D2 binds the top lateral edge of the receptor-binding motif within the receptor-binding domain (RBD) with a binding footprint centered around the loop477-489, and efficiently neutralizes all variant pseudoviruses, but the potency against B.1.617.2 was observed to decrease significantly. S5G2 targets the highly conserved RBD core region and exhibits comparable neutralization towards the variant panel. S3H3 binds a previously unreported epitope located within the evolutionarily stable SD1 region and is able to near equally neutralize all of the variants tested. Our work thus defines three distinct cross-variant neutralizing sites on the SARS-CoV-2 spike protein, providing guidance for design and development of broadly effective vaccines and MAb-based therapies.

3.
Cell Rep ; 38(3): 110271, 2022 Jan 18.
Article in English | MEDLINE | ID: covidwho-1588135

ABSTRACT

The utility of the urinary proteome in infectious diseases remains unclear. Here, we analyzed the proteome and metabolome of urine and serum samples from patients with COVID-19 and healthy controls. Our data show that urinary proteins effectively classify COVID-19 by severity. We detect 197 cytokines and their receptors in urine, but only 124 in serum using TMT-based proteomics. The decrease in urinary ESCRT complex proteins correlates with active SARS-CoV-2 replication. The downregulation of urinary CXCL14 in severe COVID-19 cases positively correlates with blood lymphocyte counts. Integrative multiomics analysis suggests that innate immune activation and inflammation triggered renal injuries in patients with COVID-19. COVID-19-associated modulation of the urinary proteome offers unique insights into the pathogenesis of this disease. This study demonstrates the added value of including the urinary proteome in a suite of multiomics analytes in evaluating the immune pathobiology and clinical course of COVID-19 and, potentially, other infectious diseases.

4.
EBioMedicine ; 75: 103789, 2021 Dec 24.
Article in English | MEDLINE | ID: covidwho-1587925

ABSTRACT

BACKGROUND: The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients with severe COVID-19, who were recruited in our previous UC-MSC clinical trial. METHODS: In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6 min walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102). FINDINGS: MSC administration improved in whole-lung lesion volume compared with the placebo with a difference of -10.8% (95% CI: -20.7%, -1.5%, p = 0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point. More interestingly, 17.9% (10/56) of patients in the MSC group had normal CT images at month 12, but none in the placebo group (p = 0.013). The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time. Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.6%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups. INTERPRETATION: UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients. FUNDING: The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.

5.
Preprint in English | EuropePMC | ID: ppcovidwho-293976

ABSTRACT

Severe COVID-19 patients account for most of the mortality of this disease. Early detection and effective treatment of severe patients remain major challenges. Here, we performed proteomic and metabolomic profiling of sera from 46 COVID-19 and 53 control individuals. We then trained a machine learning model using proteomic and metabolomic measurements from a training cohort of 18 non-severe and 13 severe patients. The model correctly classified severe patients with an accuracy of 93.5%, and was further validated using ten independent patients, seven of which were correctly classified. We identified molecular changes in the sera of COVID-19 patients implicating dysregulation of macrophage, platelet degranulation and complement system pathways, and massive metabolic suppression. This study shows that it is possible to predict progression to severe COVID-19 disease using serum protein and metabolite biomarkers. Our data also uncovered molecular pathophysiology of COVID-19 with potential for developing anti-viral therapies.<br><br>Funding: This work is supported by grants from Westlake Special Program for COVID19 (2020), and Tencent foundation (2020), National Natural Science Foundation of China (81972492, 21904107, 81672086), Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholars (LR19C050001), Hangzhou Agriculture and Society Advancement Program (20190101A04). <br><br>Conflict of Interest: The research group of T.G. is partly supported by Tencent, Thermo Fisher Scientific, SCIEX and Pressure Biosciences Inc. C.Z., Z.K., Z.K. and S.Q. are employees of DIAN Diagnostics.

6.
Viruses ; 13(11)2021 Nov 04.
Article in English | MEDLINE | ID: covidwho-1538544

ABSTRACT

Pseudorabies virus (PRV) is the causative agent of Aujeszky's disease, which still causes large economic losses for the swine industry. Therefore, it is urgent to find a new strategy to prevent and control PRV infection. Previous studies have proven that guanine (G)-rich DNA or RNA sequences in some other viruses' genomes have the potential to form G-quadruplex (G4), which serve as promising antivirus targets. In this study, we identified two novel G4-forming sequences, OriL-A and OriL-S, which are located at the upstream origin of replication (OriL) in the PRV genome and conserved across 32 PRV strains. Circular dichroism (CD) spectroscopy and a gel electrophoresis assay showed that the two G-rich sequences can fold into parallel G4 structures in vitro. Moreover, fluorescence resonance energy transfer (FRET) melting and a Taq polymerase stop assay indicated that the G4 ligand PhenDC3 has the capacity to bind and stabilize the G4. Notably, the treatment of PRV-infected cells with G4-stabilizer PhenDC3 significantly inhibited PRV DNA replication in host cells but did not affect PRV's attachment and entry. These results not only expand our knowledge about the G4 characteristics in the PRV genome but also suggest that G4 may serve as an innovative therapeutic target against PRV.

7.
Preprint in English | EuropePMC | ID: ppcovidwho-292947

ABSTRACT

In this research, we have constructed and optimized the colloidal gold labeled lateral flow strip (LFS) for rapid detection of antigen of SARS-CoV-2 and rapid screening of COVID-19. Based on the constructed and optimized colloidal gold lateral flow strip, the parameters of the LFS have been well evaluated with the clinical samples in the professional labs. The screening performance have also been evaluated from the aspects including the CT values, age distribution and onset of symptoms. Finally, based on the detection results of 420 clinical samples, the LFS can achieve the screening of COVID-19 with the positive percentage agreement (PPA, sensitivity), negative percent agreement (NPA, specificity), the positive predictive value (PPV) and the negative predictive value (NPV) of 96.8%, 100%, 100% and 96.6%, respectively, indicating the powerful potential for practical screening applications in pandemic control. Of great significance, this developed SARS-CoV-2 antigen detection method has also been successfully utilized for screening of delta-variant of SARS-CoV-2.

8.
J Proteome Res ; 2021 Nov 16.
Article in English | MEDLINE | ID: covidwho-1531980

ABSTRACT

RT-PCR is the primary method to diagnose COVID-19 and is also used to monitor the disease course. This approach, however, suffers from false negatives due to RNA instability and poses a high risk to medical practitioners. Here, we investigated the potential of using serum proteomics to predict viral nucleic acid positivity during COVID-19. We analyzed the proteome of 275 inactivated serum samples from 54 out of 144 COVID-19 patients and shortlisted 42 regulated proteins in the severe group and 12 in the non-severe group. Using these regulated proteins and several key clinical indexes, including days after symptoms onset, platelet counts, and magnesium, we developed two machine learning models to predict nucleic acid positivity, with an AUC of 0.94 in severe cases and 0.89 in non-severe cases, respectively. Our data suggest the potential of using a serum protein-based machine learning model to monitor COVID-19 progression, thus complementing swab RT-PCR tests. More efforts are required to promote this approach into clinical practice since mass spectrometry-based protein measurement is not currently widely accessible in clinic.

9.
J Am Soc Nephrol ; 32(1): 41-51, 2021 01.
Article in English | MEDLINE | ID: covidwho-1496668

ABSTRACT

BACKGROUND: Mutations in PKD1 and PKD2, which encode the transmembrane proteins polycystin-1 and polycystin-2, respectively, cause autosomal dominant polycystic kidney disease (ADPKD). Polycystins are expressed in the primary cilium, and disrupting cilia structure significantly slows ADPKD progression following inactivation of polycystins. The cellular mechanisms of polycystin- and cilia-dependent cyst progression in ADPKD remain incompletely understood. METHODS: Unbiased transcriptional profiling in an adult-onset Pkd2 mouse model before cysts formed revealed significant differentially expressed genes (DEGs) in Pkd2 single-knockout kidneys, which were used to identify candidate pathways dysregulated in kidneys destined to form cysts. In vivo studies validated the role of the candidate pathway in the progression of ADPKD. Wild-type and Pkd2/Ift88 double-knockout mice that are protected from cyst growth served as controls. RESULTS: The RNASeq data identified cell proliferation as the most dysregulated pathway, with 15 of 241 DEGs related to cell cycle functions. Cdk1 appeared as a central component in this analysis. Cdk1 expression was similarly dysregulated in Pkd1 models of ADPKD, and conditional inactivation of Cdk1 with Pkd1 markedly improved the cystic phenotype and kidney function compared with inactivation of Pkd1 alone. The Pkd1/Cdk1 double knockout blocked cyst cell proliferation that otherwise accompanied Pkd1 inactivation alone. CONCLUSIONS: Dysregulation of Cdk1 is an early driver of cyst cell proliferation in ADPKD due to Pkd1 inactivation. Selective targeting of cyst cell proliferation is an effective means of slowing ADPKD progression caused by inactivation of Pkd1.


Subject(s)
CDC2 Protein Kinase/metabolism , Polycystic Kidney, Autosomal Dominant/genetics , Polycystic Kidney, Autosomal Dominant/metabolism , TRPP Cation Channels/metabolism , Animals , Apoptosis , CDC2 Protein Kinase/genetics , Catalytic Domain , Cell Proliferation , Crosses, Genetic , DNA Replication , Female , Gene Expression Profiling , Gene Expression Regulation , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutation , Phenotype , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics , RNA-Seq , TRPP Cation Channels/genetics , Transcription, Genetic , Whole Exome Sequencing
10.
Vaccine ; 39(48): 7001-7011, 2021 11 26.
Article in English | MEDLINE | ID: covidwho-1488001

ABSTRACT

COVID-19 pandemic has severely impacted the public health and social economy worldwide. A safe, effective, and affordable vaccine against SARS-CoV-2 infections/diseases is urgently needed. We have been developing a recombinant vaccine based on a prefusion-stabilized spike trimer of SARS-CoV-2 and formulated with aluminium hydroxide and CpG 7909. The spike protein was expressed in Chinese hamster ovary (CHO) cells, purified, and prepared as a stable formulation with the dual adjuvant. Immunogenicity studies showed that candidate vaccines elicited robust neutralizing antibody responses and substantial CD4+ T cell responses in both mice and non-human primates. And vaccine-induced neutralizing antibodies persisted at high level for at least 6 months. Challenge studies demonstrated that candidate vaccine reduced the viral loads and inflammation in the lungs of SARS-CoV-2 infected golden Syrian hamsters significantly. In addition, the vaccine-induced antibodies showed cross-neutralization activity against B.1.1.7 and B.1.351 variants. These data suggest candidate vaccine is efficacious in preventing SARS-CoV-2 infections and associated pneumonia, thereby justifying ongoing phase I/II clinical studies in China (NCT04982068 and NCT04990544).


Subject(s)
COVID-19 Vaccines , COVID-19 , Alum Compounds , Aluminum Hydroxide , Animals , Antibodies, Neutralizing , Antibodies, Viral , CHO Cells , Cricetinae , Cricetulus , Humans , Mice , Pandemics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics
11.
Viruses ; 13(10)2021 Oct 13.
Article in English | MEDLINE | ID: covidwho-1481011

ABSTRACT

Human noroviruses are a common pathogen causing acute gastroenteritis worldwide. Among all norovirus genotypes, GII.3 is particularly prevalent in the pediatric population. Here we report the identification of two distinct blockade antibody epitopes on the GII.3 capsid. We generated a panel of monoclonal antibodies (mAbs) from mice immunized with virus-like particle (VLP) of a GII.3 cluster 3 strain. Two of these mAbs, namely 8C7 and 8D1, specifically bound the parental GII.3 VLP but not VLPs of GII.4, GII.17, or GI.1. In addition, 8C7 and 8D1 efficiently blocked GII.3 VLP binding with its ligand, histo-blood group antigens (HBGA). These data demonstrate that 8C7 and 8D1 are GII.3-specific blockade antibodies. By using a series of chimeric VLPs, we mapped the epitopes of 8C7 and 8D1 to residues 385-400 and 401-420 of the VP1 capsid protein, respectively. These two blockade antibody epitopes are highly conserved among GII.3 cluster 3 strains. Structural modeling shows that the 8C7 epitope partially overlaps with the HBGA binding site (HBS) while the 8D1 epitope is spatially adjacent to HBS. These findings may enhance our understanding of the immunology and evolution of GII.3 noroviruses.

12.
Small ; : e2102711, 2021 Oct 08.
Article in English | MEDLINE | ID: covidwho-1460273

ABSTRACT

Because of high sensitivity and specificity, isothermal nucleic acid amplification are widely applied in many fields. To facilitate and improve their performance, various nanomaterials, like nanoparticles, nanowires, nanosheets, nanotubes, and nanoporous films are introduced in isothermal nucleic acid amplification. However, the specific application, roles, and prospect of nanomaterials in isothermal nucleic acid amplification have not been comprehensively reviewed. Here, the application of different nanomaterials (0D, 1D, 2D, and 3D) in isothermal nucleic acid amplification is comprehensively discussed and recent progress in the field is summarized. The nanomaterials are mainly used for reaction enhancer, signal generation/amplification, or surface loading carriers. In addition, 3D nanomaterials can be also functioned as isolated chambers for digital nucleic acid amplification and the tools for DNA sequencing of amplified products. Challenges and future recommendations are also proposed to be better used for recent covid-19 detection, point-of-care diagnostic, food safety, and other fields.

13.
Appl Math Model ; 102: 35-61, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1446414

ABSTRACT

The storage and distribution of medical supplies are important parts of epidemic prevention and control. This paper first proposes a new nonsmooth two-stage stochastic equilibrium model of medical supplies in epidemic management. The first stage addresses the storage in the pre-disaster phase, and the second stage focuses on the dynamic distribution by enrolling competitions among multiple hospitals over a period of time in the post-disaster phase. The uncertainties are the numbers of infected people treated in multiple hospitals during the period of time, which are time-varying around a nominal distribution predicted by historical experience. The two-stage stochastic equilibrium model is further approximated and transformed to a monotone two-stage stochastic variational inequality (SVI) model that is computationally tractable, with the aid of a smooth approximation technique. We employ the progressive hedging method (PHM) to solve a case study in the city of Wuhan in China suffered from the COVID-19 pandemic. Numerical results are presented to demonstrate the effectiveness of the proposed model in planning the storage and dynamic distribution of medical supplies in epidemic management.

14.
mBio ; 12(5): e0233521, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1430167

ABSTRACT

Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with astonishing mortality and morbidity. The high replication and transmission of SARS-CoV-2 are remarkably distinct from those of previous closely related coronaviruses, and the underlying molecular mechanisms remain unclear. The innate immune defense is a physical barrier that restricts viral replication. We report here that the SARS-CoV-2 Nsp5 main protease targets RIG-I and mitochondrial antiviral signaling (MAVS) protein via two distinct mechanisms for inhibition. Specifically, Nsp5 cleaves off the 10 most-N-terminal amino acids from RIG-I and deprives it of the ability to activate MAVS, whereas Nsp5 promotes the ubiquitination and proteosome-mediated degradation of MAVS. As such, Nsp5 potently inhibits interferon (IFN) induction by double-stranded RNA (dsRNA) in an enzyme-dependent manner. A synthetic small-molecule inhibitor blunts the Nsp5-mediated destruction of cellular RIG-I and MAVS and processing of SARS-CoV-2 nonstructural proteins, thus restoring the innate immune response and impeding SARS-CoV-2 replication. This work offers new insight into the immune evasion strategy of SARS-CoV-2 and provides a potential antiviral agent to treat CoV disease 2019 (COVID-19) patients. IMPORTANCE The ongoing COVID-19 pandemic is caused by SARS-CoV-2, which is rapidly evolving with better transmissibility. Understanding the molecular basis of the SARS-CoV-2 interaction with host cells is of paramount significance, and development of antiviral agents provides new avenues to prevent and treat COVID-19 diseases. This study describes a molecular characterization of innate immune evasion mediated by the SARS-CoV-2 Nsp5 main protease and subsequent development of a small-molecule inhibitor.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Coronavirus 3C Proteases/metabolism , DEAD Box Protein 58/metabolism , Receptors, Immunologic/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , A549 Cells , Adaptor Proteins, Signal Transducing/genetics , Animals , Caco-2 Cells , Coronavirus 3C Proteases/genetics , DEAD Box Protein 58/genetics , Enzyme-Linked Immunosorbent Assay , HCT116 Cells , HEK293 Cells , Humans , Immunity, Innate/genetics , Immunity, Innate/physiology , Immunoblotting , Interferon Type I/metabolism , Mice , Receptors, Immunologic/genetics , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/genetics , Signal Transduction/physiology , Ubiquitination , Virus Replication/genetics , Virus Replication/physiology
15.
Signal Transduct Target Ther ; 6(1): 339, 2021 09 08.
Article in English | MEDLINE | ID: covidwho-1402052

ABSTRACT

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has placed a global public burden on health authorities. Although the virological characteristics and pathogenesis of COVID-19 has been largely clarified, there is currently no specific therapeutic measure. In severe cases, acute SARS-CoV-2 infection leads to immune disorders and damage to both the adaptive and innate immune responses. Having roles in immune regulation and regeneration, mesenchymal stem cells (MSCs) serving as a therapeutic option may regulate the over-activated inflammatory response and promote recovery of lung damage. Since the outbreak of the COVID-19 pandemic, a series of MSC-therapy clinical trials has been conducted. The findings indicate that MSC treatment not only significantly reduces lung damage, but also improves patient recovery with safety and good immune tolerance. Herein, we summarize the recent progress in MSC therapy for COVID-19 and highlight the challenges in the field.


Subject(s)
COVID-19/therapy , Lung Injury/therapy , Lung/immunology , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/immunology , SARS-CoV-2/immunology , Animals , COVID-19/immunology , COVID-19/pathology , Humans , Lung/pathology , Lung/virology , Lung Injury/immunology , Lung Injury/virology , Mesenchymal Stem Cells/pathology
16.
Sci Adv ; 7(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1388433

ABSTRACT

The recent outbreaks of SARS-CoV-2 pose a global health emergency. The SARS-CoV-2 trimeric spike (S) glycoprotein interacts with the human ACE2 receptor to mediate viral entry into host cells. We report the cryo-EM structures of a tightly closed SARS-CoV-2 S trimer with packed fusion peptide and an ACE2-bound S trimer at 2.7- and 3.8-Å resolution, respectively. Accompanying ACE2 binding to the up receptor-binding domain (RBD), the associated ACE2-RBD exhibits continuous swing motions. Notably, the SARS-CoV-2 S trimer appears much more sensitive to the ACE2 receptor than the SARS-CoV S trimer regarding receptor-triggered transformation from the closed prefusion state to the fusion-prone open state, potentially contributing to the superior infectivity of SARS-CoV-2. We defined the RBD T470-T478 loop and Y505 as viral determinants for specific recognition of SARS-CoV-2 RBD by ACE2. Our findings depict the mechanism of ACE2-induced S trimer conformational transitions from the ground prefusion state toward the postfusion state, facilitating development of anti-SARS-CoV-2 vaccines and therapeutics.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Animals , Cryoelectron Microscopy , Enzyme-Linked Immunosorbent Assay , Humans , Image Processing, Computer-Assisted , Ligands , Mice , Mice, Inbred BALB C , Mutation , Peptides/chemistry , Polysaccharides , Principal Component Analysis , Protein Binding , Protein Domains
17.
Infect Drug Resist ; 13: 3715-3725, 2020.
Article in English | MEDLINE | ID: covidwho-1389036

ABSTRACT

The renin-angiotensin system (RAS) is the most important regulatory system of electrolyte homeostasis and blood pressure and acts through angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II type 1 (AT1) receptor axis and angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7)/MAS receptor axis. RAS dysfunction is related to the occurrence and development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and causes a serious prognosis and even death. ALI/ARDS can be induced by various ways, one of which is viral infections, such as SARS-CoV, SARS-CoV-2, H5N1, H7N9, and EV71. This article reviews the specific mechanism on how RAS dysfunction affects ALI/ARDs caused by viral infections. SARS-CoV and SARS-CoV-2 enter the host cells by binding with ACE2. H5N1 and H7N9 avian influenza viruses reduce the ACE2 level in the body, and EV71 increases Ang II concentration. Treatment with angiotensin-converting enzyme inhibitor and angiotensin AT1 receptor blocker can alleviate ALI/ARDS symptoms. This review provides suggestions for the treatment of lung injury caused by viral infections.

18.
Front Med (Lausanne) ; 8: 673253, 2021.
Article in English | MEDLINE | ID: covidwho-1376705

ABSTRACT

Background: The coronavirus disease 2019 (COVID-19) pandemic has lasted much longer than an influenza season, but the main signs, symptoms, and some imaging findings are similar in COVID-19 and influenza patients. The aim of the current study was to construct an accurate and robust model for initial screening and differential diagnosis of COVID-19 and influenza A. Methods: All patients in the study were diagnosed at Fuyang No. 2 People's Hospital, and they included 151 with COVID-19 and 155 with influenza A. The patients were randomly assigned to training set or a testing set at a 4:1 ratio. Predictor variables were selected based on importance, assessed by random forest algorithms, and analyzed to develop classification and regression tree models. Results: In the optimal model A, the best single predictor of COVID-19 patients was a normal or high level of low-density lipoprotein cholesterol, followed by low level of creatine kinase, then the presence of <3 respiratory symptoms, then a highest temperature on the first day of admission <38°C. In the suboptimal model B, the best single predictor of COVID-19 was a low eosinophil count, then a normal monocyte ratio, then a normal hematocrit value, then a highest temperature on the first day of admission of <37°C, then a complete lack of respiratory symptoms. Conclusions: The two models provide clinicians with a rapid triage tool. The optimal model can be used to developed countries/regions and major hospitals, and the suboptimal model can be used in underdeveloped regions and small hospitals.

19.
Cell Discov ; 7(1): 71, 2021 Aug 18.
Article in English | MEDLINE | ID: covidwho-1364581

ABSTRACT

Massive production of efficacious SARS-CoV-2 vaccines is essential for controlling the ongoing COVID-19 pandemic. We report here the preclinical development of yeast-produced receptor-binding domain (RBD)-based recombinant protein SARS-CoV-2 vaccines. We found that monomeric RBD of SARS-CoV-2 could be efficiently produced as a secreted protein from transformed Pichia pastoris (P. pastoris) yeast. Yeast-derived RBD-monomer possessed functional conformation and was able to elicit protective level of neutralizing antibodies in mice. We further designed and expressed a genetically linked dimeric RBD protein in yeast. The engineered dimeric RBD was more potent than the monomeric RBD in inducing long-lasting neutralizing antibodies. Mice immunized with either monomeric RBD or dimeric RBD were effectively protected from live SARS-CoV-2 virus challenge even at 18 weeks after the last vaccine dose. Importantly, we found that the antisera raised against the RBD of a single SARS-CoV-2 prototype strain could effectively neutralize the two predominant circulating variants B.1.1.7 and B.1.351, implying broad-spectrum protective potential of the RBD-based vaccines. Our data demonstrate that yeast-derived RBD-based recombinant SARS-CoV-2 vaccines are feasible and efficacious, opening up a new avenue for rapid and cost-effective production of SARS-CoV-2 vaccines to achieve global immunization.

20.
Brief Bioinform ; 22(2): 976-987, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1343642

ABSTRACT

Emerging viral infections seriously threaten human health globally. Several challenges exist in identifying effective compounds against viral infections: (1) at the initial stage of a new virus outbreak, little information, except for its genome information, may be available; (2) although the identified compounds may be effective, they may be toxic in vivo and (3) cytokine release syndrome (CRS) triggered by viral infections is the primary cause of mortality. Currently, an integrative tool that takes all those aspects into consideration for identifying effective compounds to prevent viral infections is absent. In this study, we developed iDMer, as an integrative and mechanism-driven response system for addressing these challenges during the sudden virus outbreaks. iDMer comprises three mechanism-driven compound identification modules, that is, a virus-host interaction-oriented module, an autophagy-oriented module and a CRS-oriented module. As a one-stop integrative platform, iDMer incorporates compound toxicity evaluation and compound combination identification for virus treatment with clear mechanisms. iDMer was successfully tested on five viruses, including the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results indicated that, for all five tested viruses, compounds that were reported in the literature or experimentally validated for virus treatment were enriched at the top, demonstrating the generalized effectiveness of iDMer. Finally, we demonstrated that combinations of the individual modules successfully identified combinations of compounds effective for virus intervention with clear mechanisms.


Subject(s)
COVID-19/epidemiology , Disease Outbreaks , Algorithms , Autophagy , COVID-19/virology , Host Microbial Interactions , Humans , SARS-CoV-2/isolation & purification , Sequence Analysis, RNA
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