Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 43
Filter
1.
Health Psychol ; 2023 Jun 01.
Article in English | MEDLINE | ID: covidwho-20234023

ABSTRACT

OBJECTIVE: Previous literature has indicated a strong negative correlation between the moral foundation of purity/sanctity and vaccination rates. The current research investigated how purity concerns impact COVID-19 vaccination hesitancy and tested an information intervention to bolster vaccination intention among people with purity concerns. METHOD: Study 1 surveyed 566 Republicans and Republican-leaning Independents in the United States. Study 2 was a between-subject-designed survey experiment that investigated the impact of three statements on the COVID-19 vaccination attitudes and intentions of 637 Republicans and Republican-leaning Independents. Statement 1 argued that vaccines are not impure from a scientific perspective; Statement 2 made the same argument with quotes from the Bible; and Statement 3 was a control statement. RESULTS: Study 1 established a significant correlation between the existence of vaccination history and purity as a moral foundation. Study 2 found that among those with no COVID-19 vaccination history, statements arguing that vaccines are not impure from either a scientific perspective or a religious perspective improved attitudes toward vaccination and intention to get vaccinated. CONCLUSION: Purity concerns can be leveraged as a way to bolster vaccination rates, especially among conservatives. However, the impurity perception only mediated the causal relationship between the treatment and the attitude toward vaccines (but not the actual intention), suggesting that changes in the actual vaccination behavior are subject to factors other than purity concerns. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

2.
Res Sq ; 2023 Mar 28.
Article in English | MEDLINE | ID: covidwho-2320852

ABSTRACT

The mechanism of syncytium formation, caused by spike-induced cell-cell fusion in severe COVID-19, is largely unclear. Here we combine chemical genetics with 4D confocal imaging to establish the cell surface heparan sulfate (HS) as a critical host factor exploited by SARS-CoV-2 to enhance spike’s fusogenic activity. HS binds spike to facilitate ACE2 clustering, generating synapse-like cell-cell contacts to promote fusion pore formation. ACE2 clustering, and thus, syncytium formation is significantly mitigated by chemical or genetic elimination of cell surface HS, while in a cell-free system consisting of purified HS, spike, and lipid-anchored ACE2, HS directly induces ACE2 clustering. Importantly, the interaction of HS with spike allosterically enables a conserved ACE2 linker in receptor clustering, which concentrates spike at the fusion site to overcome fusion-associated activity loss. This fusion-boosting mechanism can be effectively targeted by an investigational HS-binding drug, which reduces syncytium formation in vitro and viral infection in mice.

3.
BMC Med Educ ; 23(1): 235, 2023 Apr 12.
Article in English | MEDLINE | ID: covidwho-2293236

ABSTRACT

Identifying systems failures and contributing to a safety culture is the Association of American Colleges (AAMC's) thirteenth Entrustable Professional Activity (EPA). While most curricula teach Patient Safety (PS) and Quality Improvement (QI) principles, student participation in live QI/PS activities remains limited. This workshop enabled late Clerkship phase students to apply these Health Systems Science (HSS) principles to real adverse patient event cases through team-based simulation.This 3-h capstone included both a didactic review of QI, PS, and TeamSTEPPS® tools and an experiential component where student-led interactive small group discussions were augmented by resident and faculty preceptors. Collaboratively, students composed an adverse patient event report, conducted a Root Cause Analysis (RCA) during role-play, and proposed error prevention ideas after identifying systems problems. In April 2020, the in-person workshop became fully virtual due to the COVID-19 pandemic.A statistically significant increase in ability to identify Serious Safety Events, Escalation Chain of Command, and define a Plan-Do-Study-Act (PDSA) cycle was observed. Comfort with RCA increased from 48 to 87% and comfort with TeamSTEPPS® principles increased from 68% to 85.5%This novel capstone provided students with the tools to synthesize HSS concepts through problem-solving processes and recognize EPA 13's importance. Their increased capability to identify appropriate chain of command, escalate concerns, and recognize serious adverse patient events also has training and practice readiness implications.


Subject(s)
COVID-19 , Internship and Residency , Humans , Quality Improvement , Patient Safety , Pandemics , COVID-19/prevention & control , Curriculum
4.
mBio ; : e0323821, 2022 Jan 11.
Article in English | MEDLINE | ID: covidwho-2275679

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a serious threat to global public health, underscoring the urgency of developing effective therapies. Therapeutics and, more specifically, direct-acting antiviral development are still very much in their infancy. Here, we report that two hepatitis C virus (HCV) fusion inhibitors identified in our previous study, dichlorcyclizine and fluoxazolevir, broadly block human coronavirus entry into various cell types. Both compounds were effective against various human-pathogenic CoVs in multiple assays based on vesicular stomatitis virus (VSV) pseudotyped with the spike protein and spike-mediated syncytium formation. The antiviral effects were confirmed in SARS-CoV-2 infection systems. These compounds were equally effective against recently emerged variants, including the delta variant. Cross-linking experiments and structural modeling suggest that the compounds bind to a hydrophobic pocket near the fusion peptide of S protein, consistent with their potential mechanism of action as fusion inhibitors. In summary, these fusion inhibitors have broad-spectrum antiviral activities and may be promising leads for treatment of SARS-CoV-2, its variants, and other pathogenic CoVs. IMPORTANCE SARS-CoV-2 is an enveloped virus that requires membrane fusion for entry into host cells. Since the fusion process is relatively conserved among enveloped viruses, we tested our HCV fusion inhibitors, dichlorcyclizine and fluoxazolevir, against SARS-CoV-2. We performed in vitro assays and demonstrated their effective antiviral activity against SARS-CoV-2 and its variants. Cross-linking experiments and structural modeling suggest that the compounds bind to a hydrophobic pocket in spike protein to exert their inhibitory effect on the fusion step. These data suggest that both dichlorcyclizine and fluoxazolevir are promising candidates for further development as treatment for SARS-CoV-2.

5.
Crit Care Explor ; 5(1): e0831, 2023 Jan.
Article in English | MEDLINE | ID: covidwho-2232780

ABSTRACT

Describe the clinical characteristics and outcomes of 32 critically ill patients who underwent central venous cannulation of the internal jugular vein while in prone position. DESIGN: Retrospective cohort analysis. SETTING: Single tertiary-care urban academic safety-net hospital. PATIENTS/SUBJECTS: Patients requiring mechanical ventilation and prone positioning for severe acute respiratory distress syndrome from March 1, 2020, through March 31, 2021. INTERVENTIONS: Internal jugular vein cannulation while in the prone position. MEASUREMENTS AND MAIN RESULTS: The technique used for venous access, procedural complications, patient demographics, and clinical outcomes are described. Thirty-six prone internal jugular vein cannulations for 32 hemodialysis catheters and four central venous catheters were successfully performed in 32 patients. One immediate and one delayed pneumothorax occurred. Inhospital mortality was 88%. CONCLUSIONS: In the largest series to date, cannulation of the internal jugular vein with the patient in prone position is feasible but associated with a 6% risk of pneumothorax. Severity of illness in patients intolerant of supine positioning results in high inhospital mortality.

6.
Int J Environ Res Public Health ; 19(20)2022 Oct 17.
Article in English | MEDLINE | ID: covidwho-2071474

ABSTRACT

BACKGROUND: While a number of population preventive measures for COVID-19 exist that help to decrease the spread of the virus in the community, there are still many areas in preventative efforts that need improvement or refinement, particularly as new strains of the virus develop. Some of the key issues currently include incorrect and/or inconsistent use of face masks, low acceptance of early screening or vaccination for COVID-19, vaccine hesitance, and misinformation. This is particularly the case in some vulnerable populations, such as older people with chronic illnesses, ethnic minorities who may not speak the mainstream language well and children. The current protocol introduces a large programme of research through five interrelated studies that all focus on social and behavioural interventions to improve different aspects of community-related preventative indicators. Hence, the specific objectives of the overall programme are to (1) increase early testing for COVID-19 and promote the uptake of COVID-19 vaccines in the community (Study 1); (2) increase COVID-19-related health literacy and vaccine literacy and promote improved preventative measures in minority ethnic groups, chronically ill populations and caregivers (Study 2); (3) strengthen the public's motivation to stay at home and avoid nonessential high-risk activities (Study 3); (4) decrease COVID-19 vaccine hesitancy (Study 4); and (5) enhance the adherence to COVID-19-related hygiene practices and the uptake of early testing in school children (Study 5). METHODS: We will utilise a community-based participatory research (CBPR) approach in the proposed studies. All studies will incorporate an intervention development phase in conjunction with key community stakeholders, a feasibility study and an execution stage. A variety of self-reported and objective-based measures will be used to assess various outcomes, based on the focus of each study, in both the short- and long-term, including, for example, the 8-item self-reported eHealth Literacy Scale (eHEAL) and objective measures such as vaccine uptake. DISCUSSION: Theory-driven interventions will address each study's focus (e.g., social distancing, promotion of vaccine uptake, eHealth education, preventive measures and early detection). Improvements are expected to be seen in the outcomes of vulnerable and high-risk groups. Decreased infection rates are expected due to improved preventative behaviours and increased vaccine uptake. Long-term sustainability of the approach will be achieved through the CBPR model. The publication of this protocol can assist not only in sharing a large-scale and complex community-based design, but will also allow all to learn from this, so that we will have better insight in the future whether sharing of study designs can elicit timely research initiatives.


Subject(s)
COVID-19 , Vaccines , Child , Humans , Aged , SARS-CoV-2 , COVID-19/epidemiology , COVID-19/prevention & control , Community-Based Participatory Research , COVID-19 Vaccines , Hong Kong/epidemiology , COVID-19 Testing , Chronic Disease
7.
Front Pharmacol ; 13: 918083, 2022.
Article in English | MEDLINE | ID: covidwho-2009894

ABSTRACT

Preclinical pharmacokinetics (PK) and In Vitro ADME properties of GS-441524, a potential oral agent for the treatment of Covid-19, were studied. GS-441524 was stable in vitro in liver microsomes, cytosols, and hepatocytes of mice, rats, monkeys, dogs, and humans. The plasma free fractions of GS-441524 were 62-78% across all studied species. The in vitro transporter study results showed that GS-441524 was a substrate of MDR1, BCRP, CNT3, ENT1, and ENT2; but not a substrate of CNT1, CNT2, and ENT4. GS-441524 had a low to moderate plasma clearance (CLp), ranging from 4.1 mL/min/kg in dogs to 26 mL/min/kg in mice; the steady state volume distribution (Vdss) ranged from 0.9 L/kg in dogs to 2.4 L/kg in mice after IV administration. Urinary excretion appeared to be the major elimination process for GS-441524. Following oral administration, the oral bioavailability was 8.3% in monkeys, 33% in rats, 39% in mice, and 85% in dogs. The PK and ADME properties of GS-441524 support its further development as an oral drug candidate.

8.
PLoS One ; 17(8): e0272364, 2022.
Article in English | MEDLINE | ID: covidwho-1987156

ABSTRACT

Neutralizing antibodies targeting the SARS-CoV-2 spike protein have shown a great preventative/therapeutic potential. Here, we report a rapid and efficient strategy for the development and design of SARS-CoV-2 neutralizing humanized nanobody constructs with sub-nanomolar affinities and nanomolar potencies. CryoEM-based structural analysis of the nanobodies in complex with spike revealed two distinct binding modes. The most potent nanobody, RBD-1-2G(NCATS-BL8125), tolerates the N501Y RBD mutation and remains capable of neutralizing the B.1.1.7 (Alpha) variant. Molecular dynamics simulations provide a structural basis for understanding the neutralization process of nanobodies exclusively focused on the spike-ACE2 interface with and without the N501Y mutation on RBD. A primary human airway air-lung interface (ALI) ex vivo model showed that RBD-1-2G-Fc antibody treatment was effective at reducing viral burden following WA1 and B.1.1.7 SARS-CoV-2 infections. Therefore, this presented strategy will serve as a tool to mitigate the threat of emerging SARS-CoV-2 variants.


Subject(s)
Bacteriophages , COVID-19 , Single-Domain Antibodies , Antibodies, Neutralizing , Antibodies, Viral , Bacteriophages/metabolism , Humans , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
9.
JMIR Res Protoc ; 11(6): e37334, 2022 Jun 22.
Article in English | MEDLINE | ID: covidwho-1910907

ABSTRACT

BACKGROUND: Up-to-date and accurate information about the health problems encountered by primary care doctors is essential to understanding the morbidity pattern of the community to better inform health care policy and practice. Morbidity surveys of doctors allow documentation of actual consultations, reflecting the patient's reason for seeking care as well as the doctor's diagnostic interpretation of the illness and management approach. Such surveys are particularly critical in the absence of a centralized primary care electronic medical record database. OBJECTIVE: With the changing sociodemographic profile of the population and implementation of health care initiatives in the past 10 years, the aim of this study is to determine the morbidity and management patterns in Hong Kong primary care during a pandemic and compare the results with the last survey conducted in 2007-2008. METHODS: This will be a prospective, practice-based survey of Hong Kong primary care doctors. Participants will be recruited by convenience and targeted sampling from both public and private sectors. Participating doctors will record the health problems and corresponding management activities for consecutive patient encounters during one designated week in each season of the year. Coding of health problems will follow the International Classification of Primary Care, Second Edition. Descriptive statistics will be used to calculate the prevalence of health problems and diseases as well as the rates of management activities (referral, investigation, prescription, preventive care). Nonlinear mixed effects models will assess the differences between the private and public sectors as well as factors associated with morbidity and management patterns in primary care. RESULTS: The data collection will last from March 1, 2021, to August 31, 2022. As of April 2022, 176 doctor-weeks of data have been collected. CONCLUSIONS: The results will provide information about the health of the community and inform the planning and allocation of health care resources. TRIAL REGISTRATION: ClinicalTrials.gov NCT04736992; https://clinicaltrials.gov/ct2/show/NCT04736992. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37334.

10.
ACS Infect Dis ; 8(6): 1191-1203, 2022 06 10.
Article in English | MEDLINE | ID: covidwho-1873405

ABSTRACT

SARS-CoV-2 is the causative viral pathogen driving the COVID-19 pandemic that prompted an immediate global response to the development of vaccines and antiviral therapeutics. For antiviral therapeutics, drug repurposing allows for rapid movement of the existing clinical candidates and therapies into human clinical trials to be tested as COVID-19 therapies. One effective antiviral treatment strategy used early in symptom onset is to prevent viral entry. SARS-CoV-2 enters ACE2-expressing cells when the receptor-binding domain of the spike protein on the surface of SARS-CoV-2 binds to ACE2 followed by cleavage at two cut sites by TMPRSS2. Therefore, a molecule capable of inhibiting the protease activity of TMPRSS2 could be a valuable antiviral therapy. Initially, we used a fluorogenic high-throughput screening assay for the biochemical screening of 6030 compounds in NCATS annotated libraries. Then, we developed an orthogonal biochemical assay that uses mass spectrometry detection of product formation to ensure that hits from the primary screen are not assay artifacts from the fluorescent detection of product formation. Finally, we assessed the hits from the biochemical screening in a cell-based SARS-CoV-2 pseudotyped particle entry assay. Of the six molecules advanced for further studies, two are approved drugs in Japan (camostat and nafamostat), two have entered clinical trials (PCI-27483 and otamixaban), while the other two molecules are peptidomimetic inhibitors of TMPRSS2 taken from the literature that have not advanced into clinical trials (compounds 92 and 114). This work demonstrates a suite of assays for the discovery and development of new inhibitors of TMPRSS2.


Subject(s)
COVID-19 Drug Treatment , Percutaneous Coronary Intervention , Angiotensin-Converting Enzyme 2 , Antiviral Agents/pharmacology , Drug Repositioning/methods , Humans , Pandemics , SARS-CoV-2 , Serine Endopeptidases
11.
Proc Natl Acad Sci U S A ; 119(18): e2201433119, 2022 05 03.
Article in English | MEDLINE | ID: covidwho-1815698

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is a trimer of S1/S2 heterodimers with three receptor-binding domains (RBDs) at the S1 subunit for human angiotensin-converting enzyme 2 (hACE2). Due to their small size, nanobodies can recognize protein cavities that are not accessible to conventional antibodies. To isolate high-affinity nanobodies, large libraries with great diversity are highly desirable. Dromedary camels (Camelus dromedarius) are natural reservoirs of coronaviruses like Middle East respiratory syndrome CoV (MERS-CoV) that are transmitted to humans. Here, we built large dromedary camel VHH phage libraries to isolate nanobodies that broadly neutralize SARS-CoV-2 variants. We isolated two VHH nanobodies, NCI-CoV-7A3 (7A3) and NCI-CoV-8A2 (8A2), which have a high affinity for the RBD via targeting nonoverlapping epitopes and show broad neutralization activity against SARS-CoV-2 and its emerging variants of concern. Cryoelectron microscopy (cryo-EM) complex structures revealed that 8A2 binds the RBD in its up mode with a long CDR3 loop directly involved in the ACE2 binding residues and that 7A3 targets a deeply buried region that uniquely extends from the S1 subunit to the apex of the S2 subunit regardless of the conformational state of the RBD. At a dose of ≥5 mg/kg, 7A3 efficiently protected transgenic mice expressing hACE2 from the lethal challenge of variants B.1.351 or B.1.617.2, suggesting its therapeutic use against COVID-19 variants. The dromedary camel VHH phage libraries could be helpful as a unique platform ready for quickly isolating potent nanobodies against future emerging viruses.


Subject(s)
COVID-19 , Single-Domain Antibodies , Animals , Camelus , Humans , Mice , SARS-CoV-2/genetics , Single-Domain Antibodies/genetics
12.
Sci Rep ; 12(1): 6294, 2022 04 15.
Article in English | MEDLINE | ID: covidwho-1805651

ABSTRACT

Spike-mediated entry of SARS-CoV-2 into human airway epithelial cells is an attractive therapeutic target for COVID-19. In addition to protein receptors, the SARS-CoV-2 spike (S) protein also interacts with heparan sulfate, a negatively charged glycosaminoglycan (GAG) attached to certain membrane proteins on the cell surface. This interaction facilitates the engagement of spike with a downstream receptor to promote viral entry. Here, we show that Mitoxantrone, an FDA-approved topoisomerase inhibitor, targets a heparan sulfate-spike complex to compromise the fusogenic function of spike in viral entry. As a single agent, Mitoxantrone inhibits the infection of an authentic SARS-CoV-2 strain in a cell-based model and in human lung EpiAirway 3D tissues. Gene expression profiling supports the plasma membrane as a major target of Mitoxantrone but also underscores an undesired activity targeting nucleosome dynamics. We propose that Mitoxantrone analogs bearing similar heparan sulfate-binding activities but with reduced affinity for DNA topoisomerases may offer an alternative therapy to overcome breakthrough infections in the post-vaccine era.


Subject(s)
COVID-19 Drug Treatment , Spike Glycoprotein, Coronavirus , Heparin/metabolism , Heparitin Sulfate/metabolism , Humans , Mitoxantrone/pharmacology , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
13.
J Chem Inf Model ; 62(8): 1988-1997, 2022 04 25.
Article in English | MEDLINE | ID: covidwho-1783923

ABSTRACT

The cell entry of SARS-CoV-2 has emerged as an attractive drug development target. We previously reported that the entry of SARS-CoV-2 depends on the cell surface heparan sulfate proteoglycan (HSPG) and the cortex actin, which can be targeted by therapeutic agents identified by conventional drug repurposing screens. However, this drug identification strategy requires laborious library screening, which is time consuming, and often limited number of compounds can be screened. As an alternative approach, we developed and trained a graph convolutional network (GCN)-based classification model using information extracted from experimentally identified HSPG and actin inhibitors. This method allowed us to virtually screen 170,000 compounds, resulting in ∼2000 potential hits. A hit confirmation assay with the uptake of a fluorescently labeled HSPG cargo further shortlisted 256 active compounds. Among them, 16 compounds had modest to strong inhibitory activities against the entry of SARS-CoV-2 pseudotyped particles into Vero E6 cells. These results establish a GCN-based virtual screen workflow for rapid identification of new small molecule inhibitors against validated drug targets.


Subject(s)
Antiviral Agents , SARS-CoV-2 , Virus Internalization , Actins , Antiviral Agents/chemistry , Heparan Sulfate Proteoglycans , Humans , SARS-CoV-2/drug effects , Virus Internalization/drug effects , COVID-19 Drug Treatment
14.
J Med Chem ; 65(6): 4590-4599, 2022 03 24.
Article in English | MEDLINE | ID: covidwho-1740391

ABSTRACT

Identification of anti-SARS-CoV-2 compounds through traditional high-throughput screening (HTS) assays is limited by high costs and low hit rates. To address these challenges, we developed machine learning models to identify compounds acting via inhibition of the entry of SARS-CoV-2 into human host cells or the SARS-CoV-2 3-chymotrypsin-like (3CL) protease. The optimal classification models achieved good performance with area under the receiver operating characteristic curve (AUC-ROC) values of >0.78. Experimental validation showed that the best performing models increased the assay hit rate by 2.1-fold for viral entry inhibitors and 10.4-fold for 3CL protease inhibitors compared to those of the original drug repurposing screens. Twenty-two compounds showed potent (<5 µM) antiviral activities in a SARS-CoV-2 live virus assay. In conclusion, machine learning models can be developed and used as a complementary approach to HTS to expand compound screening capacities and improve the speed and efficiency of anti-SARS-CoV-2 drug discovery.


Subject(s)
COVID-19 Drug Treatment , SARS-CoV-2 , Antiviral Agents/pharmacology , Drug Repositioning , Humans , Protease Inhibitors/pharmacology
15.
Transplantation ; 106(4): e202-e211, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-1684929

ABSTRACT

BACKGROUND: Studies indicate that the recovery from coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome may be slower than other viral pneumonia. There are limited data to guide decisions among patients who need extracorporeal membrane oxygenation (ECMO) support, especially the expected time of recovery and considering lung transplantation (LT). METHODS: This was a retrospective chart review of patients with COVID-19-associated acute respiratory distress syndrome placed on ECMO between March 1, 2020, and September 15, 2021 (n = 20; median age, 44 y; range, 22-62 y; male:female, 15:5). We contrasted the baseline variables and clinical course of patients with and without the need for ECMO support >30 d (ECMO long haulers, n = 10). RESULTS: Ten patients met the criteria for ECMO long haulers (median duration of ECMO, 86 d; range, 42-201 d). The long haulers were healthier at baseline with fewer comorbidities but had worse pulmonary compliance and higher partial pressure of CO2. They had a significantly higher number of membrane oxygenator failures, changes to their cannulation sites, and suffer more complications on ECMO. One of the long hauler was bridged to LT while another 6 patients recovered and were discharged. Overall survival was better among the ECMO long haulers (70% versus 20%; 9.3, 1.2-73; P = 0.03). CONCLUSIONS: Despite worse pulmonary physiology, frequent complications, and a tortuous hospital course that may appear to portend a poor prognosis, ECMO long haulers have the potential to recover and be weaned off ECMO without the need for LT. A customized approach comprising a more conservative timeline for the consideration of LT may be prudent among these patients.


Subject(s)
COVID-19 , Extracorporeal Membrane Oxygenation , Lung Transplantation , Respiratory Distress Syndrome , Adult , COVID-19/complications , Extracorporeal Membrane Oxygenation/adverse effects , Female , Humans , Male , Middle Aged , Phenotype , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/therapy , Retrospective Studies , Young Adult
16.
Mol Med ; 27(1): 160, 2021 12 20.
Article in English | MEDLINE | ID: covidwho-1631040

ABSTRACT

COVID-19 clinical presentation differs considerably between individuals, ranging from asymptomatic, mild/moderate and severe disease which in some cases are fatal or result in long-term effects. Identifying immune mechanisms behind severe disease development informs screening strategies to predict who are at greater risk of developing life-threatening complications. However, to date clear prognostic indicators of individual risk of severe or long COVID remain elusive. Autoantibodies recognize a range of self-antigens and upon antigen recognition and binding, important processes involved in inflammation, pathogen defence and coagulation are modified. Recent studies report a significantly higher prevalence of autoantibodies that target immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins in COVID-19 patients experiencing severe disease compared to those who experience mild or asymptomatic infections. Here we discuss the diverse impacts of autoantibodies on immune processes and associations with severe COVID-19 disease.


Subject(s)
Autoantibodies/immunology , Autoantibodies/metabolism , COVID-19/complications , COVID-19/immunology , SARS-CoV-2/immunology , Animals , Autoimmunity/physiology , COVID-19/metabolism , Humans , SARS-CoV-2/metabolism , Post-Acute COVID-19 Syndrome
17.
ACS Pharmacol Transl Sci ; 5(1): 8-19, 2022 Jan 14.
Article in English | MEDLINE | ID: covidwho-1621207

ABSTRACT

Drug development for specific antiviral agents against coronavirus disease 2019 (COVID-19) is still an unmet medical need as the pandemic continues to spread globally. Although huge efforts for drug repurposing and compound screens have been put forth, only a few compounds are in late-stage clinical trials. New approaches and assays are needed to accelerate COVID-19 drug discovery and development. Here, we report a time-resolved fluorescence resonance energy transfer-based assay that detects the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein (NP) produced in infected cells. It uses two specific anti-NP monoclonal antibodies conjugated to donor and acceptor fluorophores that produce a robust ratiometric signal for high throughput screening of large compound collections. Using this assay, we measured a half maximal inhibitory concentration (IC50) for remdesivir of 9.3 µM against infection with SARS-CoV-2 USA/WA1/2020 (WA-1). The assay also detected SARS-CoV-2 South African (Beta, ß), Brazilian/Japanese P.1 (Gamma, γ), and Californian (Epsilon, ε) variants of concern (VoC). Therefore, this homogeneous SARS-CoV-2 NP detection assay can be used for accelerating lead compound discovery for drug development and for evaluating drug efficacy against emerging SARS-CoV-2 VoC.

19.
SLAS Discov ; 27(2): 86-94, 2022 03.
Article in English | MEDLINE | ID: covidwho-1586501

ABSTRACT

Effective small molecule therapies to combat the SARS-CoV-2 infection are still lacking as the COVID-19 pandemic continues globally. High throughput screening assays are needed for lead discovery and optimization of small molecule SARS-CoV-2 inhibitors. In this work, we have applied viral pseudotyping to establish a cell-based SARS-CoV-2 entry assay. Here, the pseudotyped particles (PP) contain SARS-CoV-2 spike in a membrane enveloping both the murine leukemia virus (MLV) gag-pol polyprotein and luciferase reporter RNA. Upon addition of PP to HEK293-ACE2 cells, the SARS-CoV-2 spike protein binds to the ACE2 receptor on the cell surface, resulting in priming by host proteases to trigger endocytosis of these particles, and membrane fusion between the particle envelope and the cell membrane. The internalized luciferase reporter gene is then expressed in cells, resulting in a luminescent readout as a surrogate for spike-mediated entry into cells. This SARS-CoV-2 PP entry assay can be executed in a biosafety level 2 containment lab for high throughput screening. From a collection of 5,158 approved drugs and drug candidates, our screening efforts identified 7 active compounds that inhibited the SARS-CoV-2-S PP entry. Of these seven, six compounds were active against live replicating SARS-CoV-2 virus in a cytopathic effect assay. Our results demonstrated the utility of this assay in the discovery and development of SARS-CoV-2 entry inhibitors as well as the mechanistic study of anti-SARS-CoV-2 compounds. Additionally, particles pseudotyped with spike proteins from SARS-CoV-2 B.1.1.7 and B.1.351 variants were prepared and used to evaluate the therapeutic effects of viral entry inhibitors.


Subject(s)
Antiviral Agents/pharmacology , High-Throughput Screening Assays/methods , SARS-CoV-2/drug effects , Virus Internalization/drug effects , HEK293 Cells , Humans
20.
Crit Care Med ; 50(1): e40-e51, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1584019

ABSTRACT

OBJECTIVES: Multicenter data on the characteristics and outcomes of children hospitalized with coronavirus disease 2019 are limited. Our objective was to describe the characteristics, ICU admissions, and outcomes among children hospitalized with coronavirus disease 2019 using Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: Coronavirus Disease 2019 registry. DESIGN: Retrospective study. SETTING: Society of Critical Care Medicine Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) registry. PATIENTS: Children (< 18 yr) hospitalized with coronavirus disease 2019 at participating hospitals from February 2020 to January 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was ICU admission. Secondary outcomes included hospital and ICU duration of stay and ICU, hospital, and 28-day mortality. A total of 874 children with coronavirus disease 2019 were reported to Viral Infection and Respiratory Illness Universal Study registry from 51 participating centers, majority in the United States. Median age was 8 years (interquartile range, 1.25-14 yr) with a male:female ratio of 1:2. A majority were non-Hispanic (492/874; 62.9%). Median body mass index (n = 817) was 19.4 kg/m2 (16-25.8 kg/m2), with 110 (13.4%) overweight and 300 (36.6%) obese. A majority (67%) presented with fever, and 43.2% had comorbidities. A total of 238 of 838 (28.2%) met the Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children, and 404 of 874 (46.2%) were admitted to the ICU. In multivariate logistic regression, age, fever, multisystem inflammatory syndrome in children, and pre-existing seizure disorder were independently associated with a greater odds of ICU admission. Hospital mortality was 16 of 874 (1.8%). Median (interquartile range) duration of ICU (n = 379) and hospital (n = 857) stay were 3.9 days (2-7.7 d) and 4 days (1.9-7.5 d), respectively. For patients with 28-day data, survival was 679 of 787, 86.3% with 13.4% lost to follow-up, and 0.3% deceased. CONCLUSIONS: In this observational, multicenter registry of children with coronavirus disease 2019, ICU admission was common. Older age, fever, multisystem inflammatory syndrome in children, and seizure disorder were independently associated with ICU admission, and mortality was lower among children than mortality reported in adults.


Subject(s)
COVID-19/complications , COVID-19/epidemiology , COVID-19/physiopathology , Child, Hospitalized/statistics & numerical data , Systemic Inflammatory Response Syndrome/epidemiology , Systemic Inflammatory Response Syndrome/physiopathology , Adolescent , Age Factors , Body Mass Index , COVID-19/mortality , Child , Child, Preschool , Comorbidity , Female , Hospital Mortality/trends , Humans , Infant , Intensive Care Units/statistics & numerical data , Logistic Models , Male , Retrospective Studies , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/mortality
SELECTION OF CITATIONS
SEARCH DETAIL