- Human Cytokine and Coronavirus Nucleocapsid Protein Interactivity Using Large-Scale Virtual Screens -
In the battle against the ever-changing SARS-CoV-2 landscape, understanding the interactions between viral proteins and the human immune system is paramount as it helps to explain potential factors contributing to diverse immunological responses in infected individuals. In this study, we employed state-of-the-art molecular docking tools to conduct large-scale virtual screens, predicting the binding affinities between 64 human cytokines against 17 coronavirus nucleocapsid proteins. Our comprehensive in silico analyses reveal specific changes in cytokine-nucleocapsid protein interactions, shedding light on potential modulators of the host immune response during infection. These findings offer valuable insights into the molecular mechanisms underlying viral pathogenesis and may guide the future development of targeted interventions. This manuscript serves as insight into the comparison of deep learning based AlphaFold2-Multimer and the semi-physicochemical based HADDOCK for protein-protein docking. We show the two methods are complementary in their predictive capabilities. We also introduce a novel algorithm for rapidly assessing the binding interface of protein-protein docks using graph edit distance: graph-based residue assessment function (G-RAF). The high-performance computational framework presented here will not only aid in accelerating the discovery of effective interventions against emerging viral threats, but extend to other applications of high throughput protein-protein screens.
- Mechanism-based classification of SARS-CoV-2 Variants by Molecular Dynamics Resembles Phylogenetic Tree -
The COVID-19 pandemics has demonstrated the vulnerability of our societies to viral infectious disease. The mitigation of COVID-19 was complicated by the emergence of Variants of Concern (VOCs) with varying properties including increased transmissibility and immune evasion. Traditional population sequencing proved to be slow and not conducive for timely action. To tackle this challenge, we introduce the Persistence Score (PS) that assesses the pandemic potential of VOCs based on molecular dynamics of the interactions between the SARS-CoV-2 Receptor Binding Domain (RBD) and the ACE2 residues. Our mechanism-based classification approach successfully grouped VOCs into clinically relevant subgroups with higher sensitivity than classical affinity estimations and allows for risk assessment of hypothetical new VOCs. The PS-based interaction analysis across VOCs resembled the phylogenetic tree of SARS-Cov-2 demonstrating its predictive relevance for pandemic preparedness. Thus, PS allows for early detection of a variant's pandemic potential, and an early risk evaluation for data-driven policymaking.
- Functional and antigenic characterization of SARS-CoV-2 spike fusion peptide by deep mutational scanning -
The fusion peptide of SARS-CoV-2 spike protein is functionally important for membrane fusion during virus entry and is part of a broadly neutralizing epitope. However, sequence determinants at the fusion peptide and its adjacent regions for pathogenicity and antigenicity remain elusive. In this study, we performed a series of deep mutational scanning (DMS) experiments on an S2 region spanning the fusion peptide of authentic SARS-CoV-2 in different cell lines and in the presence of broadly neutralizing antibodies. We identified mutations at residue 813 of the spike protein that reduced TMPRSS2-mediated entry with decreased virulence. In addition, we showed that an F823Y mutation, present in bat betacoronavirus HKU9 spike protein, confers resistance to broadly neutralizing antibodies. Our findings provide mechanistic insights into SARS-CoV-2 pathogenicity and also highlight a potential challenge in developing broadly protective S2-based coronavirus vaccines.
- copepodTCR: Identification of Antigen-Specific T Cell Receptors with combinatorial peptide pooling -
T cell receptor (TCR) repertoire diversity enables the orchestration of antigen-specific immune responses against the vast space of possible pathogens. Identifying TCR/antigen binding pairs from the large TCR repertoire and antigen space is crucial for biomedical research. Here, we introduce copepodTCR, an open-access tool for the design and interpretation of high-throughput experimental assays to determine TCR specificity. copepodTCR implements a combinatorial peptide pooling scheme for efficient experimental testing of T cell responses against large overlapping peptide libraries, useful for "deorphaning" TCRs of unknown specificity. The scheme detects experimental errors and, coupled with a hierarchical Bayesian model for unbiased results interpretation, identifies the response-eliciting peptide for a TCR of interest out of hundreds of peptides tested using a simple experimental set-up. We experimentally validated our approach on a library of 253 overlapping peptides covering the SARS-CoV-2 spike protein. We provide experimental guides for efficient design of larger screens covering thousands of peptides which will be crucial for the identification of antigen-specific T cells and their targets from limited clinical material.
- Reasons for not getting vaccinated against COVID-19 in German-speaking Switzerland: An online survey among vaccine hesitant 16-60 year olds -
Background: Several research studies have examined the reasons why people are hesitant to be vaccinated against COVID-19. However, there is no published data to date on Switzerland. Identifying these reasons among the Swiss population who are vaccine hesitant may help inform campaigns to encourage vaccine confidence. Aims: The primary aim of this study is to identify the reasons for not getting vaccinated against COVID-19 among Swiss residents who are vaccine hesitant. The secondary aim is to examine whether reasons differ by age, gender, education, and likelihood of accepting a vaccination to better target campaigns and design interventions. Design: An online survey asked participants to indicate the reasons why they were hesitant to be vaccinated against COVID-19. Setting: German-speaking Swiss Cantons, the survey was administered online between 5 May 2021 and 16 May 2021. Participants: The participants in this analysis were a sample of (N=1191) Swiss residents age 16-60 years old from German-speaking Cantons, who could answer an online survey in German, who had yet not been vaccinated, who had not yet registered for a vaccination appointment, and who did not indicate that they would definitely be vaccinated if offered the chance. Findings: Among people who are vaccine hesitant in Switzerland, the most common reasons for being hesitant were side-effect, safety, and effectiveness concerns. It was also common for people to indicate that they were healthy/at low risk, would decide later, and that they wanted to build immunity naturally. Less common, but still prevalent concerns included wanting more information, thinking COVID-19 was not a real threat, and concerns that the vaccine may serve another purpose. Differences in reasons for being vaccine hesitant were found by age, gender, education, and likelihood of accepting a vaccination if offered. Conclusions: To increase the likelihood of accepting a vaccination, vaccination campaigns should address side-effect, safety, and effectiveness concerns. Campaigns could also consider informing people why it is necessary for people in lower risk groups to be vaccinated, and why vaccination is preferable to infection for building immunity. While campaigns may be effective in reaching some of the population, alternative strategies might be necessary to strengthen the trust relationship with vaccines and vaccine providers in some groups. Less prevalent concerns, such as not liking needles, could be addressed through individual level interventions.
- Expression and fusogenic activity of SARS CoV-2 Spike protein displayed in the HSV-1 Virion. -
Severe acute respiratory syndrome coronavirus (SARS-CoV) is a zoonotic pathogen that can cause severe respiratory disease in humans. The new SARS-CoV-2 is the cause of the current global pandemic termed coronavirus disease 2019 (COVID-19) that has resulted in many millions of deaths world-wide. The virus is a member of the Betacoronavirus family, its genome is a positive strand RNA molecule that encodes for many genes which are required for virus genome replication as well as for structural proteins that are required for virion assembly and maturation. A key determinant of this virus is the Spike (S) protein embedded in the virion membrane and mediates attachment of the virus to the receptor (ACE2). This protein also is required for cell-cell fusion (syncytia) that is an important pathogenic determinant. We have developed a pseudotyped herpes simplex virus type 1 (HSV-1) recombinant virus expressing S protein in the virion envelop. This virus has also been modified to express a Venus fluorescent protein fusion to VP16, a virion protein of HSV-1. The virus expressing Spike can enter cells and generates large multi-nucleated syncytia which are evident by the Venus fluorescence. The HSV-1 recombinant virus is genetically stable and virus amplification can be easily done by infecting cells. This recombinant virus provides a reproducible platform for Spike function analysis and thus adds to the repertoire of pseudotyped viruses expressing Spike.
- Streamlining Computational Fragment-Based Drug Discovery through Evolutionary Optimization Informed by Ligand-Based Virtual Prescreening -
Recent advancements in computational methods provide the promise of dramatically accelerating drug discovery. While mathematical modeling and machine learning have become vital in predicting drug-target interactions and properties, there is untapped potential in computational drug discovery due to the vast and complex chemical space. This paper advances a novel computational fragment-based drug discovery (FBDD) method called Fragments from Ligands Drug Discovery (FDSL-DD), which aims to streamline drug design by applying a two-stage optimization process informed by machine learning and evolutionary principles. In this approach, in silico screening identifies ligands from a vast library, which are then fragmentized while attaching specific attributes based on predicted binding affinity and interaction with the target sub-domain. This process both shrinks the search space and focuses on promising regions within it. The first optimization stage assembles these fragments into larger compounds using evolutionary strategies, and the second stage iteratively refines resulting compounds for enhanced bioactivity. The methodology is validated across three diverse protein targets involved in human solid cancers, bacterial antimicrobial resistance, and SARS-CoV-2 viral entry, demonstrating the approach's broad applicability. Using the proposed FDSL-DD and two-stage optimization approach yields high-affinity ligand candidates more efficiently than other state-of-the-art computational methods. Furthermore, a multiobjective optimization is presented that accounts for druglikeness while still producing potential candidate ligands with high binding affinity. In conclustion, the results demonstrate that integrating detailed chemical information with a constrained search framework can markedly optimize the initial drug discovery process, offering a more precise and efficient route to developing new therapeutics.
- Epitope mapping of SARS-CoV-2 RBDs by hydroxyl radical protein footprinting reveals the importance of including negative antibody controls. -
Understanding protein-protein interaction is essential when designing drugs or investigating biological processes. A variety of techniques can be employed in order to map the regions on proteins that are involved in binding eg., CryoEM, X-ray spectroscopy, linear epitope mapping, or mass spectrometry-based methods. The most commonly utilized mass spectrometry-based techniques are cross-linking and hydrogen-deuterium exchange (HDX). An alternative technique for identifying residues on the three-dimensional structure of proteins, that are involved in binding, can be hydroxyl radical protein footprinting (HRPF). However, this method is currently hampered by high initial cost and complex experimental setup. Here we set out to present a generally applicable method using Fenton chemistry for mapping of epitopes in a standard mass spectrometry laboratory. Furthermore, the described method illustrates the importance of controls on several levels when performing mass spectrometry-based epitope mapping. In particular, the inclusion of a negative antibody control has not previously been widely utilized in epitope mapping by HRPF analysis. In order to limit the number of false positives, we further introduced quantification by TMT labelling, thereby allowing for direct comparison between sample conditions and biological triplicates. Lastly, up to six technical replicates were incorporated in the experimental setup in order to achieve increased depth of the final analysis. Both binding and opening of regions on receptor-binding domain (RBD) from SARS-CoV-2 Spike Protein, Alpha and Delta variants, were observed. The negative control antibody experiment combined with the high overlap between biological triplicates resulted in the exclusion of 40% of the significantly changed regions, including both binding and opening regions. The final identified binding region was mapped to a three-dimensional structure and agrees with the literature for neutralizing antibodies towards SARS-CoV-2 Spike Protein. The presented method is straightforward to implement for the analysis of HRPF in a generic MS-based laboratory. The high reliability of the data was achieved by increasing the number of technical and biological replicates combined with negative antibody controls.
- Generation and evaluation of protease inhibitor-resistant SARS-CoV-2 strains -
Since the start of the SARS-CoV-2 pandemic, the search for antiviral therapies has been at the forefront of medical research. To date, the 3CLpro inhibitor nirmatrelvir (Paxlovid) has shown the best results in clinical trials and the greatest robustness against variants. A second SARS-CoV-2 protease inhibitor, ensitrelvir (Xocova), has been developed. Ensitrelvir, currently in Phase 3, was approved in Japan under the emergency regulatory approval procedure in November 2022, and is available since March 31, 2023. One of the limitations for the use of antiviral monotherapies is the emergence of resistance mutations. Here, we experimentally generated mutants resistant to nirmatrelvir and ensitrelvir in vitro following repeating passages of SARS-CoV-2 in the presence of both antivirals. For both molecules, we demonstrated a loss of sensitivity for resistance mutants in vitro. Using a Syrian golden hamster infection model, we showed that the ensitrelvir M49L mutation confers a high level of in vivo resistance. Finally, we identified a recent increase in the prevalence of M49L-carrying sequences, which appears to be associated with multiple repeated emergence events in Japan and may be related to the use of Xocova in the country since November 2022. These results highlight the strategic importance of genetic monitoring of circulating SARS-CoV-2 strains to ensure that treatments administered retain their full effectiveness.
- Identification of the host reservoir of SARS-CoV-2 and determining when it spilled over into humans -
Since the emergence of SARS-CoV-2 in Wuhan in 2019 its host reservoir has not been established. Phylogenetic analysis was performed on whole genome sequences (WGS) of 71 coronaviruses and a Breda virus. A subset comprising two SARS-CoV-2 Wuhan viruses and 8 of the most closely related coronavirus sequences were used for host reservoir analysis using Bayesian Evolutionary Analysis Sampling Trees (BEAST). Within these genomes, 20 core genome fragments were combined into 2 groups each with similar clock rates (5.9x10 -3 and 1.1x10 -3 subs/site/year). Pooling the results from these fragment groups yielded a most recent common ancestor (MRCA) shared between SARS-COV-2 and the bat isolate RaTG13 around 2007 (95% HPD: 2003, 2011). Further, the host of the MRCA was most likely a bat (probability 0.64 - 0.87). Hence, the spillover into humans must have occurred at some point between 2007 and 2019 and bats may have been the most likely host reservoir.
- XBB.1.5 monovalent mRNA vaccine booster elicits robust neutralizing antibodies against emerging SARS-CoV-2 variants -
COVID-19 vaccines have recently been updated with the spike protein of SARS-Co-V-2 XBB.1.5 subvariant alone, but their immunogenicity in humans has yet to be fully evaluated and reported, particularly against emergent viruses that are rapidly expanding. We now report that administration of an updated monovalent mRNA vaccine (XBB.1.5 MV) to uninfected individuals boosted serum virus-neutralization antibodies significantly against not only XBB.1.5 (27.0-fold) and the currently dominant EG.5.1 (27.6-fold) but also key emergent viruses like HV.1, HK.3, JD.1.1, and JN.1 (13.3-to-27.4-fold). In individuals previously infected by an Omicron subvariant, serum neutralizing titers were boosted to highest levels (1,764-to-22,978) against all viral variants tested. While immunological imprinting was still evident with the updated vaccines, it was not nearly as severe as the previously authorized bivalent BA.5 vaccine. Our findings strongly support the official recommendation to widely apply the updated COVID-19 vaccines to further protect the public.
- Variant- and Vaccination-Specific Alternative Splicing Profiles in SARS-CoV-2 Infections -
The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, and its subsequent variants has underscored the importance of understanding the host-viral molecular interactions to devise effective therapeutic strategies. A significant aspect of these interactions is the role of alternative splicing in modulating host responses and viral replication mechanisms. Our study sought to delineate the patterns of alternative splicing of RNAs from immune cells across different SARS-CoV-2 variants and vaccination statuses, utilizing a robust dataset of 190 RNA-seq samples from our previous studies, encompassing an average of 212 million reads per sample. We identified a dynamic alteration in alternative splicing and genes related to RNA splicing were highly deactivated in COVID-19 patients and showed variant- and vaccination-specific expression profiles. Overall, Omicron-infected patients exhibited a gene expression profile akin to healthy controls, unlike the Alpha or Beta variants. However, significantly, we found identified a subset of infected individuals, most pronounced in vaccinated patients infected with Omicron variant, that exhibited a specific dynamic in their alternative splicing patterns that was not widely shared amongst the other groups. Our findings underscore the complex interplay between SARS-CoV-2 variants, vaccination-induced immune responses, and alternative splicing, emphasizing the necessity for further investigations into these molecular cross-talks to foster deeper understanding and guide strategic therapeutic development.
- Evolution-guided large language model is a predictor of virus mutation trends -
Emerging viral infections, especially the global pandemic COVID-19, have had catastrophic impacts on public health worldwide. The culprit of this pandemic, SARS-CoV-2, continues to evolve, giving rise to numerous sublineages with distinct characteristics. The traditional post-hoc wet-lab approach is lagging behind, and it cannot quickly predict the evolutionary trends of the virus while consuming high costs. Capturing the evolutionary drivers of virus and predicting potential high-risk mutations has become an urgent and critical problem to address. To tackle this challenge, we introduce ProtFound-V, an evolution-inspired deep-learning framework designed to explore the mutational trajectory of virus. Take SARS-CoV-2 as an example, ProtFound-V accurately identifies the evolutionary advantage of Omicron and proposes evolutionary trends consistent with wet-lab experiments through in silico deep mutational scanning. This showcases the potential of deep learning predictions to replace traditional wet-lab experimental measurements. With the evolution-guided large language model, ProtFound-V presents a new state-of-the-art performance in key property predictions. Despite the challenge posed by epistasis to model generalization, ProtFound-V remains robust when extrapolating to lineages with different genetic backgrounds. Overall, this work paves the way for rapid responses to emerging viral infections, allowing for a plug-and-play approach to understanding and predicting virus evolution.
- Modulation of human kinase activity through direct interaction with SARS-CoV-2 proteins -
The dysregulation of cellular signaling upon SARS-CoV-2 infection is mediated via direct protein interactions, with the human protein kinases constituting the major impact nodes in the signaling networks. Here, we employed a targeted yeast two-hybrid matrix approach to identify direct SARS-CoV-2 protein interactions with an extensive set of human kinases. We discovered 51 interactions involving 14 SARS-CoV-2 proteins and 29 human kinases, including many of the CAMK and CMGC kinase family members, as well as non-receptor tyrosine kinases. By integrating the interactions identified in our screen with transcriptomics and phospho-proteomics data, we revealed connections between SARS-CoV-2 protein interactions, kinase activity changes, and the cellular phospho-response to infection and identified altered activity patterns in infected cells for AURKB, CDK2, CDK4, CDK7, ABL2, PIM2, PLK1, NEK2, TRIB3, RIPK2, MAPK13, and MAPK14. Finally, we demonstrated direct inhibition of the FER human tyrosine kinase by the SARS-CoV-2 auxiliary protein ORF6, hinting at pressures underlying ORF6 changes observed in recent SARS-CoV-2 strains. Our study expands the SARS-CoV-2 - host interaction knowledge, illuminating the critical role of dysregulated kinase signaling during SARS-CoV-2 infection.
- Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection. -
Pathogen encounter results in long-lasting epigenetic imprinting that shapes diseases caused by heterologous pathogens. The breadth of this innate immune memory is of particular interest in the context of respiratory pathogens with increased pandemic potential and wide-ranging impact on global health. Here, we investigated epigenetic imprinting across cell lineages in a disease relevant murine model of SARS-CoV-2 recovery. Past SARS-CoV-2 infection resulted in increased chromatin accessibility of type I interferon (IFN-I) related transcription factors in airway-resident macrophages. Mechanistically, establishment of this innate immune memory required viral pattern recognition and canonical IFN-I signaling and augmented secondary antiviral responses. Past SARS-CoV-2 infection ameliorated disease caused by the heterologous respiratory pathogen influenza A virus. Insights into innate immune memory and how it affects subsequent infections with heterologous pathogens to influence disease pathology could facilitate the development of broadly effective therapeutic strategies.
A Randomized Trial Evaluating a mRNA VLP Vaccine’s Immunogenicity and Safety for COVID-19 - Conditions: COVID-19; SARS-CoV-2 Infection
Interventions: Biological: AZD9838; Biological: Licensed mRNA vaccine
Sponsors: AstraZeneca
Not yet recruiting
Effect of Metformin in Reducing Fatigue in Long COVID in Adolescents - Conditions: Long COVID
Interventions: Drug: Metformin; Other: Placebo
Sponsors: Trust for Vaccines and Immunization, Pakistan
Not yet recruiting
“The Effect of Aerobic Exercise and Strength Training on Physical Activity Level, Quality of Life and Anxiety-Stress Disorder in Young Adults With and Without Covid-19” - Conditions: COVID-19
Interventions: Behavioral: Aerobic Exercise and Strength Training
Sponsors: Pamukkale University
Active, not recruiting
Vale+Tú Salud: Corner-Based Randomized Trial to Test a Latino Day Laborer Program Adapted to Prevent COVID-19 - Conditions: COVID-19
Interventions: Behavioral: COVID-19 Group Problem Solving; Behavioral: Standard of Care; Behavioral: Booster session
Sponsors: The University of Texas Health Science Center, Houston; National Institute on Minority Health and Health Disparities (NIMHD)
Recruiting
Safety Study of SLV213 for the Treatment of COVID-19. - Conditions: COVID-19
Interventions: Other: Placebo for SLV213; Drug: SLV213
Sponsors: National Institute of Allergy and Infectious Diseases (NIAID)
Not yet recruiting
Collection of Additional Biological Samples From Potentially COVID-19 Patients for Monitoring of Biological Parameters Carried Out as Part of the Routine - Conditions: SARS CoV 2 Infection
Interventions: Diagnostic Test: RIPH2
Sponsors: CerbaXpert
Not yet recruiting
Promoting Engagement and COVID-19 Testing for Health - Conditions: COVID-19
Interventions: Behavioral: COVID-19 Test Reporting; Behavioral: Personalized Nudges via Text Messaging; Behavioral: Non-personalized Nudges via Text Messaging
Sponsors: Emory University; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Morehouse School of Medicine; Georgia Institute of Technology
Not yet recruiting
Development and Qualification of Methods for Analyzing the Mucosal Immune Response to COVID-19 - Conditions: Certain Disorders Involving the Immune Mechanism
Interventions: Biological: Sampling; Biological: PCR (polymerase chain reaction) SARS-CoV-2
Sponsors: University Hospital, Tours
Not yet recruiting
Water-based Activity to Enhance Recovery in Long COVID - Conditions: Long COVID
Interventions: Behavioral: WATER+CT; Behavioral: Usual Care
Sponsors: VA Office of Research and Development
Not yet recruiting
Mitigating Mental and Social Health Outcomes of COVID-19: A Counseling Approach - Conditions: Social Determinants of Health; Mental Health Issue; COVID-19
Interventions: Behavioral: Individual counseling; Behavioral: Group counseling; Other: Resources
Sponsors: Idaho State University
Not yet recruiting
Efficacy of Two Therapeutic Exercise Modalities for Patients With Persistent COVID - Conditions: Persistent COVID-19
Interventions: Other: exercise programe
Sponsors: Facultat de ciencies de la Salut Universitat Ramon Llull
Recruiting
Performance Evaluation of the Lucira COVID-19 & Flu Test - Conditions: COVID-19; Influenza
Interventions: Device: Lucira COVID-19 & Flu Test
Sponsors: Lucira Health Inc
Completed
Robotic Assisted Hand Rehabilitation Outcomes in Adults After COVID-19 - Conditions: Robotic Exoskeleton; Post-acute Covid-19 Syndrome; Rehabilitation Outcome; Physical And Rehabilitation Medicine
Interventions: Device: Training with a Robotic Hand Exoskeleton
Sponsors: University of Valladolid; Centro Hospitalario Padre Benito Menni
Completed
Cognitive Rehabilitation in Post-COVID-19 Syndrome - Conditions: Post-COVID-19 Syndrome
Interventions: Behavioral: CO-OP Procedures; Behavioral: Inactive Control Group
Sponsors: University of Missouri-Columbia; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Not yet recruiting
Antiviral peptides inhibiting the main protease of SARS-CoV-2 investigated by computational screening and in vitro protease assay - The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays an important role in viral replication and transcription and received great attention as a vital target for drug/peptide development. Therapeutic agents such as small-molecule drugs or peptides that interact with the Cys-His present in the catalytic site of Mpro are an efficient way to inhibit the protease. Although several emergency-approved vaccines showed good efficacy and drastically dropped the…
Plant-Derived Natural Compounds as an Emerging Antiviral in Combating COVID-19 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human virus that burst at Wuhan in China and spread quickly over the world, leading to millions of deaths globally. The journey of this deadly virus to different mutant strains is still ongoing. The plethora of drugs and vaccines have been tested to cope up this pandemic. The herbal plants and different spices have received great attention during pandemic, because of their anti-inflammatory, and immunomodulatory properties in…
Enumeration of olive derived lignan, pinoresinol for activity against recent Omicron variant spike protein for structure-based drug design, DFT, molecular dynamics simulations, and MMGBSA studies - The coronavirus disease 2019 (COVID-19) was first found in Wuhan, China, in December 2019. Because the virus spreads quickly, it quickly became a global worry. Coronaviridae is the family that contains both SARS-CoV-2 and the viruses that came before (i.e., MERS-CoV and SARS-CoV). Recent sources portray that the COVID-19 virus has affected 344,710,576 people worldwide and killed about 5,598,511 people in the last 2 years. The B.1.1.529 strain, later called “Omicron,” was named a Variant of…
Amplification of poly(I:C)-induced interleukin-6 production in human bronchial epithelial cells by priming with interferon-γ - Proinflammatory cytokine interleukin (IL)-6 was associated with disease severity in patients with COVID-19. The mechanism underlying the excessive IL-6 production by SARS-Cov-2 infection remains unclear. Respiratory viruses initially infect nasal or bronchial epithelial cells that produce various inflammatory mediators. Here, we show that pretreatment of human bronchial epithelial cells (NCl-H292) with interferon (IFN)-γ (10 ng/mL) markedly increased IL-6 production induced by the toll-like…
Diabetic individuals with COVID-19 exhibit reduced efficacy of gliptins in inhibiting dipeptidyl peptidase 4 (DPP4). A suggested explanation for increased COVID-19 susceptibility in patients with type 2 diabetes mellitus (T2DM) - AIMS: Dipeptidyl peptidase 4 (DPP4) has been proposed as a coreceptor for SARS-CoV-2 cellular entry. Considering that type 2 diabetes mellitus (T2DM) has been identified as the most important risk factor for SARS-CoV-2, and that gliptins (DPP4 inhibitors) are a prescribed diabetic treatment, this study aims to unravel the impact of DPP4 in the intersection of T2DM/COVID-19.
Engineering irradiated tumor-derived microparticles as personalized vaccines to enhance anti-tumor immunity - The inadequate activation of antigen-presenting cells, the entanglement of T cells, and the highly immunosuppressive conditions in the tumor microenvironment (TME) are important factors that limit the effectiveness of cancer vaccines. Studies show that a personalized and broad antigen repertoire fully activates anti-tumor immunity and that inhibiting the function of transforming growth factor (TGF)-β facilitates T cell migration. In our study, we introduce a vaccine strategy by engineering…
Willow (Salix spp.) bark hot water extracts inhibit both enveloped and non-enveloped viruses: study on its anti-coronavirus and anti-enterovirus activities - CONCLUSION: Salix spp. bark extracts contain several virucidal agents that are likely to act synergistically and directly on the viruses.
Unveiling the role of PUS7-mediated pseudouridylation in host protein interactions specific for the SARS-CoV-2 RNA genome - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive single-stranded RNA virus, engages in complex interactions with host cell proteins throughout its life cycle. While these interactions enable the host to recognize and inhibit viral replication, they also facilitate essential viral processes such as transcription, translation, and replication. Many aspects of these virus-host interactions remain poorly understood. Here, we employed the catRAPID algorithm and utilized the…
Case report: Supratherapeutic tacrolimus concentrations with nirmatrelvir/ritonavir in a lung transplant patient: a case report using Rifampin for reversal - Paxlovid (nirmatrelvir/ritonavir) is an antiviral drug used to treat COVID-19, nirmatrelvir, a SARS-CoV-2 main protease inhibitor, works by inhibiting viral replication in the early stages, and ritonavir is a strong cytochrome P450 (CYP) 3A inhibitor that helps the nirmatrelvir reach and maintain the therapeutic concentrations. Paxlovid has a potential risk of drug interaction by elevating the plasma concentration of other drugs metabolized by CYP3A, like tacrolimus. This report examines the…
The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A - Lung epithelial cells and fibroblasts poorly express angiotensin-converting enzyme 2, and the study aimed to investigate the role of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on inflammation and epithelial-mesenchymal transition (EMT) in two lung cell lines and to understand the potential mechanism. Lung epithelial cells (BEAS-2B) and fibroblasts (MRC-5) were treated with the spike protein, then inflammatory and EMT phenotypes were detected by…
Exploring Novel Vitamin K Derivatives with Anti-SARS-CoV-2 Activity - From our compound library of vitamin K derivatives, we found that some compounds exhibited anti-SARS-CoV-2 activity in VeroE6/TMPRSS2 cells. The common structure of these compounds was menaquinone-2 (MK-2) with either the m-methylphenyl or the 1-naphthyl group introduced at the end of the side chain. Therefore, new vitamin K derivatives having more potent anti-SARS-CoV-2 activity were explored by introducing various functional groups at the ω-position of the side chain. MK-2 derivatives with a…
The role of tocilizumab in the treatment of post-transfusion hyperhaemolysis - Hyperhaemolysis syndrome (HHS) is a serious complication of transfusion mostly reported in patients with sickle cell disease. HHS is characterised by the destruction of both donor and autologous red blood cells. Tocilizumab is a recombinant humanised monoclonal antibody that inhibits the binding of interleukin-6 and has been used in the treatment of severe/critical coronavirus disease 2019 infection but also some cases of HHS. We describe two further cases of HHS successfully treated with…
Immune responses and clinical outcomes following the third dose of SARS-CoV-2 mRNA-BNT162b2 vaccine in advanced breast cancer patients receiving targeted therapies: a prospective study - CONCLUSIONS: Our results confirm that the immune response to tozinameran is impaired by CDK4/6 inhibitors, increasing the odds of breakthrough infections despite the third vaccine dose. Current evidence recommends maintaining efforts to provide booster immunizations to the most vulnerable cancer patients, including those with advanced breast cancer undergoing CDK4/6 inhibition.
Targeting Viral ORF3a Protein: A New Approach to Mitigate COVID-19 Induced Immune Cell Apoptosis and Associated Respiratory Complications - Infection with SARS-CoV-2 is a growing concern to the global well-being of the public at present. Different amino acid mutations alter the biological and epidemiological characteristics, as well as immune resistance of SARS-CoV-2. The virus-induced pulmonary impairment and inflammatory cytokine storm are directly related to its clinical manifestations. But, the fundamental mechanisms of inflammatory responses are found to be the reason for the death of immune cells which render the host immune…
SARS-CoV-2 N protein induced acute kidney injury in diabetic db/db mice is associated with a Mincle-dependent M1 macrophage activation - “Cytokine storm” is common in critically ill COVID-19 patients, however, mechanisms remain largely unknown. Here, we reported that overexpression of SARS-CoV-2 N protein in diabetic db/db mice significantly increased tubular death and the release of HMGB1, one of the damage-associated molecular patterns (DAMPs), to trigger M1 proinflammatory macrophage activation and production of IL-6, TNF-α, and MCP-1 via a Mincle-Syk/NF-κB-dependent mechanism. This was further confirmed in vitro that…