- CGRP inhibits SARS-CoV-2 infection of bronchial epithelial cells and its pulmonary levels correlate with viral clearance in critical COVID-19 patients -
Upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with critical coronavirus disease 2019 (COVID-19) present with life-threatening respiratory distress, pulmonary damage and cytokine storm. One unexplored hub in COVID-19 is the neuropeptide calcitonin gene-related peptide (CGRP), which is highly abundant in the airways and could converge in multiple aspects of COVID-19-related pulmonary pathophysiology. Whether CGRP affects SARS-CoV-2 infection directly remains elusive. We show that in critical COVID-19 patients, CGRP is increased in both plasma and lungs. Importantly, CGRP pulmonary levels are elevated in early SARS-CoV-2-positive patients, and restore to baseline upon subsequent viral clearance in SARS-CoV-2-negative patients. We further show that CGRP and its stable analogue SAX directly inhibit infection of bronchial Calu-3 epithelial cells with SARS-CoV-2 Omicron and Alpha variants in a dose-dependent manner. Both pre- and post-infection treatment with GRRP and/or SAX is enough to block SARS-CoV-2 productive infection of Calu3 cells. CGRP-mediated inhibition occurs via activation of the CGRP receptor and involves down-regulation of SARS-CoV-2 entry receptors at the surface of Calu-3 cells. Together, we propose that increased pulmonary CGRP mediates beneficial viral clearance in critical COVID-19 patients, by directly inhibiting SARS-CoV-2 infection. Hence, CGRP-based interventions could be harnessed for management of COVID-19.
- Rapid Emergence and Evolution of SARS-CoV-2 Variants in Advanced HIV Infection -
Previous studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions, but the evolutionary processes underlying these observations are incompletely understood. Here we used high-throughput, single-genome amplification and sequencing (HT-SGS) to obtain up to ~103 SARS-CoV-2 spike gene sequences in each of 184 respiratory samples from 22 people with HIV (PWH) and 25 people without HIV (PWOH). Twelve of 22 PWH had advanced HIV infection, defined by peripheral blood CD4 T cell counts (i.e., CD4 counts) <200 cells/L. In PWOH and PWH with CD4 counts [≥]200 cells/L, most single-genome spike sequences in each person matched one haplotype that predominated throughout the infection. By contrast, people with advanced HIV showed elevated intra-host spike diversity with a median of 46 haplotypes per person (IQR 14-114). Higher intra-host spike diversity immediately after COVID-19 symptom onset predicted longer SARS-CoV-2 RNA shedding among PWH, and intra-host spike diversity at this timepoint was significantly higher in people with advanced HIV than in PWOH. Composition of spike sequence populations in people with advanced HIV fluctuated rapidly over time, with founder sequences often replaced by groups of new haplotypes. These population-level changes were associated with a high total burden of intra-host mutations and positive selection at functionally important residues. In several cases, delayed emergence of detectable serum binding to spike was associated with positive selection for presumptive antibody-escape mutations. Taken together, our findings show remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern (VOCs).
- Antigen-display exosomes provide adjuvant-free protection against SARS-CoV-2 disease at nanogram levels of spike protein -
As the only bionormal nanovesicle, exosomes have high potential as a nanovesicle for delivering vaccines and therapeutics. We show here that the loading of type-1 membrane proteins into the exosome membrane is induced by exosome membrane anchor domains, EMADs, that maximize protein delivery to the plasma membrane, minimize protein sorting to other compartments, and direct proteins into exosome membranes. Using SARS-CoV-2 spike as an example and EMAD13 as our most effective exosome membrane anchor, we show that cells expressing a spike-EMAD13 fusion protein produced exosomes that carry dense arrays of spike trimers on 50% of all exosomes. Moreover, we find that immunization with spike-EMAD13 exosomes induced strong neutralizing antibody responses and protected hamsters against SARS-CoV-2 disease at doses of just 0.5-5 ng of spike protein, without adjuvant, demonstrating that antigen-display exosomes are particularly immunogenic, with important implications for both structural and expression-dependent vaccines.
- Longitudinal transcriptional changes reveal genes from the natural killer cell-mediated cytotoxicity pathway as critical players underlying COVID-19 progression -
Patients present a wide range of clinical severities in response SARS-CoV-2 infection, but the underlying molecular and cellular reasons why clinical outcomes vary so greatly within the population remains unknown. Here, we report that negative clinical outcomes in severely ill patients were associated with divergent RNA transcriptome profiles in peripheral immune cells compared with mild cases during the first weeks after disease onset. Protein-protein interaction analysis indicated that early-responding cytotoxic NK cells were associated with an effective clearance of the virus and a less severe outcome. This innate immune response was associated with the activation of select cytokine-cytokine receptor pathways and robust Th1/Th2 cell differentiation profiles. In contrast, severely ill patients exhibited a dysregulation between innate and adaptive responses affiliated with divergent Th1/Th2 profiles and negative outcomes. This knowledge forms the basis of clinical triage that may be used to preemptively detect high-risk patients before life-threatening outcomes ensue.
- Revisit the Inhibitory Effects of Glucocorticoids on Immunocytes -
Glucocorticoids (GCs) are efficacious agents for reducing inflammation and suppressing immune responses, exerting various effects on immune cells through the intracellular glucocorticoid receptor (GR), and impacting both innate and adaptive immunity. In the context of COVID-19, glucocorticoids are often used to treat severe cases of patients by reducing inflammation, suppressing immune responses, and ameliorating the severity of COVID-19. However, the precise inhibitory effects on immune cells have yet to be comprehensively delineated. In this study, we extensively examined the inhibitory effects of treating Balb/c mice with dexamethasone (DEX) on lymphoid and myeloid cells. We observed that high doses of DEX treatment resulted in a reduction in the number of immunocytes and an attenuation of their activity. Particularly noteworthy, macrophages, DC cells, and monocytes were diminished by approximately 90% following high doses of DEX, while B cells experienced a reduction of about 70% and CD3 T cells were less affected. Furthermore, our findings demonstrated that DEX induces the inhibition of immune cells by engaging in high-affinity binding to GR. Consequently, we conclude that DEX treatments affect a broad range of immune cells, encompassing both lymphoid and myeloid cells, through depletion or the down-regulation of immune function, potentially acting via the GR signaling pathway. These findings may enhance the clinical applicability of DEX in achieving transient immune deficiency.
- Stably-Inverted Apical-Out Human Upper Airway Organoids for SARS-CoV-2 Infection and Therapeutic Testing -
Apical-out organoids produced through eversion triggered by extra-organoid extracellular matrix (ECM) removal or degradation are generally small, structurally variable, and limited for viral infection and therapeutics testing. This work describes ECM-encapsulating, stably-inverted apical-out human upper airway organoids (AORBs) that are large (~500 um diameter), consistently spherical, recapitulate in vivo-like cellular heterogeneity, and maintain their inverted morphology for over 60 days. Treatment of AORBs with IL-13 skews differentiation towards goblet cells and the apical-out geometry allows extra-organoid mucus collection. AORB maturation for 14 days induces strong co-expression of ACE2 and TMPRSS2 to allow high-yield infection with five SARS-CoV-2 variants. Dose-response analysis of three well-studied SARS-CoV-2 antiviral compounds [remdesivir, bemnifosbuvir (AT-511), and nirmatrelvir] shows AORB antiviral assays to be comparable to gold-standard air-liquid interface cultures, but with higher throughput (~10-fold) and fewer cells (~100-fold). While this work focuses on SARS-CoV-2 applications, the consistent AORB shape and size, and one-organoid-per-well modularity broadly impacts in vitro human cell model standardization efforts in line with economic imperatives and recently updated FDA regulation on therapeutic testing.
- A speed limit on serial strain replacement from original antigenic sin -
Many pathogens evolve to escape immunity, yet it remains difficult to predict whether immune pressure will lead to diversification, serial replacement of one variant by another, or more complex patterns. Pathogen strain dynamics are mediated by cross-protective immunity, whereby exposure to one strain partially protects against infection by antigenically diverged strains. There is growing evidence that this protection is influenced by early exposures, a phenomenon referred to as original antigenic sin (OAS) or imprinting. In this paper, we derive new constraints on the emergence of the pattern of successive strain replacements demonstrated by influenza, SARS-CoV-2, seasonal coronaviruses, and other pathogens. We find that OAS implies that the limited diversity characteristic of successive strain replacement can only be maintained if R0 is less than a threshold set by the characteristic antigenic distances for cross-protection and for the creation of new immune memory. This bound implies a "speed limit" on the evolution of new strains and a minimum variance of the distribution of infecting strains in antigenic space at any time. To carry out this analysis, we develop a theoretical model of pathogen evolution in antigenic space that implements OAS by decoupling the antigenic distances required for protection from infection and strain-specific memory creation. Our results demonstrate that OAS can play an integral role in the emergence of strain structure from host immune dynamics, preventing highly transmissible pathogens from maintaining serial strain replacement without diversification.
- Lethal Infection of Human ACE2-Transgenic Mice Caused by SARS-CoV-2-related Pangolin Coronavirus GX_P2V(short_3UTR) -
SARS-CoV-2-related pangolin coronavirus GX_P2V(short_3UTR) can cause 100% mortality in human ACE2-transgenic mice, potentially attributable to late-stage brain infection. This underscores a spillover risk of GX_P2V into humans and provides a unique model for understanding the pathogenic mechanisms of SARS-CoV-2-related viruses.
- A Murine Model of Post-acute Neurological Sequelae Following SARS-CoV-2 Variant Infection -
Viral variant is one known risk factor associated with post-acute sequelae of COVID-19 (PASC), yet the pathogenesis is largely unknown. Here, we studied SARS-CoV-2 Delta variant-induced PASC in K18-hACE2 mice. The virus replicated productively, induced robust inflammatory responses in lung and brain tissues, and caused weight loss and mortality during the acute infection. Longitudinal behavior studies in surviving mice up to 4 months post-acute infection revealed persistent abnormalities in neuropsychiatric state and motor behaviors, while reflex and sensory functions recovered over time. Surviving mice showed no detectable viral RNA in the brain and minimal neuroinflammation post-acute infection. Transcriptome analysis revealed persistent activation of immune pathways, including humoral responses, complement, and phagocytosis, and reduced levels of genes associated with ataxia telangiectasia, impaired cognitive function and memory recall, and neuronal dysfunction and degeneration. Furthermore, surviving mice maintained potent T helper 1 prone cellular immune responses and high neutralizing antibodies against Delta and Omicron variants in the periphery for months post-acute infection. Overall, infection in K18-hACE2 mice recapitulates the persistent clinical symptoms reported in long COVID patients and may be useful for future assessment of the efficacy of vaccines and therapeutics against SARS-CoV-2 variants.
- Prototype mRNA vaccines imprint broadly neutralizing human serum antibodies after Omicron variant-matched boosting -
Immune imprinting is a phenomenon in which an individual's prior antigenic experiences influence responses to subsequent infection or vaccination. Here, using antibody depletion and multiplexed spike-binding assays, we characterized the type-specificity and cross-reactivity of serum antibody responses after mRNA vaccination in mice and human clinical trial participants. In mice, a single priming dose of a preclinical version of mRNA-1273 vaccine encoding Wuhan-1 spike minimally imprinted serum responses elicited by Omicron boosters, enabling a robust generation of type-specific antibodies. However, substantial imprinting was observed in mice receiving an Omicron booster after two priming doses of mRNA-1273, an effect that was mitigated by a second booster dose of Omicron mRNA vaccine. In humans who received two BA.5 or XBB.1.5 Omicron-matched boosters after two or more doses of the prototype mRNA-1273 vaccine, spike-binding and neutralizing serum antibodies cross-reacted with circulating Omicron variants as well as more distantly related sarbecoviruses. Because the serum neutralizing response against Omicron strains and other sarbecoviruses was completely abrogated after pre-clearing with the Wuhan-1 spike protein, antibodies induced by XBB.1.5 boosting in humans focus on conserved epitopes shaped and shared by the antecedent mRNA-1273 primary series. Our depletion analysis also identified cross-reactive neutralizing antibodies that recognize distinct epitopes in the receptor binding domain (RBD) and S2 proteins with differential inhibitory effects on members of the sarbecovirus subgenus. Thus, although the serum antibody response to Omicron-based boosters in humans is dominantly imprinted by prior immunizations with prototype mRNA-1273 vaccines, this outcome can be beneficial as it drives expansion of multiple classes of cross-neutralizing antibodies that inhibit infection of emerging SARS-CoV-2 variants and extend activity to distantly related sarbecoviruses.
- Change in Anti-COVID-19 Behavior and Prejudice against Minorities during the COVID-19 Pandemic: Longitudinal Evidence from Five European Countries -
In the COVID-19 pandemic, it is vital to identify factors increasing behaviors that limit the transmission of COVID-19 (i.e., anti-COVID-19 behavior) and factors protecting against the negative consequences of the pandemic on societies (i.e., prejudice). A simultaneous investigation of a change in anti-COVID behavior and prejudice during the pandemic is essential because some factors (e.g., fear of COVID-19) could increase both outcomes, whilst other factors (e.g., norms in anti-COVID behavior or intergroup contact in prejudice) could bring desirable changes in one outcome without negatively affecting the other. In a three-wave longitudinal study (NT1 = 4275) in five European countries from April to October 2020, we employed a latent change score model to distinguish between intra- and inter-individual changes in anti-COVID-19 behavior and prejudice. On the intra-individual level, anti-COVID-19 behavior was increased by anti-COVID-19 norms; and prejudice against migrants from the Middle East was influenced by positive and negative direct and mass-media intergroup contact.
- Mutation of highly conserved residues in loop 2 of the coronavirus macrodomain demonstrates that enhanced ADP-ribose binding is detrimental to infection -
All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in nonstructural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown that Mac1 is important for virus replication and pathogenesis. Within Mac1, there are several regions that are highly conserved across CoVs, including the GIF (glycine-isoleucine-phenylalanine) motif. To determine how the biochemical activities of these residues impact CoV replication, the isoleucine and the phenylalanine residues were mutated to alanine (I-A/F-A) in both recombinant Mac1 proteins and recombinant CoVs, including murine hepatitis virus (MHV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The F-A mutant proteins had ADP-ribose binding and/or hydrolysis defects that led to attenuated replication and pathogenesis in cell culture and mice. In contrast, the I-A mutations had normal enzyme activity and enhanced ADP-ribose binding. Despite increased ADP-ribose binding, I-A mutant MERS-CoV and SARS-CoV-2 were highly attenuated in both cell culture and mice, indicating that this isoleucine residue acts as a gate that controls ADP-ribose binding for efficient virus replication. These results highlight the function of this highly conserved residue and provide unique insight into how macrodomains control ADP-ribose binding and hydrolysis to promote viral replication and pathogenesis.
- BCG activation of trained immunity is associated with induction of cross reactive COVID-19 antibodies in a BCG vaccinated population. -
Background: During the current COVID 19 pandemic, the rate of morbidity and mortality was considerably lower in BCG vaccinated countries like Pakistan. BCG has been shown to provide cross protection to both disseminated TB as well as non related viral infections in BCG vaccinated children which is consistent with COVID 19 morbidity in the younger age group. Recently, this cross protection was attributed to trained immunity (TI) associated with BCG recall responses in the innate arm of the immune system. Little is known about the longevity of BCG Trained Immunity (TI) beyond early childhood. Objective: To assess the BCG induced recall responses in healthy individuals by cytokines secreted from the TI network and its potential role in providing cross protection against COVID 19 and other viral infections. Study Design: In this cross sectional study, healthy young adults and adolescents (n=20) were recruited from 16-40 years of age, with no prior history of TB treatment, autoimmune, or chronic inflammatory condition. Methods: BCG induced cytokine responses were assessed using prototypic markers for cells of the TI network macrophages [M1 (TNF alpha, IFN gamma), M2 (IL10)], NK (IL2), Gamma delta (gamma delta]) T (IL17, IL4)} and SARS CoV2 IgG antibodies against RBD using short term (12 hours) cultures assay. Results: Significant differences were observed in the magnitude of recall responses to BCG with macrophage cytokines showing the highest mean levels of TNF alpha (9148 pg/ml) followed by IL10 (488 pg/ml) and IFN gamma(355 pg/ml). The ratio of unstimulated vs BCG stimulated cytokines was 132 fold higher for TNF alpha, 40 fold for IL10, and 27 fold for IFN gamma. Furthermore, SARS-CoV-2 antibodies were also detected in unstimulated plasma which showed cross reactivity with BCG. Conclusion: The presence of cross reactive antibodies to SARS-CoV-2 and the relative ratio of pro and anti inflammatory cytokines secreted by activated TI cellular network may play a pivotal role in protection in the early stages of infection as observed during the COVID 19 pandemic in the younger age groups resulting in lower morbidity and mortality.
- VLP-Based Model for Study of Airborne Viral Pathogens -
The recent COVID-19 pandemic has underscored the danger of airborne viral pathogens. The lack of model systems to study airborne pathogens limits the understanding of airborne pathogen distribution, as well as potential surveillance and mitigation strategies. In this work, we develop a novel model system to study airborne pathogens using virus like particles (VLP). Specifically, we demonstrate the ability to aerosolize VLP and detect and quantify aerosolized VLP RNA by Reverse Transcription-Loop-Mediated Isothermal Amplification (RT-LAMP) in real-time fluorescent and colorimetric assays. Importantly, the VLP model presents many advantages for the study of airborne viral pathogens: (i) similarity in size and surface components; (ii) ease of generation and noninfectious nature enabling study of BSL3 and BSL4 viruses; (iii) facile characterization of aerosolization parameters; (iv) ability to adapt the system to other viral envelope proteins including those of newly discovered pathogens and mutant variants; (v) the ability to introduce viral sequences to develop nucleic acid amplification assays.
- Antigen non-specific CD8+ T cells accelerate cognitive decline in aged mice following respiratory coronavirus infection -
Primarily a respiratory infection, numerous patients infected with SARS-CoV-2 present with neurologic symptoms, some continuing long after viral clearance as a persistent symptomatic phase termed long COVID. Advanced age increases the risk of severe disease, as well as incidence of long COVID. We hypothesized that perturbations in the aged immune response predispose elderly individuals to severe coronavirus infection and post-infectious sequelae. Using a murine model of respiratory coronavirus, mouse hepatitis virus strain A59 (MHV-A59), we found that aging increased clinical illness and lethality to MHV infection, with aged animals harboring increased virus in the brain during acute infection. This was coupled with an unexpected increase in activated CD8+ T cells within the brains of aged animals but reduced antigen specificity of those CD8+ T cells. Aged animals demonstrated spatial learning impairment following MHV infection, which correlated with increased neuronal cell death and reduced neuronal regeneration in aged hippocampus. Using primary cell culture, we demonstrated that activated CD8+ T cells induce neuronal death, independent of antigen-specificity. Specifically, higher levels of CD8+ T cell-derived IFN-{gamma} correlated with neuronal death. These results support the evidence that CD8+ T cells in the brain directly contribute to cognitive dysfunction following coronavirus infection in aged individuals.
Studying SARS-CoV-2 interactions using phage-displayed receptor binding domain as a model protein - SARS-CoV-2 receptor binding domain (RBD) mediates viral entry into human cells through its interaction with angiotensin converting enzyme 2 (ACE2). Most neutralizing antibodies elicited by infection or vaccination target this domain. Such a functional relevance, together with large RBD sequence variability arising during viral spreading, point to the need of exploring the complex landscape of interactions between RBD-derived variants, ACE2 and antibodies. The current work was aimed at developing…
Development of an integrated sample amplification control for salivary point-of-care pathogen testing - BACKGROUND: The COVID-19 pandemic has led to a rise in point-of-care (POC) and home-based tests, but concerns over usability, accuracy, and effectiveness have arisen. The incorporation of internal amplification controls (IACs), essential control for translational POC diagnostics, could mitigate false-negative and false-positive results due to sample matrix interference or inhibition. Although emerging POC nucleic acid amplification tests (NAATs) for detecting SARS-CoV-2 show impressive…
Multifunctional polymeric guanidine and hydantoin halamines with broad biocidal activity - Prolonged and excessive use of biocides during the coronavirus disease era calls for incorporating new antiviral polymers that enhance the surface design and functionality for existing and potential future pandemics. Herein, we investigated previously unexplored polyamines with nucleophilic biguanide, guanidine, and hydantoin groups that all can be halogenated leading to high contents of oxidizing halogen that enables enhancement of the biocidal activity. Primary amino groups can be used to…
Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19 - CONCLUSIONS: Olgotrelvir is an oral inhibitor targeting M^(pro) and CTSL with high antiviral activity and plasma exposure and is a standalone treatment candidate for COVID-19.
Ligand fishing approach to explore Amaryllidaceae alkaloids as potential antiviral candidates targeting SARS-CoV-2 Nsp4 - Ligand fishing, also described as affinity-based assay, represents a convenient and efficient approach to separate potential ligands from complex matrixes or chemical libraries. This approach contributes to the identification of lead compounds that can bind to a specific target. In the context of COVID-19, the search for novel therapeutic agents is crucial. Small molecule-based antiviral drugs, such as Amaryllidaceae alkaloids, have been described as potential candidates because they can inhibit…
Regulation of innate immune and inflammatory responses by supersulfides - Innate immunity plays an important role in host defense against microbial infections. It also participates in activation of acquired immunity through cytokine production and antigen presentation. Pattern recognition receptors such as Toll-like receptors and nucleotide oligomerization domain-like receptors sense invading pathogens and associated tissue injury, after which inflammatory mediators such as pro-inflammatory cytokines and nitric oxide are induced. Supersulfides are molecular species…
Evaluation of the humoral and mucosal immune response of a multiepitope vaccine against COVID-19 in pigs - INTRODUCTION: This study evaluated the immune response to a multiepitope recombinant chimeric protein (CHIVAX) containing B- and T-cell epitopes of the SARS-CoV-2 spike’s receptor binding domain (RBD) in a translational porcine model for pre-clinical studies.
In Silico Study on Natural Chemical Compounds from Citric Essential Oils as Potential Inhibitors of an Omicron (BA.1) SARS-CoV-2 Mutants’ Spike Glycoprotein - CONCLUSION: The outcomes of this investigation hold significant potential for the utilization of a homology modeling approach for the prediction of RBD’s secondary structure based on its sequence when the 3D structure of a mutated protein is not available. This opens the opportunities for further advancing the drug discovery process, offering novel avenues for the development of multifunctional, non-toxic natural medications.
A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir - Nirmatrelvir is a potent and selective inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease that is used as an oral antiviral coronavirus disease 2019 (COVID-19) treatment. To sustain unbound systemic trough concentrations above the antiviral in vitro 90% effective concentration value (EC(90)), nirmatrelvir is coadministered with 100 mg of ritonavir, a pharmacokinetic enhancer. Ritonavir inhibits nirmatrelvir’s cytochrome P450 (CYP) 3A4-mediated metabolism…
A stapled lipopeptide platform for preventing and treating highly pathogenic viruses of pandemic potential - The continued emergence of highly pathogenic viruses, which either thwart immune- and small molecule-based therapies or lack interventions entirely, mandates alternative approaches, particularly for prompt and facile pre- and post-exposure prophylaxis. Many highly pathogenic viruses, including coronaviruses, employ the six-helix bundle heptad repeat membrane fusion mechanism to achieve infection. Although heptad-repeat-2 decoys can inhibit viral entry by blocking six-helix bundle assembly, the…
ACE2 Receptor-Targeted Inhaled Nanoemulsions Inhibit SARS-CoV-2 and Attenuate Inflammatory Responses - Three kinds of coronaviruses are highly pathogenic to humans, and two of them mainly infect humans through Angiotensin-converting enzyme 2 （ACE2）receptors. Therefore, specifically blocking ACE2 binding at the interface with the receptor-binding domain is promising to achieve both preventive and therapeutic effects of coronaviruses. Alternatively, drug-targeted delivery based on ACE2 receptors can further improve the efficacy and safety of inhalation drugs. Here, these two approaches are…
TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence - Viruses, as opportunistic intracellular parasites, hijack the cellular machinery of host cells to support their survival and propagation. Numerous viral proteins are subjected to host-mediated post-translational modifications. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein (SARS2-NP) is SUMOylated on the lysine 65 residue, which efficiently mediates SARS2-NP’s ability in homo-oligomerization, RNA association, liquid-liquid phase separation (LLPS). Thereby the innate antiviral…
Plant extracts modulate cellular stress to inhibit replication of mouse Coronavirus MHV-A59 - The Covid-19 infection outbreak led to a global epidemic, and although several vaccines have been developed, the appearance of mutations has allowed the virus to evade the immune response. Added to this is the existing risk of the appearance of new emerging viruses. Therefore, it is necessary to explore novel antiviral therapies. Here, we investigate the potential in vitro of plant extracts to modulate cellular stress and inhibit murine hepatitis virus (MHV)-A59 replication. L929 cells were…
A randomized double-blind placebo-controlled trial of an inhibitor of plasminogen activator inhibitor-1 (TM5614) in mild to moderate COVID-19 - An inhibitor of plasminogen activator inhibitor (PAI)-1, TM5614, inhibited thrombosis, inflammation, and fibrosis in several experimental mouse models. To evaluate the efficacy and safety of TM5614 in human COVID-19 pneumonia, phase IIa and IIb trials were conducted. In an open-label, single-arm trial, 26 Japanese COVID-19 patients with mild to moderate pneumonia were treated with 120-180 mg of TM5614 daily, and all were discharged without any notable side effects. Then, a randomized,…
Antiviral effect of palmatine against infectious bronchitis virus through regulation of NF-κB/IRF7/JAK-STAT signalling pathway and apoptosis - 1. Infectious bronchitis virus (IBV), a gamma-coronavirus, can infect chickens of all ages and leads to an acute contact respiratory infection. This study evaluated the anti-viral activity of palmatine, a natural non-flavonoid alkaloid, against IBV in chicken embryo kidney (CEK) cells.2. The half toxic concentration (CC(50)) of palmatine was 672.92 μM, the half inhibitory concentration (IC(50)) of palmatine against IBV was 7.76 μM and the selection index (SI) was 86.74.3. Mode of action assay…