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The common reported adverse impacts of COVID-19 vaccination include the injection site's local reaction followed by various non-specific flu-like symptoms. Nevertheless, uncommon cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) and cerebral venous sinus thrombosis (CVST) following viral vector vaccines (ChAdOx1 nCoV-19 vaccine, Ad26.COV2 vaccine) have been reported. This literature review was performed using PubMed and Google Scholar databases using appropriate keywords and their combinations: SARS-CoV-2, adenovirus, spike protein, thrombosis, thrombocytopenia, vaccine-induced immune thrombotic thrombocytopenia (VITT), NF-kappaB, adenoviral vector, platelet factor 4 (PF4), COVID-19 Vaccine, AstraZeneca COVID vaccine, ChAdOx1 nCoV-19 COVID vaccine, AZD1222 COVID vaccine, coagulopathy. The s and titles of each article were assessed by authors for screening and inclusion English reports about post-vaccine CVST and VITT in humans were also collected. Some SARS-CoV-2 vaccines based on viral vector, mRNA, or inactivated SARS-CoV-2 virus have been accepted and are being pragmatic global. Nevertheless, the recent augmented statistics of normally very infrequent types of thrombosis associated with thrombocytopenia have been stated, predominantly in the context of the adenoviral vector vaccine ChAdOx1 nCoV-19 from Astra Zeneca. The numerical prevalence of these side effects seems to associate with this particular vaccine type, i.e., adenoviral vector-based vaccines, but the meticulous molecular mechanisms are still not clear. The present review summarizes the latest data and hypotheses for molecular and cellular mechanisms into one integrated hypothesis demonstrating that coagulopathies, including thromboses, thrombocytopenia, and other associated side effects, are correlated to an interaction of the two components in the COVID-19 vaccine.Copyright © 2022, Iranian Pediatric Hematology and Oncology Society. All rights reserved.
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COVID-19 has been found to affect the expression profile of several mRNAs and miRNAs, leading to dysregulation of a number of signaling pathways, particularly those related to inflammatory responses. In the current study, a systematic biology procedure was used for the analysis of high-throughput expression data from blood specimens of COVID-19 and healthy individuals. Differentially expressed miRNAs in blood specimens of COVID-19 vs. healthy specimens were then identified to construct and analyze miRNA-mRNA networks and predict key miRNAs and genes in inflammatory pathways. Our results showed that 171 miRNAs were expressed as outliers in box plot and located in the critical areas according to our statistical analysis. Among them, 8 miRNAs, namely miR-1275, miR-4429, miR-4489, miR-6721-5p, miR-5010-5p, miR-7110-5p, miR-6804-5p and miR-6881-3p were found to affect expression of key genes in NF-KB, JAK/STAT and MAPK signaling pathways implicated in COVID-19 pathogenesis. In addition, our results predicted that 25 genes involved in above-mentioned inflammatory pathways were targeted not only by these 8 miRNAs but also by other obtained miRNAs (163 miRNAs). The results of the current in silico study represent candidate targets for further studies in COVID-19.Copyright © 2023 Elsevier B.V.
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Background: SARS-CoV-2 has led to a sharp increase in the number of hospitalizations and deaths from pneumonia and multiorgan disease worldwide;therefore, SARS-CoV-2 has become a global health problem. Supportive therapies remain the mainstay treatments against COVID-19, such as oxygen inhalation, antiviral drugs, and antibiotics. Traditional Chinese medicine (TCM) has been shown clinically to relieve the symptoms of COVID-19 infection, and TCMs can affect the pathogenesis of SARS-CoV-2 infection in vitro. Jing Si Herbal Drink (JSHD), an eight herb formula jointly developed by Tzu Chi University and Tzu Chi Hospital, has shown potential as an adjuvant treatment for COVID-19 infection. A randomized controlled trial (RCT) of JSHD as an adjuvant treatment in patients with COVID-19 infection is underway Objectives: This article aims to explore the efficacy of the herbs in JSHD against COVID-19 infection from a mechanistic standpoint and provide a reference for the rational utilization of JSHD in the treatment of COVID-19. Method(s): We compiled evidence of the herbs in JSHD to treat COVID-19 in vivo and in vitro. Result(s): We described the efficacy and mechanism of action of the active ingredients in JSHD to treat COVID-19 based on experimental evidence. JSHD includes 5 antiviral herbs, 7 antioxidant herbs, and 7 anti-inflammatory herbs. In addition, 2 herbs inhibit the overactive immune system, 1 herb reduces cell apoptosis, and 1 herb possesses antithrombotic ability. Conclusion(s): Although experimental data have confirmed that the ingredients in JSHD are effective against COVID-19, more rigorously designed studies are required to confirm the efficacy and safety of JSHD as a COVID-19 treatment.Copyright © 2021
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Considering the urgency of the ongoing COVID-19 pandemic, detection of new mutant strains and potential re-emergence of novel coronaviruses, repurposing of drugs such as ivermectin could be worthy of attention. This review article aims to discuss the probable mechanisms of action of ivermectin against SARS-CoV-2 by summarizing the available literature over the years. A schematic of the key cellular and biomolecular interactions between ivermectin, host cell, and SARS-CoV-2 in COVID-19 pathogenesis and prevention of complications has been proposed.Copyright © 2022 Japan Antibiotics Research Association. All rights reserved.
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An outburst of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a grave threat to global health and the economy. As of May 13, 2020, a total of 42,81,838 cases have been confirmed, with over 2,92,376 deaths worldwide. In India, 75,048 cases have been reported to date with 2,440 deaths. Management of this new coronavirus (COVID19) has mainly focused on infection prevention, case detection, monitoring, and supportive care. As there is no vaccine or specific antiviral treatment for human SARS-CoV-2, therefore identifying the drug treatment options as soon as possible is critical for the response to the COVID19 outbreak. Pro-inflammatory cascade and cytokine storm play a key role in the pathogenesis of new coronavirus. A large number of therapeutic interventions such as antiviral, antimalarial, convalescent plasma therapy, BCG vaccine, mTOR inhibi-tors, Tissue Plasminogen Activator, Human monoclonal antibodies, Anti-parasitic agents, Immunoen-hancers, Nutritional interventions, JAK-STAT signaling inhibitors, ACE2 receptor modulators, and An-giotensin II receptor blockers have been either tried or suggested for effective treatment of patients with SARS-CoV-2 disease. Hence, we recommend that all the above potential interventions must be imple-mented in terms of their safety and efficacy through proper clinical experiments to control the emerging SARS-CoV-2 disease.Copyright © 2021 Bentham Science Publishers.
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Despite the measures taken and the molecular advances for the development of new agents for the control of SARS-CoV-2 infection, there is still insufficient development of an effective treatment. The objective of the review was to de-scribe the clinical studies and reported articles on drugs used as possible therapeutic agents for COVID-19 and the main conclusions on their reuse. A non-systematic review through PubMed, ScienceDirect, and clinical trials at ClinicalTrials. gov on original articles and case report in English and Span-ish that will report information on COVID-19 treatment and its main conclusions. Articles that were not relevant or that did not mention updated information to that reported in other articles were excluded. A total of 99 bibliographic references were included. COVID-19 appears as a multisystemic disease with variable clinical symptoms. Since no specific treatment is yet known, multiple drugs have been proposed that attack the different pathways of SARS-CoV-2. For severe disease in patients who require hospitalization and oxygen support, the use of remdesivir, dexamethasone, or tocilizumab is recommended if there are patient conditions that apply to use them. The use of ivermectin, colchicine, lopinavir/ritonavir, hydroxy-chloroquine, and chloroquine have not reported benefits that surpass adverse effects.
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To date, there is no consensus explaining the relationship between varying concentrations of IFNgamma and the severity of infection caused by SARS-CoV-2. The aim of this article was to analyze and formulate conclusions from the selected studies and publications, which, in sum, provide a potentially reasonable view on the role of IFNgamma in COVID-19 pathogenesis. This article highlights current data on the immunological role of IFNgamma which affects differentiation of naive T helper cells, acting as a polarizing factor. It activates the major histocompatibility complex (MHC) class I and II, by increasing the expression of MHC I/II subunits, inhibiting replication of the viral particles by initiating activation of interferon-stimulated genes followed by subsequent synthesis of antiviral proteins. Moreover, IFNgamma activates the production of cytokines by T cells, enhancing cytotoxic activity of the T killers. IFNgamma exerts immunostimulatory and immunomodulatory effects via STAT1, SOCS1 and PIAS genes, thus regulating activation of the JAK-STAT signaling pathway. A number of studies were considered where the patterns of changes in serum IFNgamma concentration were examined in viral infections and SARS-CoV-2. We performed a systemic analysis of the results of studies that showed a relationship between high concentrations of IFNgamma and COVID-19 severity. In a number of studies, the significantly high levels of IFNgamma in COVID-19 patients were often associated with a poor outcome of the disease. The median values of the IFNgamma concentration in severe COVID-19 were found to be significantly higher compared to the results obtained in the cases of moderate severity. It shows an increase, in parallel with viral load in the nasopharyngeal samples upon worsening of the clinical condition. Based on the data on the decreased IFNgamma concentrations in convalescent patients, the mechanism of antagonism between IFNgamma and IL-4 is considered, where the decreases serum concentrations of IFNgamma along with increasing level of IL-4 may be an indirect proof of normal adaptive immune response with subsequent development of antibodies to SARS-CoV-2 and gradual elimination of the virus from the body. Moreover, the evidence is discussed that the patients harboring some parasitic infections (Toxoplasma gondii, Cryptosporidium, Blastocystis hominis, Giardia duodenalis, Entamoeba histolytica) with persistently elevated level of IFNgamma are at reduced risk for severe course of COVID-19. Copyright © 2022, SPb RAACI.
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Background: Novel coronavirus (COVID-19) is an infectious disease which causes the outbreak as a pandemic and reiterated the call for countries to take immediate actions and proportion response to treat, detect and cut back transmission to save lots of people's lives. Several targeting specific functional proteins and ligands against coronavirus have been reported to prevent replication of virus RNA. Aim(s): The study was aimed to targetthe interleukin-6 protein, that may further block the binding of the virus to human cell receptor and signal transduction which activate the intracellular JAK-MAPK (Janus Kinase\Mitogenactivated protein kinase) and JAK- STAT3 (Janus Kinase/Signal Transducer and Activator of Transcription) signaling pathways. Method(s): In this study, we selected 36 reported compounds and 2 standard anti-HIV drugs such as Abacavir and Hydroxychloroquine for the inhibition of IL-6 protein. It has been reportable with their antiviral efficacies against alternative virus-infected diseases. Molecular docking analyses were performed to identify the best affinity compound against IL-6. Result(s): Among 38 reported compounds, gallic acid and luteolin are the best binding affinity against Interleukin-6 protein. Conclusion(s): Therefore, the results suggest that gallic acid and luteolin has a potential inhibitory function against IL-6 protein, which inhibits the interaction and signal transduction of the virus with the host cell and it provide a potential lead molecule for the development of a new drug against COVID-19disease. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.
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The immune status of patients plays an essential role in COVID-19. Herbal medicine with immunomodulatory and anti-inflammatory effect could have potential as a complementary therapeutic along with modern medicine. This study aims to investigate the anti-inflammatory and immunomodulatory constituents of Curcuma longa (C. longa) and its possible mechanisms in COVID-19. We systematically sorted the biochemical of C. longa rhizome from literature and repository. Next, we investigated targets related to COVID-19 in the selected active phytochemical constituents and analyzed the possible mechanisms against COVID-19 and performed molecular docking with four essential target proteins in COVID-19 for further verification. Ten active phytochemical constituents of C. longa were predicted to interact with four protein targets. The epidermal growth factor was the most interacted protein targeted by Calebin A, curcumin, cyclocurcumin, demethoxycurcumin, turmeronol a, turmeronol b, caffeic acid, and quercetin. Interferon-gamma was performed as the most critical protein targeted by 4-hydroxycinnamic acid. Curcumin was also predicted to interact with toll-like receptor 4 and Ar-turmerone with angiotensin II receptor type 2. We also reported four signaling pathways associated with target proteins-active phytochemical constituents against COVID-19: cytokine-cytokine receptor interaction, tolllike receptor signaling pathway, Jak-STAT signaling pathway, and PI3K-Akt signaling pathway. In conclusion, multi compounds in C. longa might act synergistically against COVID-19 by affecting the inflammatory and immune responses, and other pathological processes through multiple targets and pathways. Copyright © Indradi RB et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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The occurrence of SARS-CoV-2 in 2019 is the second coronavirus spread-out after the SARS-CoV, which has pandemic potential. Search for its remedies is dependent on integrative knowledge of cell signaling pathways, which is under clinical scrutiny. The major cascades triggered by coronavirus entry include Renin-Angiotensin System, MAPK, NF-κB, JAK/STAT which are involved with innate immunity. Some other modes are, unfolded protein response signaling and inflammasome mediated apoptosis activation. Virulence factors of the SARS-CoVs like spike, envelope, nonstructural proteins etc., interfere with some of these viral defense pathways. Therapeutically, the viral intrusion, multiplication, as well as tissue-injurious cytokine overreactions are targeted by pathway-specific drugs. Viral entry blockers, p38 MAPK inhibitors, cytokine regulators, JAK inhibitors, and anti-inflammatory drugs are either being repurposed or innovated with scopes for futuristic modeling. This chapter is aimed to elucidate the pathological signaling network behind Severe Acute Respiratory Syndrome, for evaluation of existing and postulated drug targets. © 2022 Elsevier Inc. All rights reserved.
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Acute respiratory distress syndrome (ARDS) is characterized by noncardiogenic pulmonary edema. It has a high mortality rate and lacks effective pharmacotherapy. With the outbreak of COVID-19 worldwide, the mortality of ARDS has increased correspondingly, which makes it urgent to find effective targets and strategies for the treatment of ARDS. Recent clinical trials of Janus kinase (JAK) inhibitors in treating COVID-19-induced ARDS have shown a positive outcome, which makes the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway a potential therapeutic target for treating ARDS. Here, we review the complex cause of ARDS, the molecular JAK/STAT pathway involved in ARDS pathology, and the progress that has been made in strategies targeting JAK/STAT to treat ARDS. Specifically, JAK/STAT signaling directly participates in the progression of ARDS or colludes with other pathways to aggravate ARDS. We summarize JAK and STAT inhibitors with ARDS treatment benefits, including inhibitors in clinical trials and preclinical studies and natural products, and discuss the side effects of the current JAK inhibitors to reveal future trends in the design of JAK inhibitors, which will help to develop effective treatment strategies for ARDS in the future.
Subject(s)
COVID-19 , Janus Kinases , Respiratory Distress Syndrome , STAT Transcription Factors , Humans , COVID-19/genetics , Janus Kinase Inhibitors/pharmacology , Janus Kinases/genetics , Janus Kinases/metabolism , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/genetics , Signal Transduction , STAT Transcription Factors/genetics , STAT Transcription Factors/metabolismABSTRACT
Curcumae Longae Rhizoma (CLR) is the rhizome of Curcuma longa L. Pharmacological studies show that CLR can be used to treat cervical cancer, lung cancer, lupus nephritis, and other conditions. In this paper, we review botany, traditional application, phytochemistry, pharmacological activity, and pharmacokinetics of CLR. The literature from 1981 to date was entirely collected from online databases, such as Web of Science, Google Scholar, China Academic Journals full-text database (CNKI), Wiley, Springer, PubMed, and ScienceDirect. The data were also obtained from ancient books, theses and dissertations, and Flora Reipublicae Popularis Sinicae. There are a total of 275 compounds that have been isolated from CLR, including phenolic compounds, volatile oils, and others. The therapeutic effect of turmeric has been expanded from breaking blood and activating qi in the traditional sense to antitumor, anti-inflammatory, antioxidation, neuroprotection, antibacterial, hypolipidemic effects, and other benefits. However, the active ingredients and mechanisms of action related to relieving disease remain ill defined, which requires more in-depth research and verification at a clinical level.
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Coronaviruses (CoVs) are RNA viruses that can infect a wide range of animals, including humans, and cause severe respiratory and gastrointestinal disease. The Gammacoronavirus avian infectious bronchitis virus (IBV) causes acute and contagious diseases in chickens, leading to severe economic losses. Nonstructural protein 14 (Nsp14) is a nonstructural protein encoded by the CoV genome. This protein has a regulatory role in viral virulence and replication. However, the function and mechanism of IBV Nsp14 in regulating the host's innate immune response remain unclear. Here we report that IBV Nsp14 was a JAK-STAT signaling pathway antagonist in chicken macrophage (HD11) cells. In these cells, Nsp14 protein overexpression blocked IBV suppression induced by exogenous chIFN-γ treatment. Meanwhile, Nsp14 remarkably reduced interferon-gamma-activated sequence (GAS) promoter activation and chIFN-γ-induced interferon-stimulated gene expression. Nsp14 impaired the nuclear translocation of chSTAT1. Furthermore, Nsp14 interacted with Janus kinase 1 (JAK1) to degrade JAK1 via the autophagy pathway, thereby preventing the activation of the JAK-STAT signaling pathway and facilitating viral replication. These results indicated a novel mechanism by which IBV inhibits the host antiviral response and provide new insights into the selection of antiviral targets against CoV.
Subject(s)
Infectious bronchitis virus , Animals , Antiviral Agents/pharmacology , Chickens , Infectious bronchitis virus/physiology , Janus Kinase 1/genetics , Signal TransductionABSTRACT
Recent emergence of SARS-Cov-2 has resulted in unprecedented spread of COVID-19 exhibiting wide variability in individuals’ symptoms. Despite rapid progress in characterizing the role of host genetics in SARS-Cov-2 infection, there is limited understanding of the role of host genetic variation and the molecular mechanisms including the knowledge of genes and pathways that contribute to COVID-19. Previous research to understand the mechanisms underlying severe COVID-19 outcomes have focused on lung- and brain-related pathologies. Here, we integrated a genome-wide association study of COVID-19 hospitalization (7,885 cases and 961,804 controls from COVID-19 Host Genetics Initiative) with mRNA expression, splicing, and protein levels (n = 18,502). We identified 27 genes related to inflammation and coagulation pathways whose genetically predicted expression was associated with COVID-19 hospitalization. These genes converge on cytokine-cytokine and the JAK-STAT signaling pathways. We functionally characterized the 27 genes using phenome- and laboratory-wide association scans in Vanderbilt Biobank (BioVU;n = 85,460) and identified coagulation-related clinical symptoms, immunologic, and blood-cell-related biomarkers. We replicated these findings in the African-American cohort here in BioVU and found concordant results. This study highlights putative causal genes impacting COVID-19 severity and symptomology through the host inflammatory response.
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Excessive inflammation post-traumatic spinal cord injury (SCI) induces microglial activation, which leads to prolonged neurological dysfunction. However, the mechanism underlying microglial activation-induced neuroinflammation remains poorly understood. Ruxolitinib (RUX), a selective inhibitor of JAK1/2, was recently reported to inhibit inflammatory storms caused by SARS-CoV-2 in the lung. However, its role in disrupting inflammation post-SCI has not been confirmed. In this study, microglia were treated with RUX for 24 hours and then activated with interferon-γ for 6 hours. The results showed that interferon-γ-induced phosphorylation of JAK and STAT in microglia was inhibited, and the mRNA expression levels of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1ß, interleukin-6, and cell proliferation marker Ki67 were reduced. In further in vivo experiments, a mouse model of spinal cord injury was treated intragastrically with RUX for 3 successive days, and the findings suggest that RUX can inhibit microglial proliferation by inhibiting the interferon-γ/JAK/STAT pathway. Moreover, microglia treated with RUX centripetally migrated toward injured foci, remaining limited and compacted within the glial scar, which resulted in axon preservation and less demyelination. Moreover, the protein expression levels of tumor necrosis factor-α, interleukin-1ß, and interleukin-6 were reduced. The neuromotor function of SCI mice also recovered. These findings suggest that RUX can inhibit neuroinflammation through inhibiting the interferon-γ/JAK/STAT pathway, thereby reducing secondary injury after SCI and producing neuroprotective effects.
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Background: Gastrointestinal (GI) symptoms are the most common extrapulmonary manifestation of coronavirus disease 2019 (COVID-19). Therefore, we sought to determine the impact of GI symptoms on disease outcomes and the systemic inflammatory response in COVID-19. Methods: In two large, independent cohorts of hospitalized COVID-19 patients in the United States (n=634) and Italy (n=287) we examined GI symptoms on admission and related them to mortality and circulating proteomic biomarkers. Disease severity defined by oxygenation and end organ damage was also examined as an outcome in the US cohort. In both cohorts, a multivariate logistic regression was performed to determine the association of GI symptoms (nausea, vomiting, and diarrhea) present on admission and outcomes adjusting for age, gender and examined comorbid diseases. A prediction model was built based on the initial US cohort and validated with a distinct US cohort (n=242). In a subset of patients (n=238), circulating cytokines and chemokines were examined using a multiplexed proteomic assay (Olink) that simultaneously quantified 92 protein analytes. Results: A significant reduction in disease-associated mortality in COVID-19 patients presenting with GI symptoms was observed both in the US cohort (OR 0.54, 95% CI 0.34-0.86) and the Italian cohort (OR 0.33, 95% CI 0.13-0.67) which was independent of age, gender and comorbidities. A prediction model consisting of age and BMI with the addition of GI symptoms had a significantly improved ability to predict disease severity and mortality compared with age and BMI alone (median area under the curve (AUC) of 0.64 (age + BMI+ GI symptoms) vs 0.59 (age + BMI) for disease severity and 0.73 (age + BMI + GI symptoms) vs 0.70 (age + BMI) for mortality). The proteomic analysis revealed 6 clusters based on their co-segregation across all COVID-19 patients. Among these 6 clusters, clusters 4 and 5, which were enriched in the "Hallmark Inflammatory Response" and “KEGG JAK/STAT Signaling Pathway” respectively, and were reduced in patients with diarrhea. The observed mortality reduction in COVID-19 patients with GI symptoms was associated with lower circulating levels of key inflammatory proteins including IL-6, IL-8, IL-17A and CCL28 that are known to be associated with poor outcomes in COVID-19;while there was an increase in IL-7 and TRAIL, which both have important immunoregulatory functions. Conclusions: COVID-19 patients with GI symptoms have reduced inflammatory biomarkers and improved survival after adjusting for comorbidities, age and gender. These data highlight GI involvement as an important parameter for severity stratification in COVID-19 and point towards an immunomodulatory role of the GI tract in response to SARS-CoV-2 infection. (Figure presented)
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Comprehensive proteomic studies of HSC derived from bone marrow of healthy human subjects (n = 59) in different age groups (range: 20 - 72 years) showed that aging HSCs are characterized not only by myeloid lineage skewing, senescence associated secretory phenotype (SASP), accumulation of reactive oxygen species (ROS), anti-apoptosis, but prominently by elevated glycolysis, glucose uptake, and accumulation of glycogen. This is caused by a subset of HSC that has become more glycolytic than others and not on a per cell basis. Subsequent comparative transcriptome studies of HSCs from human subjects >60 years versus those from <30 years have confirmed this association of elevated glycolysis with aging transcriptome signature. Provided with this background and based on glucose metabolism levels, we have developed a method to isolate human HSCs (CD34+ cells) from bone marrow into three distinct subsets with high, intermediate, and low glucose uptake (GU) capacity (GU high, GU inter, GU low). For human subjects >60 years old (n=9), the proportions of these subsets are: GU high= 5.4+3.5 %, GU inter= 66.4+22.5 %, GU low= 28.2+21.7 %. For subjects <30 years (n=5), the proportions are GU high= 1.7+1.5 %, GU inter= 66.5+36.9 %, GU low= 31.8+36.7. Single-cell RNA-sequencing (scRNA-seq) studies and gene ontology analysis of biological processes revealed that, compared to the GU inter and GU low subsets, the GU high cells showed a significantly higher expression of genes involved in myeloid development, inflammation response (AIF1, CASP2, ANXA1, ZFP36), anti-apoptosis (GSTP1, NME1, BCL2, DMNT1, BAX), cell cycle checkpoint (MCL1, CDK1, CDK4, EIF5A), histone regulation (BCL6, EGR1, KDM1A, MLLT3), b-galactosidase, and significantly lower expressions of genes involved in lymphoid development, and of MDM4, MDM2, FOXP1, SOX4, RB1. Functional studies indicated that the glycolytic enzymes were elevated in elderly HSCs, and the GU low subset corresponded to primitive and more pluripotent HSCs than the GU interand GU high subsets. Pathway analyses have then demonstrated that the GU high subset is associated with up-regulated p53 as well as JAK/STAT signaling pathways, characteristic of senescent HSCs observed in murine models. Applying Gene Set Enrichment Analysis (GSEA) algorithms, we have compared the scRNA-seq data of CD34+ cells derived from young (<30 years) versus older (>60 years) subjects, as well as the scRNA-seq data from GU high subset versus GU inter and GU lowsubsets from each individual subject (n = 6). The results are shown in Figure 1. In analogy to the comparison between old (>60 years) versus young (<30 years) HSCs (CD34+ cells), GSEA of the GU high versus GU inter and GU low subsets shows the same pattern of changes - significant upregulation of gene-set expressions for (a) inflammatory response (b) G2M checkpoint, (c) MTORC1, (d) ROS, (Fig. 1B), (e) allograft rejection;and down-regulation of gene-set expressions for (f) pluripotency, (g) androgen response, (h) UV response (Fig. 1C) as well as (i) interferon-a induction during SARS-CoV2-infection (data not shown in Fig. 1). Thus, our novel findings of elevated glycolysis coupled with significant activation of MTORC1 in the senescent cells of the HSC compartment have provided evidence for the important role of calorie restriction (CR) for healthy aging of HSCs. In numerous animal models, aging has been shown to be driven by the nutrient-sensing MTORC1 network. In animal models of aging, CR has been reported to deactivate the MTOR pathway, thus slowing aging and delaying diseases of aging. Conclusion: In a series of multi-omics studies, we have demonstrated that the GU high subset is identical to the senescent cells (SCs) in human HSC compartment. Studies in animal models have shown that SCs in murine bone marrow are responsible for driving the aging process, and elimination of this subset by inhibitors of anti-apoptotic factors is able to rejuvenate hematopoiesis in mice. Our present results have provided cellular and molecular evidence that SCs in human HSC compartment re also dependent on anti-apoptotic factors, elevated MTORC1 as well as increased glycolysis for survival. Inhibition of MTORC1 or glycolysis, either by specific inhibitors or by CR, may eliminate senescent HSCs and promote rejuvenation of human hematopoiesis. [Formula presented] Disclosures: No relevant conflicts of interest to declare.
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Coronavirus disease 2019 (COVID-19) has caused a crisis to global public health since its outbreak at the end of 2019. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of COVID-19, appears to efficiently evade the host immune responses, including interferon (IFN) signaling. Several SARS-CoV-2 viral proteins are believed to involve in the inhibition of IFN signaling. In this study, we discovered that ORF3a, an accessory protein of SARS-CoV-2, inhibited IFN-activated Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling via upregulating suppressor of cytokine signaling 1 (SOCS1), a negative regulator of cytokine signaling. ORF3a induced SOCS1 elevation in a dose- and time-dependent manner. RNAi-mediated silencing of SOCS1 efficiently abolished ORF3a-induced blockage of JAK/STAT signaling. Interestingly, we found that ORF3a also promoted the ubiquitin-proteasomal degradation of Janus kinase 2 (JAK2), an important kinase in IFN signaling. Silencing of SOCS1 by siRNA distinctly blocked ORF3a-induced JAK2 ubiquitination and degradation. These results demonstrate that ORF3a dampens IFN signaling via upregulating SOCS1, which suppressed STAT1 phosphorylation and accelerated JAK2 ubiquitin-proteasomal degradation. Furthermore, analysis of ORF3a deletion constructs showed that the middle domain of ORF3a (amino acids 70-130) was responsible for SOCS1 upregulation. These findings contribute to our understanding of the mechanism of SARS-CoV-2 antagonizing host antiviral response.
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COVID-19, a novel identified coronavirus disease due to Severe Acute Respiratory Syndrome coronaviruses 2 (SARS-Cov-2) infection, has posed a significant threat to public health worldwide. It has been reported COVID-19 keeps substantial nucleotide similarity and shares common receptor, Angiotensin-converting enzyme 2 (ACE2) with Severe Acute Respiratory Syndrome coronaviruses (SARS-Cov). Here, we investigated the gene expression of ACE2 and identified associated pathways of SARS-Cov as a useful reference for a deepening understanding of COVID-19. The results indicated the ACE2 was overexpressed in human airway epithelial cells (HAEs), especially at 72 h after SARS-Cov infection. We found ACE2 might regulate immune response through immunological activation-associated pathways in the process of in both SARS-Cov and SARS-Cov-2 infection, where the activation of B cells, macrophages, helper T cells 1 (Th1 cells) and the inhibition of Foxp3 + regulatory T (Treg) cells and CD8 + T cells were found to be prominent. Finally, significant correlation between ACE2 and JAK-STAT signaling pathway was identified which indicate that JAK-STAT signaling pathway might involve in the downstream action of the overactivation of ACE2. These findings are expected to gain a further insight into the action mechanism of COVID-19 infection and provide a promising target for designing effective therapeutic strategies.
Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Janus Kinases/metabolism , STAT Transcription Factors/metabolism , COVID-19/genetics , Case-Control Studies , Humans , Lung/immunology , Lung/virology , Signal Transduction , TranscriptomeABSTRACT
Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational "transcriptotype" that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.