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    Regulation of Lysosome-Associated Membrane Protein 3 ( LAMP3 HGNC) in Lung Epithelial Cells by Coronaviruses (SARS-CoV-1/2) and Type I Interferon Signaling MESHD

    Authors: Ramana Chilakamarti

    doi:10.1101/2021.04.28.441840 Date: 2021-04-28 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major risk factor for mortality and morbidity in critical care hospitals around the world. Lung epithelial type II cells play a major role in several physiological processes, including recognition and clearance of respiratory viruses as well as repair of lung injury MESHD in response to environmental toxicants. Gene expression profiling of lung epithelial type II-specific genes led to the identification of lysosomal-associated membrane protein 3 HGNC ( LAMP3 HGNC). Intracellular locations of LAMP3 HGNC include plasma membrane, endosomes, and lysosomes. These intracellular organelles are involved in vesicular transport and facilitate viral entry and release of the viral RNA into the host cell cytoplasm. In this study, regulation of LAMP3 HGNC expression in human lung epithelial cells by several respiratory viruses and type I interferon signaling was investigated. Coronaviruses including SARS-CoV-1 and SARS-CoV-2 MESHD significantly induced LAMP3 HGNC expression in lung epithelial cells within 24 hours after infection that required the presence of ACE2 HGNC viral entry receptor. Time-course experiments revealed that the induced expression of LAMP3 HGNC by SARS-CoV-2 was correlated with the induced expression of interferon-beta1 HGNC ( IFNB1 HGNC) and signal transducers and activator of transcription 1 ( STAT1 HGNC) mRNA levels. LAMP3 HGNC was also induced by direct IFN-beta treatment or by infection with influenza virus lacking the non-structural protein1(NS1) in NHBE bronchial epithelial cells. LAMP3 HGNC expression was induced in human lung epithelial cells by several respiratory viruses, including respiratory syncytial virus MESHD ( RSV MESHD) and the human parainfluenza virus 3 (HPIV3). Location in lysosomes and endosomes as well as induction by respiratory viruses and type I Interferon suggests that LAMP3 HGNC may have an important role in inter-organellar regulation of innate immunity and a potential target for therapeutic modulation in health and disease. Furthermore, bioinformatics revealed that a subset of lung type II cell genes were differentially regulated in the lungs of COVID-19 MESHD patients.

    Modeling SARS-CoV-2 infection MESHD and its individual differences with ACE2 HGNC-expressing human iPS cells

    Authors: Emi Sano; Ayaka Sakamoto; Natsumi Mimura; Ai Hirabayashi; Yukiko Muramoto; Takeshi Noda; Takuya Yamamoto; Kazuo Takayama

    doi:10.1101/2021.02.22.432218 Date: 2021-02-22 Source: bioRxiv

    Genetic differences are a primary reason for differences in the susceptibility and severity of coronavirus disease 2019 MESHD ( COVID-19 MESHD). Because induced pluripotent stem MESHD (iPS) cells maintain the genetic information of the donor, they can be used to model individual differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection MESHD in vitro. Notably, undifferentiated MESHD human iPS cells themselves cannot be infected bySARS-CoV-2. Using adenovirus vectors, here we found that human iPS cells expressing the SARS-CoV-2 receptor angiotensin-converting enzyme 2 ( ACE2 HGNC) ( ACE2 HGNC-iPS cells) can be infected with SARS-CoV-2. In infected ACE2 HGNC-iPS cells, the expression of SARS-CoV-2 nucleocapsid protein PROTEIN, the budding of viral particles, the production of progeny virus, double membrane spherules, and double-membrane vesicles were confirmed. We also evaluated COVID-19 MESHD therapeutic drugs in ACE2 HGNC-iPS cells and confirmed the strong antiviral effects of Remdesivir, EIDD-2801, and interferon-beta HGNC. In addition, we performed SARS-CoV-2 infection MESHD experiments on ACE2 HGNC-iPS/ES cells from 8 individuals. Male iPS/ES cells were more capable of producing the virus as compared with female iPS/ES cells. These findings suggest that ACE2 HGNC-iPS cells can not only reproduce individual differences in SARS-CoV-2 infection MESHD in vitro, but they are also a useful resource to clarify the causes of individual differences in COVID-19 MESHD due to genetic differences.

    An Investigation Into the Beneficial Effects of High-Dose Interferon beta 1 HGNC-a, Compared to Low-Dose Interferon Beta 1-a (the base therapeutic regimen) in moderate to severe COVID-19 MESHD

    Authors: Ilad Alavi Darazam; Firouze Hatami; Mohammad Mahdi Rabiei; Mohamad Amin Pourhoseingholi; Minoosh Shabani; Shervin Shokouhi; Omid Moradi; Farid Javandoust Gharehbagh; Nasrinsadat Mirtalaee; Halimeh Negahban; Mahdi Amirdosara; Masoud Zangi; Mohammadreza Hajiesmaeili; Muhanna Kazempour; Navid Shafigh

    doi:10.21203/rs.3.rs-138540/v2 Date: 2020-12-30 Source: ResearchSquare

    Introduction: Coronavirus disease 2019 MESHD ( COVID-19 MESHD) has been a serious obstacle in front of public health. Interferon-beta 1a (IFN-β 1a) has been used to treat patients with COVID-19 MESHD. We aimed to compare the effectiveness of high-dose IFN-β 1a compared to low dose IFN-β HGNC 1a in moderate to severe COVID-19 MESHD cases.Methods: In this randomized, controlled, and clinical trial, eligible patients with confirmed SARS-CoV-2 infections MESHD were randomly assigned to receive one of the two following therapeutic regimens: The intervention group was treated with high-dose IFN-β 1a (Recigen) (Subcutaneous injections of 88μg (24,000 IU) on days 1, 3, 6) + lopinavir /ritonavir (Kaletra) and the control group was treated with low-dose IFN-β 1a (Recigen) (Subcutaneous injections of 44μg (12,000 IU) on days 1, 3, 6) + lopinavir /ritonavir (Kaletra) (400mg/100 mg twice a day for 10 days, orally, in two groups). Result: A total of 168 COVID- 19 confirmed patients underwent randomization; 83 were assigned to the intervention group and 85 were assigned to the control group. Median Time To Clinical Improvement (TTIC) for cases treated with low-dose IFN-β1a was shorter than that for cases treated with high-dose IFN-β1a (6 vs10 days). Due to differences between some baseline clinical factors between intervention and control group, we performed an adjusted analysis. The model failed to reach a significant difference between two groups. Conclusion: The use of high-dose IFN-β 1a did not improve TTCI in hospitalized patients with moderate to severe COVID-19 MESHD. Also, it did not have any significant effect on mortality reduction compared with treating with low-dose IFN-β HGNC 1a.Trial registration: The trial was confirmed by the Ethics in Medical Research Committee of the Shahid Beheshti University of Medical Sciences. Signed informed consents were obtained from all the participants or their legally authorized representatives. This trial has been registered as ClinicalTrials.gov, NCT04521400.

    A Meta-analysis of Comorbidities in COVID-19 MESHD: Which Diseases increase the Susceptibility of SARS-CoV-2 Infection MESHD?

    Authors: Srinivasan Ramachandran; Manoj Kumar Singh; Ahmed Mobeen; Amit Chandra; Sweta Joshi

    id:10.20944/preprints202009.0486.v1 Date: 2020-09-21 Source: Preprints.org

    Background: Comorbidities have been frequently reported in COVID-19 MESHD patients, which often lead to more severe outcomes. The underlying molecular mechanisms behind these clinical observations have not yet been explained. Herein, we investigated the disease-specific gene expression signatures that may induce susceptibility to SARS-CoV-2 infection MESHD. Methods: We studied 30 frequently occurring acute, chronic, or infectious diseases of recent times that have shown comorbidity in one or another respiratory disease MESHD(s) caused by pathogenic human infecting coronaviruses, especially SARS-CoV-2. We retrieved array-based gene expression data for each disease and control from relevant datasets. Subsequently, all the datasets were quantile normalized, and log-2 transformed data was used for analysis. Results The expression of ACE2 HGNC receptor and host proteases, namely FURIN HGNC and TMPRSS2 HGNC that are essential for cellular entry of SARS-CoV-2, was upregulated in all six studied subtypes of leukemia MESHD (hereafter, referred as leukemia MESHD). The expression of ACE2 HGNC was also increased in psoriasis MESHD, lung cancer MESHD, Non-alcoholic fatty liver disease MESHD ( NAFLD MESHD), breast cancer MESHD, and pulmonary arterial hypertension MESHD patients. The expression of FURIN HGNC was higher in psoriasis MESHD, NAFLD MESHD, lung cancer MESHD, and in type II diabetic liver MESHD, whereas it was lowered in breast cancer MESHD. Similarly, the expression of TMPRSS2 HGNC was increased during lung cancer MESHD and type II diabetes MESHD; it was decreased during psoriasis MESHD, NAFLD MESHD, lung cancer MESHD, breast cancer MESHD, and cervical cancer MESHD.Furthermore, a heightened expression of genes that are involved in immune response was observed in leukemia MESHD patients, as shown by the higher expression of IFNA2 HGNC, IFNA8 HGNC, IFNA10 HGNC, IFNA14 HGNC, IFNA16 HGNC, IFNA21 HGNC, IFNB1 HGNC, CXCL10 HGNC, and IL6 HGNC. The expression of JAK1 HGNC, STAT1 HGNC, IL6 HGNC, and CXCL10 HGNC was higher in NAFLD MESHD. Besides, JAK1 HGNC and STAT1 HGNC were upregulated in type II diabetic muscles MESHD. In addition, most of the upregulated genes in COVID-19 MESHD patients showed a similar trend in leukemia MESHD, NAFLD MESHD, and psoriasis MESHD. Furthermore, SARS-CoV-2, SARS-CoV MESHD and MERS CoV, were found to commonly alter two genes, namely, CARBONIC ANHYDRASE 11 and CLUSTERIN.Conclusions: The genes that may confer susceptibility to SARS-CoV-2 infection MESHD are mostly upregulated in leukemia MESHD patients; hence, leukemia MESHD patients are relatively more susceptible to develop COVID-19 MESHD, followed by other chronic disorders MESHD, such as, NAFLD MESHD, type II diabetes MESHD, psoriasis MESHD, and hypertension MESHD. This study identifies key genes that are altered in the studied diseases types, which may aid in the infection of SARS-CoV-2 MESHD and underlie COVID-19 MESHD associated comorbidities.

    Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stemcell-derived airway repair response

    Authors: Arunima Purkayastha; Chandani Sen; Gustavo Garcia Jr.; Justin Langerman; Preethi Vijayaraj; David W. Shia; Luisa K. Meneses; Tammy M. Rickabaugh; Apoorva Mulay; Bindu Konda; Myung S. Sim; Barry R. Stripp; Kathrin Plath; Vaithilingaraja Arumugaswami; Brigitte N. Gomperts

    doi:10.1101/2020.07.28.226092 Date: 2020-07-29 Source: bioRxiv

    Most demographic studies are now associating current smoking status with increased risk of severe COVID-19 MESHD and mortality from the disease but there remain many questions about how direct cigarette smoke exposure affects SARS-CoV-2 airway cell infection. We directly exposed mucociliary air-liquid interface (ALI) cultures derived from primary human nonsmoker airway basal stem cells (ABSCs) to short term cigarette smoke and infected them with live SARS-CoV-2. We found an increase in the number of infected airway cells after cigarette smoke exposure as well as an increased number of apoptotic cells. Cigarette smoke exposure alone caused airway injury that resulted in an increased number of ABSCs MESHD, which proliferate to repair the airway. But we found that acute SARS-CoV-2 infection MESHD or the combination of exposure to cigarette smoke and SARS-CoV-2 did not induce ABSC proliferation. We set out to examine the underlying mechanism governing the increased susceptibility of cigarette smoke exposed ALI to SARS-CoV-2 infection MESHD. Single cell profiling of the cultures showed that infected airway cells displayed a global reduction in gene expression across all airway cell types. Interestingly, interferon response genes were induced in SARS-CoV-2 infected MESHD airway epithelial cells in the ALI cultures but smoking exposure together with SARS-CoV-2 infection MESHD reduced the interferon response. Treatment of cigarette smoke-exposed ALI cultures with Interferon {beta}-1 HGNC abrogated the viral infection MESHD, suggesting that the lack of interferon response in the cigarette smoke-exposed ALI cultures allows for more severe viral infection and cell death. In summary, our data show that acute smoke exposure allows for more severe proximal airway epithelial disease from SARS-CoV-2 by reducing the mucosal innate immune response and ABSC proliferation and has implications for disease spread and severity in people exposed to cigarette smoke.

    Clinical evaluation of IFN beta1b in COVID-19 MESHD pneumonia: a retrospective study

    Authors: Miriam Estebanez; German Ramirez-Olivencia; Tatiana Mata; David Marti; Carlos Gutierrez; Begona De Dios; Maria Dolores Herrero; Ana Roel; Yolanda Martinez; Alejandro Aguirre; Francisco Alcantara Nicolas; Pablo Fernandez Gonzalez; Elena Lopez; Lucia E Ballester; Maria Mateo-Maestre; Sergio Campos; Maria J Sanchez-Carrillo; Antonio Fe; Francisco J Membrillo de Novales

    doi:10.1101/2020.05.15.20084293 Date: 2020-05-19 Source: medRxiv

    Background COVID-19 MESHD pneumonia MESHD is associated with significant mortality and has no approved antiviral therapy. Interferon beta1 HGNC has shown in vitro studies a potent inhibition of SARS-CoV MESHD and MERS-CoV. In an in vitro study, SARS-CoV-2 had more sensitivity to IFN-I pretreatment that SARS-CoV MESHD. A combination of IFN beta1b administered subcutaneously with other antiviral treatments has been recommended in several guidelines. However, clinical trial results for the treatment of COVID-19 MESHD are pending. We aimed to assess the efficiency of IFN beta1 HGNCb in COVID19 MESHD comparing the in-hospital mortality between patients who received IFN beta1b and patients did not receive. Methods In this retrospective cohort study, we included hospitalized adults with COVID-19 MESHD between February 23th and April 4th, 2020, at the Central Defense Hospital (Madrid, Spain). Subcutaneous interferon beta-1b HGNC was recommended in moderate-severe pneumonia MESHD. The primary endpoint was in-hospital mortality. Univariate and multivariate analysis was performed to identify variables associated with in-hospital mortality. Findings We analyzed 256 patients (106 patients in interferon group and 150 patients in control group). At admission, patients who did not receive interferon beta1 HGNCb presented a greater number of comorbidities. The overall mortality rate was 24.6% (63/256). Twenty-two patients (20.8%) in the interferon group died and 41 (27.3%) in the control group (p=0.229). In the multivariate analysis, the predictors of in-hospital mortality were age, severity of clinical picture at admission and hydroxychloroquine treatment. Interpretation In hospitalized patients with COVID-19 MESHD, interferon beta1b treatment was not associated to decrease in-hospital mortality. Further assessment of the earlier administration of this drug in randomized trials is recommended.

    Bulk and single-cell gene expression profiling of SARS-CoV-2 infected human cell lines identifies molecular targets for therapeutic intervention

    Authors: Emanuel Wyler; Kirstin Mösbauer; Vedran Franke; Asija Diag; Lina Theresa Gottula; Roberto Arsie; Filippos Klironomos; David Koppstein; Salah Ayoub; Christopher Buccitelli; Anja Richter; Ivano Legnini; Andranik Ivanov; Tommaso Mari; Simone Del Giudice; Jan Patrick Papies; Marcel Alexander Müller; Daniela Niemeyer; Matthias Selbach; Altuna Akalin; Nikolaus Rajewsky; Christian Drosten; Markus Landthaler

    doi:10.1101/2020.05.05.079194 Date: 2020-05-05 Source: bioRxiv

    The coronavirus disease 2019 MESHD ( COVID-19 MESHD) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing global health threat with more than two million infected people since its emergence in late 2019. Detailed knowledge of the molecular biology of the infection is indispensable for understanding of the viral replication, host responses, and disease progression. We provide gene expression profiles of SARS-CoV and SARS-CoV-2 infections MESHD SARS-CoV-2 infection MESHDs in three human cell lines (H1299, Caco-2 and Calu-3 cells), using bulk and single-cell transcriptomics. Small RNA profiling showed strong expression of the immunity and inflammation MESHD-associated microRNA miRNA-155 HGNC upon infection with both viruses. SARS-CoV-2 elicited approximately two-fold higher stimulation of the interferon response compared to SARS-CoV in the permissive human epithelial cell line Calu-3, and induction of cytokines such as CXCL10 HGNC or IL6 HGNC. Single cell RNA sequencing data showed that canonical interferon stimulated genes such as IFIT2 HGNC or OAS2 HGNC were broadly induced, whereas interferon beta HGNC ( IFNB1 HGNC) and lambda (IFNL1-4) were expressed only in a subset of infected cells. In addition, temporal resolution of transcriptional responses suggested interferon regulatory factors (IRFs) activities precede that of nuclear factor-{kappa}B ( NF-{kappa}B HGNC). Lastly, we identified heat shock protein 90 ( HSP90 HGNC) as a protein relevant for the infection. Inhibition of the HSP90 HGNC charperone activity by Tanespimycin/17-N-allylamino-17-demethoxygeldanamycin (17-AAG) resulted in a reduction of viral replication, and of TNF HGNC and IL1B HGNC mRNA levels. In summary, our study established in vitro cell culture models to study SARS-CoV-2 infection MESHD and identified HSP90 HGNC protein as potential drug target for therapeutic intervention of SARS-CoV-2 infection MESHD.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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