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    Characterization of SARS-CoV-2 ORF6 deletion variants detected in a nosocomial cluster during routine genomic surveillance, Lyon, France

    Authors: Gregory Queromes; Gregory Destras; Antonin Bal; Hadrien Regue; Gwendolyne Burfin; Solenne Brun; Remi Fanget; Florence Morfin; Martine Valette; Bruno Lina; Emilie Frobert; Laurence Josset

    doi:10.1101/2020.08.07.241653 Date: 2020-08-10 Source: bioRxiv

    Through routine genomic surveillance of the novel SARS-CoV-2 virus (n=229 whole genome sequences), 2 different frameshifting deletions were newly detected in the open reading frame (ORF) 6, starting at the same position (27267). While the 26-nucleotide deletion variant was only found in one sample in March 2020, the 34-nucleotide deletion variant was found within a single geriatric hospital unit in 5/9 patients sequenced and one health care worker with samples collected between April 2nd and 9th, 2020. Both the presence of the 34-nucleotide deletion variant limited to this unit and the clustering of the corresponding whole genome sequences by phylogeny analysis strongly suggested a nosocomial transmission TRANS between patients. Interestingly, prolonged viral excretion of the 34-nucleotide deletion variant was identified in a stool sample 14 days after initial diagnosis for one patient. Clinical data revealed no significant difference in disease MESHD severity between patients harboring the wild-type or the 34-nucleotide deletion variants. The in vitro infection MESHD of the two deletion variants on primate endothelial kidney cells (BGM) and human lung adenocarcinoma MESHD lung adenocarcinoma HP cells (Calu-3) yielded comparable replication kinetics with the wild-type strain. Furthermore, high viral loads were found in vivo regardless of the presence or absence of the ORF6 deletion. Our study highlights the transmission TRANS and replication capacity of two newly described deletion variants in the same ORF6 region.

    The potential effect of the angiotensin-converting enzyme 2 (ACE2) receptor of 2019-nCoV on lung adenocarcinoma MESHD lung adenocarcinoma HP patients

    Authors: qin huo; zhenwei li; ling shao; siqi chen; jiaying li; ni xie

    doi:10.21203/rs.3.rs-49009/v1 Date: 2020-07-25 Source: ResearchSquare

    BackgroundThe 2019-nCoV epidemic is the public health emergency MESHD that has had the greatest impact on the world. Our study aimed to better understand the underlying mechanisms and function of angiotensin-converting enzyme 2 (ACE2) receptor of 2019-nCoV on lung adenocarcinoma MESHD lung adenocarcinoma HP patients (LUAD), and provide a theoretical basis for early diagnosis, prognosis and targeted therapy of 2019-nCoV. MethodsThis study focuses on the expression level, functions, mutation rate, and copy number variations (CNVs) of ACE2 in LUAD using an extensive bioinformatics data mining process. The interaction between ACE2 expression and clinical-pathological parameters of patients with LUAD was investigated using UALCAN. Also, the essential biological features, single nucleotide variations (SNVs), CNVs, and pathway activities of genes interacting with ACE2 in these cancers were further analyzed. ResultsWe found that ACE2 expression in LUAD patients increased with age TRANS, but it was not related to cancer status, patient’s race, patient’s gender TRANS, or patient’s smoking habits. Moreover, our results showed that compared to that in normal tissues, ACE2 was highly expressed in colon adenocarcinoma HP adenocarcinoma MESHD (COAD), kidney renal papillary cell carcinoma HP carcinoma MESHD (KIRP), pancreatic adenocarcinoma HP adenocarcinoma MESHD (PAAD), rectum adenocarcinoma MESHD (READ), and stomach adenocarcinoma MESHD (STAD). However, there is no significant difference in the expression of ACE2 in patients of different ages TRANS. ConclusionsThese findings demonstrate the importance of ACE2 in LUAD, and provide insights into the regulatory mechanisms and function of ACE2.

    Expression and Clinical Significance of SARS-CoV-2 Human Targets in Lung Tissues: Normal, Primary Tumor and Metastasis

    Authors: Karthikeyan Subbarayan; Kamatchi Ulagappan; Claudia Wickenhauser; Barbara Seliger

    id:10.20944/preprints202007.0021.v2 Date: 2020-07-06 Source: preprints.org

    The recent COVID-19 outbreak in China led to a worldwide pandemic associated with a severe acute respiratory illness. A higher incidence of COVID-19 infection MESHD was demonstrated in cancer patients, including patients with lung cancer. This study was conducted to get insights into the reasons for this enhanced frequency of COVID-19 infection MESHD. Methods: Using different bioinformatic tools, the expression and methylation pattern of ACE2 and TMPRSS2 gene were analyzed in healthy and malignant tissues with a focus on lung adenocarcinoma MESHD lung adenocarcinoma HP (LUAD) and correlated to clinical parameters and smoking history. Results: ACE2 and TMPRSS2 were heterogeneously expressed across 36 healthy tissues with the highest expression in digestive, urinary and reproductive organs, while their expression was significantly lower in 36 cancer tissues. In LUAD, ACE2, but not TMPRSS2 was overexpressed, which inversely correlated to the promoter methylation. An age TRANS-dependent upregulation of ACE2 expression was found in LUAD compared to normal lung tissues. In a healthy lung, TMPRSS2 expression was dependent on sex and smoking history and downregulated in LUAD of smokers. Cancer progression was associated with decreased TMPRSS2, but unaltered ACE2 expression, while ACE2 expression in lung metastases of different cancers was higher than in metastasis of other sites. TMPRSS2, but not ACE2 expression, was associated with LUAD patients’ survival. Conclusions: Comprehensive molecular analyses revealed a heterogeneous, distinct expression and methylation profile of ACE2 and TMPRSS2 in healthy lung vs LUAD tissues across sex, age TRANS and smoking history, which is associated with clinical parameters and might have implications for COVID-19 disease MESHD.

    Cell differentiation and aging is accompanied by depletion of the ACE2 protein

    Authors: Eva Bartova; Sona Legartova; Jana Krejci; Orazio A. Arcidiacono

    doi:10.21203/rs.3.rs-39062/v1 Date: 2020-06-29 Source: ResearchSquare

    Angiotensin-converting enzyme (ACE) is a zinc metalloproteinase involved in the renin-angiotensin system (RAS). It is well known that ACE and ACE2 are central regulators of blood SERO pressure. Moreover, recently, it was observed that the ACE2 protein is the main target of the SARS-CoV-2 virus, so we have tried to reveal if there is a distinction in the levels of the ACE2 protein in distinct cell types (sensitive to virus infection MESHD), during cell differentiation and aging. We observed that depletion of the ACE2 protein appears in aorta-associated parts during the aging of adult TRANS mice, and the level of ACE2 was lowest in kidneys of old female TRANS animals in comparison to male TRANS mice. Differentiation into enterocytes and more pronouncedly into cardiomyocytes was accompanied by depletion of the ACE2 protein. The deficiency of histone deacetylase 1 (HDAC1) also caused a decrease in the level of both ACE2 and its interacting partner renin. However, experimental cardiomyogenesis was associated with renin up-regulation. In human lung adenocarcinoma MESHD lung adenocarcinoma HP cells, vitamin D2, but not chloroquine, slightly increased the level of ACE2. Together, the higher level of the ACE2 protein appears in non-differentiated cells and tissue of young mice, in comparisons to terminally differentiated cells and old animals; thus, a higher level of the ACE2 protein, also seen after vitamin D2 treatment, seems to be a barrier against SARS-CoV-2, because it is known that tissues of young individuals are less sensitive to viral infection MESHD.

    The Host Cell ViroCheckpoint: Identification and Pharmacologic Targeting of Novel Mechanistic Determinants of Coronavirus-Mediated Hijacked Cell States

    Authors: Pasquale Laise; Gideon Bosker; Xiaoyun Sun; Yao Shen; Eugene F Douglass; Charles Karan; Ronald B Realubit; Sergey Pampou; Andrea Califano; Mariano J Alvarez

    doi:10.1101/2020.05.12.091256 Date: 2020-05-17 Source: bioRxiv

    Most antiviral agents are designed to target virus-specific proteins and mechanisms rather than the host cell proteins that are critically dysregulated following virus-mediated reprogramming of the host cell transcriptional state. To overcome these limitations, we propose that elucidation and pharmacologic targeting of host cell Master Regulator proteins--whose aberrant activities govern the reprogramed state of infected-coronavirus cells--presents unique opportunities to develop novel mechanism-based therapeutic approaches to antiviral therapy, either as monotherapy or as a complement to established treatments. Specifically, we propose that a small module of host cell Master Regulator proteins (ViroCheckpoint) is hijacked by the virus to support its efficient replication and release. Conventional methodologies are not well suited to elucidate these potentially targetable proteins. By using the VIPER network-based algorithm, we successfully interrogated 12h, 24h, and 48h signatures from Calu-3 lung adenocarcinoma MESHD lung adenocarcinoma HP cells infected with SARS-CoV, to elucidate the time-dependent reprogramming of host cells and associated Master Regulator proteins. We used the NYS CLIA-certified Darwin OncoTreat algorithm, with an existing database of RNASeq profiles following cell perturbation with 133 FDA-approved and 195 late-stage experimental compounds, to identify drugs capable of virtually abrogating the virus-induced Master Regulator signature. This approach to drug prioritization and repurposing can be trivially extended to other viral pathogens, including SARS-CoV-2, as soon as the relevant infection MESHD signature becomes available.

    Single-cell analysis of human lung epithelia reveals concomitant expression of the SARS-CoV-2 receptor ACE2 with multiple virus receptors and scavengers in alveolar type II cells

    Authors: Guangchun Han; Ansam Sinjab; Warapen Treekitkarnmongkol; Patrick Brennan; Kieko Hara; Kyle Chang; Elena Bogatenkova; Beatriz Sanchez-Espiridion; Carmen Behrens; Boning Gao; Luc Girard; Jianjun Zhang; Boris Sepesi; Tina Cascone; Lauren Byers; Don L. Gibbons; Jichao Chen; Seyed Javad Moghaddam; Edwin J. Ostrin; Junya Fujimoto; Jerry Shay; John V. Heymach; John D. Minna; Steven Dubinett; Paul A. Scheet; Ignacio I. Wistuba; Edward Hill; Shannon Telesco; Christopher Stevenson; Avrum E. Spira; Linghua Wang; Humam Kadara

    doi:10.1101/2020.04.16.045617 Date: 2020-04-17 Source: bioRxiv

    The novel coronavirus SARS-CoV-2 was identified as the causative agent of the ongoing pandemic COVID 19. COVID-19-associated deaths MESHD are mainly attributed to severe pneumonia MESHD pneumonia HP and respiratory failure HP. Recent work demonstrated that SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2) in the lung. To better understand ACE2 abundance and expression patterns in the lung we interrogated our in-house single-cell RNA-sequencing dataset containing 70,085 EPCAM+ lung epithelial cells from paired normal and lung adenocarcinoma MESHD lung adenocarcinoma HP tissues. Transcriptomic analysis revealed a diverse repertoire of airway lineages that included alveolar type I and II, bronchioalveolar, club HP/secretory, quiescent and proliferating basal, ciliated and malignant cells as well as rare populations such as ionocytes. While the fraction of lung epithelial cells expressing ACE2 was low (1.7% overall), alveolar type II (AT2, 2.2% ACE2+) cells exhibited highest levels of ACE2 expression among all cell subsets. Further analysis of the AT2 compartment (n = 27,235 cells) revealed a number of genes co-expressed with ACE2 that are important for lung pathobiology including those associated with chronic obstructive pulmonary disease MESHD chronic obstructive pulmonary disease HP (COPD; HHIP), pneumonia MESHD pneumonia HP and infection MESHD (FGG and C4BPA) as well as malarial/bacterial (CD36) and viral (DMBT1) scavenging which, for the most part, were increased in smoker versus light or non-smoker cells. Notably, DMBT1 was highly expressed in AT2 cells relative to other lung epithelial subsets and its expression positively correlated with ACE2. We describe a population of ACE2-positive AT2 cells that co-express pathogen (including viral) receptors (e.g. DMBT1) with crucial roles in host defense thus comprising plausible phenotypic targets for treatment of COVID-19.

    Involvement of Bradykinin and Folate receptor in calming the SARS-COV2 cytokine storm: Lessons learnt from lung cancer

    Authors: Pruthvi Gowda; Ellora Sen

    doi:10.21203/rs.3.rs-23656/v1 Date: 2020-04-17 Source: ResearchSquare

    Background: Severe acute respiratory syndrome MESHD coronavirus (SARS-CoV2) is a highly pathogenic respiratory virus that causes morbidity and mortality in humans. The lungs are the major pathological target of SARS-CoV infection MESHD. The pathological derangements, aberrant signalling and dysregulated inflammation MESHD characteristics of lung cancer have marked similarities with the clinical manifestation of SARS-COV2 infection MESHD. As heightened inflammatory response is a key feature of both SARS-CoV infection MESHD and lung cancer and given the intriguing commonalities between the two, we analysed the RNA sequence dataset from lung cancer patients to get a better understanding of the critical regulators of inflammation MESHD in SAR TRANS-COV2. Methods: The Cancer Genome Atlas (TCGA) data sets of lung cancer were analyzed for correlations between ACE2, Bradykinin, and other genes associated with inflammatory responses.Results: TCGA dataset analysis indicated an inverse correlation between ACE2 and Bradykinin Receptor 1 (BDKRB1), IL-6 and IFNg in lung adenocarcinoma MESHD lung adenocarcinoma HP. A positive correlation between EGF, FOLR1, MAOA, NOSTRIN, MARC2, PHKD1, and ACE2 was noted Summary: Our analysis has identified a common (i) ACE2- BDKRB1-inflammatory network and (ii) FOLR1-Nitric oxide cross-talk in lung cancer and SARS-CoV2. Better understanding of the convergences between critical players in these networks would enable efficient repurposing of approved lung cancer therapeutics for COVID-19 infection MESHD

    Analysis the susceptibility of lung cancer patients to SARS-CoV-2 infection MESHD

    Authors: Qi Kong

    doi:10.21203/rs.3.rs-17713/v1 Date: 2020-03-17 Source: ResearchSquare

    Recent studies have reported that 2019 novel coronavirus disease (COVID-19) patients with lung cancer have a higher risk of severe events than patients without cancer. In this study, we investigated the expression of severe acute respiratory syndrome MESHD coronavirus 2 ( SAR TRANS-CoV-2) receptor angiotensin I-converting enzyme 2 (ACE2) and the cellular protease transmembrane serine protease 2 (TMPRSS2) and their associations with prognosis in lung adenocarcinoma MESHD lung adenocarcinoma HP (LUAD) and lung squamous cell carcinoma HP squamous cell carcinoma MESHD (LUSC). We found that there are significant differences in susceptibility to SAR TRANS-CoV-2 among each age TRANS stages of individuals with the expression of ACE2. ACE2 was also high expressed in LUAD and LUSC, and this suggests that COVID-19 patients with lung cancers are susceptible to SAR TRANS-CoV-2 infection. Our data showed the differential gene expression level and gene coexpression of ACE2 and TMPRSS2 among each subtypes and pathological stages of LUAD and LUSC and the data were verified by meta-analysis, gene expression omnibus (GEO) data and animal models results. 

    A Hint on the COVID-19 Risk: Population Disparities in Gene Expression of Three Receptors of SARS-CoV

    Authors: Guoshuai Cai; Xiang Cui; Xia Zhu; Jun Zhou

    id:10.20944/preprints202002.0408.v1 Date: 2020-02-27 Source: preprints.org

    The current spreading novel coronavirus SARS-CoV-2 is highly infectious and pathogenic and has attracted global attention. Recent studies have found that SARS-CoV-2 and SARS-CoV share around 80% of homology and use the same cell entry receptor, ACE2. These inspired us to study other receptors of SARS-CoV, which may be used for SARS-CoV-2 binding as well. In this study, we screened the gene expression of three receptors (ACE2, DC-SIGN and L-SIGN) in four datasets of normal lung tissue from lung adenocarcinoma MESHD lung adenocarcinoma HP patients and two single-cell RNA sequencing datasets from normal lung and bronchial epithelial cells separately. No significant difference in gene expression of these three receptors were found between gender TRANS groups ( male TRANS vs female TRANS). We found higher gene expression of DC-SIGN in elder with age TRANS>60 and higher gene expression of L-SIGN in Caucasian than Asian. Similar to ACE2, we observed significantly higher DC-SIGN gene expression in the lungs of smokers, especially former smokers. However, smokers upregulate ACE2 and DC-SIGN gene expression in different cell types. In the whole lung, ACE2 is actively expressed in remodeled Alveolar Type II cells of former smokers, while DC-SIGN is largely expressed in monocytes of former smokers and dendritic cells of current smokers. In bronchial epithelium, no obvious gene expression of DC-SIGN and L-SIGN was observed while ACE2 was found to be actively expressed in goblet cells of current smokers and club HP cells of non-smokers. In conclusion, our findings may indicate that smokers, especially former smokers, and people over 60 have higher risk and are more susceptible to SARS-CoV-2 infection MESHD. Also, this study provides hints on possible SARS-CoV-2 pathogenicity mechanisms in lung infection MESHD.

    Lung Adenocarcinoma MESHD Lung Adenocarcinoma HP Patients Own Higher Risk of SARS-CoV-2 Infection MESHD

    Authors: Long Chen; Li Zhong

    id:202002.0386/v1 Date: 2020-02-26 Source: preprints.org

    Both lung adenocarcinoma MESHD lung adenocarcinoma HP and SARS-CoV-2 infection MESHD could cause pulmonary inflammation MESHD. Angiotensin-converting enzyme 2, not only as the functional receptor of SARS-CoV-2 but also play key role in lung adenocarcinoma MESHD lung adenocarcinoma HP. To study the risk of SARS-CoV-2 infection MESHD in lung adenocarcinoma MESHD lung adenocarcinoma HP patients, mRNA and miRNA profiles were obtained from TCGA and GEO databases followed by bioinformatics analysis. A regulatory network which regards angiotensin-converting enzyme 2 as the center would be structured. In addition, via immunological analysis about key factors in lung adenocarcinoma MESHD lung adenocarcinoma HP patients, to explore the essential reasons for the susceptibility of SARS-CoV-2. Compared with normal tissue, angiotensin-converting enzyme 2 was increased in lung adenocarcinoma MESHD lung adenocarcinoma HP patients. Furthermore, a total of 7 differently expressed correlated mRNAs (ACE2, CXCL9, MMP12, IL6, AZU1, FCN3, HYAL1 and IRAK3) and 5 differently expressed correlated miRNAs (miR-125b-5p, miR-9-5p, miR-130b-5p, miR-381-3p and miR-421) were screened followed by enrichment analysis. Interestingly, toll-like receptor signaling pathway with the most frequent occurrence was enriched by mRNA (IL6) and miRNA (miR-125b-5p) sets simultaneously. Finally through comprehensive analysis, it was assumed that miR-125b-5p-ACE2-IL6 axis in the structured regulatory network could alter risk of SARS-CoV-2 infection MESHD in lung adenocarcinoma MESHD lung adenocarcinoma HP patients.

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MeSH Disease
Human Phenotype

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