Corpus overview


MeSH Disease

Human Phenotype


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    Cell-Free DNA in Blood SERO Reveals Significant Cell, Tissue and Organ Specific injury and Predicts COVID-19 Severity

    Authors: Alexandre Pellan Cheng; Matthew Pellan Cheng; Wei Gu; Joan Sesing Lenz; Elaine Hsu; Erwin Schurr; Guillaume Bourque; Mathieu Bourgey; Jerome Ritz; Francisco M Marty; Charles Y Chiu; Donald Cuong Vinh; Iwijn De Vlaminck

    doi:10.1101/2020.07.27.20163188 Date: 2020-07-29 Source: medRxiv

    COVID-19 primarily affects the lungs, but evidence of systemic disease MESHD with multi-organ involvement is emerging. Here, we developed a blood SERO test to broadly quantify cell, tissue, and organ specific injury due to COVID-19, using genome-wide methylation profiling of circulating cell-free DNA in plasma SERO. We assessed the utility of this test to identify subjects with severe disease MESHD in two independent, longitudinal cohorts of hospitalized patients. Cell-free DNA profiling was performed on 104 plasma SERO samples from 33 COVID-19 patients and compared to samples from patients with other viral infections MESHD and healthy controls. We found evidence of injury to the lung MESHD and liver and involvement of red blood SERO cell progenitors associated with severe COVID-19. The concentration of cfDNA correlated with the WHO ordinal scale for disease progression MESHD and was significantly increased in patients requiring intubation. This study points to the utility of cell-free DNA as an analyte to monitor and study COVID-19.

    Intranasal Exposure of African Green Monkeys to SARS-CoV-2 Results in Acute Phase Pneumonia MESHD Pneumonia HP With Shedding and Lung Injury MESHD Still Present in the Early Convalescence MESHD Phase

    Authors: Tom Geisbert; Robert Cross; Krystle Agans; Abhishek Prasad; Viktoriya Borisevich; Courntey Woolsey; Daniel Deer; Natalie Dobias; Joan Geisbert; Karla Fenton

    doi:10.21203/ Date: 2020-07-28 Source: ResearchSquare

    We recently reported the development of the first African green monkey (AGM) model for COVID-19 based on a combined liquid intranasal (i.n.) and intratracheal (i.t.) exposure to severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2). Here, we followed up on this work by assessing an i.n. particle only route of exposure using the LMA mucosal atomization device (MAD). Six AGMs were infected with SARS-CoV-2; three animals were euthanized near the peak stage of virus replication (day 5) and three animals were euthanized during the early convalescence MESHD period (day 34). All six AGMs supported robust SARS-CoV-2 replication and developed respiratory disease MESHD. Evidence of coagulation dysfunction as noted by a transient increases in aPTT and circulating levels of fibrinogen was observed in all AGMs. The level of SARS-CoV-2 replication and lung pathology was not quite as pronounced as previously reported with AGMs exposed by the combined i.n. and i.t. routes; however, SARS-CoV-2 RNA was detected in nasal swabs of some animals as late as day 15 and rectal swabs as late as day 28 after virus challenge. Of particular importance to this study, all three AGMs that were followed until the early convalescence MESHD stage of COVID-19 showed substantial lung pathology at necropsy as evidenced by multifocal chronic interstitial pneumonia MESHD pneumonia HP and increased collagen deposition in alveolar walls despite the absence of detectable SARS-CoV-2 in any of the lungs of these animals. These findings are consistent with human COVID-19 further demonstrating that the AGM faithfully reproduces the human condition.

    Cell type-specific immune dysregulation HP in severely ill COVID-19 patients

    Authors: Changfu Yao; Stephanie A Bora; Tanyalak Parimon; Tanzira Zaman; Oren A Friedman; Joseph A Palatinus; Nirmala S Surapaneni; Yuri P Matusov; Giuliana Cerro Chiang; Alexander G Kassar; Nayan Patel; Chelsi ER Green; Adam W Aziz; Harshpreet Suri; Jo Suda; Andres A Lopez; Gislaine A Martins; Barry R Stripp; Sina A Gharib; Helen S Goodridge; Peter Chen

    doi:10.1101/2020.07.23.20161182 Date: 2020-07-24 Source: medRxiv

    Coronavirus disease MESHD 2019 (COVID-19) has quickly become the most serious pandemic since the 1918 flu pandemic. In extreme situations, patients develop a dysregulated inflammatory lung injury MESHD called acute respiratory distress HP syndrome MESHD (ARDS) that causes progressive respiratory failure HP requiring mechanical ventilatory support. Recent studies have demonstrated immunologic dysfunction in severely ill COVID-19 patients. To further delineate the dysregulated immune response driving more severe clinical course from SARS-CoV-2 infection MESHD, we used single-cell RNA sequencing (scRNAseq) to analyze the transcriptome of peripheral blood SERO mononuclear cells (PBMC) from hospitalized COVID-19 patients having mild disease MESHD (n = 5), developing ARDS (n = 6), and recovering from ARDS (n = 6). Our data demonstrated an overwhelming inflammatory response with select immunodeficiencies HP within various immune populations in ARDS patients. Specifically, their monocytes had defects in antigen presentation and deficiencies in interferon responsiveness that contrasted the higher interferon signals in lymphocytes. Furthermore, cytotoxic activity was suppressed in both NK and CD8 lymphocytes whereas B cell activation was deficient, which is consistent with the delayed viral clearance in severely ill COVID-19 patients. Finally, we identified altered signaling pathways in the severe group that suggests immunosenescence and immunometabolic changes could be contributing to the dysfunctional immune response. Our study demonstrates that COVID-19 patients with ARDS have an immunologically distinct response when compared to those with a more innocuous disease MESHD course and show a state of immune imbalance in which deficiencies in both the innate and adaptive immune response may be contributing to a more severe disease MESHD course in COVID-19.

    Real-time IP-10 measurements as a new tool for inflammation MESHD regulation within a clinical decision support protocol for managing severe COVID-19 patients

    Authors: Shaul Lev; Tamar Gottesman; Gal Sahaf Levin; Doron Lederfein; Evgeny Berkov; Dror Diker; Aliza Zaidman; Amir Nutman; Tahel Ilan Ber; Alon Angel; Lior Kellerman; Eran Barash; Roy Navon; Olga Boico; Yael Israeli; Michal Rosenberg; Amir Gelman; Roy Kalfon; Einav Simon; Noa Avni; Mary Hainrichson; Oren Zarchin; Tanya M. Gottlieb; Kfir Oved; Eran Eden; Boaz Tadmor

    doi:10.1101/2020.07.21.20158782 Date: 2020-07-22 Source: medRxiv

    The challenge of treating severely ill COVID-19 patients is particularly great due to the need to simultaneously manage oxygenation and the inflammatory state without compromising viral clearance. Currently, there are many tools to aid in oxygen management and in monitoring viral replication. However, predictive biomarkers for monitoring the host immune response across COVID-19 disease MESHD stages and specifically, for titrating immunomodulatory therapy are lacking. We utilized a recently cleared platform (MeMed Key) that enables rapid and easy serial measurement of IP-10, a host protein implicated in lung injury MESHD due to viral-induced hyperinflammation. A dynamic clinical decision support protocol was employed for managing SARS-CoV-2 positive patients admitted to a COVID-19 dedicated medical center run by Clalit Health Services. This is the first protocol to include real-time measurements of IP-10 as a potential aid for regulating inflammation MESHD. Overall, 502 serial real-time IP-10 measurements were performed on 52 patients recruited between 7th April 2020 to 10th May 2020, with 12 patients admitted to the intensive care unit (ICU). IP-10 levels correlated with increased COVID-19 severity score and ICU admission. Within the ICU admitted patients, the number of days with IP-10 measurements >1,000 pg/ml was associated with mortality. Upon administration of corticosteroid immunomodulatory therapy, a significant decrease in IP-10 levels was observed. Real-time IP-10 monitoring represents a new tool to aid in management and therapeutic decisions relating to the inflammatory status of COVID-19 patients.

    A human disease MESHD model of SARS-CoV-2-induced lung injury MESHD and immune responses with a microengineered organ chip

    Authors: Min Zhang; Peng Wang; Ronghua Luo; Yaqing Wang; Zhongyu Li; Yaqiong Guo; Yulin Yao; Minghua Li; Tingting Tao; Wenwen Chen; Jianbao Han; Haitao Liu; Kangli Cui; Xu Zhang; Yongtang Zheng; Jianhua Qin

    doi:10.1101/2020.07.20.211789 Date: 2020-07-20 Source: bioRxiv

    Coronavirus disease MESHD 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) that seriously endangers human health. There is an urgent need to build physiological relevant human models for deep understanding the complex organ-level disease MESHD processes and facilitating effective therapeutics for COVID-19. Here, we first report the use of microengineered alveolus chip to create a human disease MESHD model of lung injury MESHD and immune responses induced by native SARS-CoV-2 at organ-level. This biomimetic system is able to reconstitute the key features of human alveolar-capillary barrier by co-culture of alveolar epithelial and microvascular endothelial cells under microfluidic flow. The epithelial cells on chip showed higher susceptibility to SARS-CoV-2 infection MESHD than endothelial cells identified by viral spike protein expression. Transcriptional analysis showed distinct responses of two cell types to SARS-CoV-2 infection MESHD, including activated type I interferon (IFN-I) signaling pathway in epithelium and activated JAK-STAT signaling pathway in endothelium. Notably, in the presence of circulating immune cells, a series of alveolar pathological changes were observed, including the detachment of endothelial cells, recruitment of immune cells, and increased production of inflammatory cytokines (IL-6, IL-8, IL-1{beta} and TNF-). These new findings revealed a crucial role of immune cells in mediating lung injury MESHD and exacerbated inflammation MESHD. Treatment with antiviral compound remdesivir could suppress viral copy and alleviate the disruption of alveolar barrier integrity induced by viral infection MESHD. This bioengineered human organ chip system can closely mirror human-relevant lung pathogenesis and immune responses to SARS-CoV-2 infection MESHD, not possible by other in vitro models, which provides a promising and alternative platform for COVID-19 research and preclinical trials.

    The Mechanism of Prevention and Treatment of Maxing Shigan Decoction on Pulmonary Heart Injury MESHD Caused by Novel Coronavirus Pneumonia MESHD Pneumonia HP

    Authors: Dongling Liu; Jing Su; Wenqian Hou; Weiyu Ren; Yijun Zheng; Yanmei Ning; Xiaojie Jin; Yongqi Liu

    doi:10.21203/ Date: 2020-07-16 Source: ResearchSquare

    Background To explore the mechanism of Maxing Shigan Decoction in the treatment of myocardial injury and lung MESHD injury through network pharmacology and molecular docking technology.Methods In Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (BATMAN-TCM) and the Comparative Toxicogenomics Database, National Center for Biotechnology Information database, Online Mendelian Inheritance in Man database, the compounds and targets of each drug in Maxing Shigan Decoction and the targets of “acute lung intervention” and “myocardial injury” diseases MESHD were searched. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed by the DAVID database. GOLD 5.1 was used for molecular docking.Results Maxing Shigan Decoction includes 327 compounds and 2722 targets, including 30 key targets. 2125 items were obtained by GO enrichment analysis, including 2047 items of Biological Process, 28 items of Cell Composition and 50 items of Molecular Function. The KEGG pathway was enriched to obtain 149 pathways. The results of molecular docking showed that Gancaonin H and Licorice Glycoside E were well combined with Angiotensin-Converting Enzyme 2-A (ACE2-A) and Angiotensin-Converting Enzyme 2-B (ACE2-B), respectively, and Licorice was well combined with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Interleukin 6 (IL-6). Supraene is an active compound of Ephedra. It has good binding with ACE2-A, ACE2-B, GM-CSF and IL-6, respectively. (6Z, 10E, 14E, 18E)-2, 6, 10, 15, 19, 23- hexamethyletracosa-2, 6, 10, 14, 18, 22- hexaene are the active compounds of Almond, which are well combined with ACE2-A, ACE2-B, GM-CSF and IL-6.Conclusion Maxing Shigan Decoction may act on ACE2, GM-CSF and IL-6 targets through the active compounds Supraene of Ephedra, and Almond (6Z, 10E, 14E, 18E)-2, 6, 10, 15, 19, 23-hexamethyletracosa-2, 6, 10, 14, 18, 22-hexaene. Gancainin H and licorice Glycide E are the active compounds of Licorice, act on A and B sites of ACE2 respectively, and Glycyrin acts on GM-CSF and IL-6 targets, coordinating multiple signal pathways to play anti-inflammatory and antiviral roles to prevent and treat lung and heart injury MESHD caused by Severe Acute Respiratory Syndrome MESHD Coronavirus 2 (SARS-CoV-2).

    The SARS-CoV-2 RNA with mild lung lesions lasts longer in non-severe COVID-19 patients: a case series study

    Authors: Chi Zhang; Jiawen Li; Jing Mu; Daitao Zhang; He Wang; Yunv Jin; Yan Han; Haiyang Li; Chunxiao Zhang; Peng Yu; Rui Guo; Xiangfeng Dou; Yanhui Chu; Zhao Wu; Xiaoqin Dong; Hong Zhao

    doi:10.21203/ Date: 2020-07-15 Source: ResearchSquare

    Background COVID-19 has become a new infectious disease MESHD in the global pandemic, most of which are non-severe patients. It is particularly important to understand the dynamic changes of the whole disease MESHD course of non-severe patients from the onset to the follow-up after discharge.Methods On February 1, 2020, 18 cases of non-severe COVID-19 appeared in a hospital in Beijing. We recorded the clinical information and viral dynamics of these patients from the onset of the disease MESHD to one month after discharge.Results Eighteen patients (median age TRANS 43) were included, including 14 females TRANS. Fever MESHD Fever HP (11/18) and cough MESHD cough HP (8/18) are the most common symptoms. According to the degree of lung inflammation MESHD, 18 patients were divided into two groups (group A imaging score ≤ 10; group B imaging score > 10). The duration of SARS-CoV-2 positive in group A was significantly longer than that in group B (the median was 30 and 13, respectively, P = 0.0025). One month after discharge, almost all patients were followed up for IgM antibody SERO disappearance and IgG antibody SERO production.Conclusion In non-severe COVID-19 patients, the positive duration of the SARS-CoV-2 in patients with mild lung injury MESHD was longer than that in patients with severe lung injury MESHD. The possible mechanism is that the virus-mediated immune system is not fully activated in mild damaged patients.

    Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease MESHD

    Authors: Joseph Golden; Curtis Cline; Xiankun Zeng; Aura Garrison; Brian Carey; Eric Mucker; Lauren White; Joshua Shamblin; Rebecca Brocato; Jun Liu; April Babka; Hypaitia Rauch; Jeffrey M Smith; Bradley Hollidge; Collin Fitzpatrick; Catherine Badger; Jay Hooper

    doi:10.1101/2020.07.09.195230 Date: 2020-07-09 Source: bioRxiv

    ABSTRACTThe emergence of SARS-CoV-2 has created an international health crisis. Small animal models mirroring SARS-CoV-2 human disease MESHD are essential for medical countermeasure (MCM) development. Mice are refractory to SARS-CoV-2 infection MESHD due to low affinity binding to the murine angiotensin-converting enzyme 2 (ACE2) protein. Here we evaluated the pathogenesis of SARS-CoV-2 in male TRANS and female TRANS mice expressing the human ACE2 gene under the control of the keratin 18 promotor. In contrast to non-transgenic mice, intranasal exposure of K18-hACE2 animals to two different doses of SARS-CoV-2 resulted in acute disease MESHD including weight loss MESHD weight loss HP, lung injury MESHD, brain infection MESHD and lethality. Vasculitis MESHD Vasculitis HP was the most prominent finding in the lungs of infected mice. Transcriptomic analysis from lungs of infected animals revealed increases in transcripts involved in lung injury MESHD and inflammatory cytokines. In the lower dose challenge groups, there was a survival advantage in the female TRANS mice with 60% surviving infection MESHD whereas all male TRANS mice succumbed to disease MESHD. Male TRANS mice that succumbed to disease MESHD had higher levels of inflammatory transcripts compared to female TRANS mice. This is the first highly lethal murine infection MESHD model for SARS-CoV-2. The K18-hACE2 murine model will be valuable for the study of SARS-CoV-2 pathogenesis and the assessment of MCMs.Competing Interest StatementThe authors have declared no competing interest.View Full Text

    Association between lung injury MESHD and cytokine profile in COVID-19 pneumonia MESHD pneumonia HP

    Authors: Li-da Chen; Zhen-Yu Zhang; Xiao-Jie Wei; Yu-Qing Cai; Weng-Zhen Yao; Ming-Hui Wang; Qiu-Fen Huang; Xiao-Bin Zhang

    doi:10.21203/ Date: 2020-06-30 Source: ResearchSquare

    Background: Coronavirus disease MESHD 2019 (COVID-19) is a systemic disease MESHD caused by severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) infection MESHD. The purpose of the present study was to investigate the association between lung injury MESHD and cytokine profile in COVID-19 pneumonia MESHD pneumonia HP.Methods: This retrospective study was conducted in COVID-19 patients. Demographic characteristics, symptoms, signs MESHD, underlying diseases MESHD, and laboratory data were collected. The patients were divided into COVID-19 with pneumonia MESHD pneumonia HP and without pneumonia MESHD pneumonia HP. CT severity score and PaO2/FiO2 ratio and were used to assess lung injury MESHD.Results: 106 patients with 12 COVID-19 without pneumonia MESHD pneumonia HP and 94 COVID-19 with pneumonia MESHD pneumonia HP were included. Compared with COVID-19 without pneumonia MESHD pneumonia HP, COVID-19 with pneumonia MESHD pneumonia HP had significant higher serum SERO interleukin (IL)-2R, IL-6, and tumor necrosis MESHD factor (TNF)-α. Correlation analysis showed that CT severity score and PaO2/FiO2 were significantly correlated with age TRANS, presence of any coexisting disorder, lymphocyte count, procalcitonin, IL-2R, and IL-6. In multivariate analysis, log IL6 was only independent explanatory variables for CT severity score (β=0.397, p<0.001) and PaO2/FiO2 (β=-0.434, p=0.003).Conclusions: Elevation of circulating cytokines was significantly associated with presence of pneumonia MESHD pneumonia HP in COVID-19 and the severity of lung injury MESHD in COVID-19 pneumonia MESHD pneumonia HP. Circulating IL-6 independently predicted the severity of lung injury MESHD in COVID-19 pneumonia MESHD pneumonia HP.

    A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury MESHD during the COVID-19 pandemic

    Authors: Maria Malimova; Abhigyan Satyam; Michelle Melanson; Brian T. Chamberlain; Seth L. Alper; Jean Santos; Juan Gutierrez; Ayshwarya Subramanian; Elizabeth Grinkevich; Estefania Reyes Bricio; Abbe Clark; Rebecca Thompson; Jamie Marshall; Juan Lorenzo Pablo; Julie Roignot; Maheswarareddy Emani; Matthew Racette; Valeria Padovano; Stephen P. McAdoo; Frederick W.K. Tam; Lucienne Ronco; Florence Wagner; George C. Tsokos; Jillian L. Shaw

    doi:10.1101/2020.06.30.180380 Date: 2020-06-30 Source: bioRxiv

    Drug repurposing is the only method capable of delivering treatments on the shortened time-scale required for patients afflicted with lung disease MESHD arising from SARS-CoV-2 infection MESHD. Mucin-1 (MUC1), a membrane-bound molecule expressed on the apical surfaces of most mucosal epithelial cells, is a biochemical marker whose elevated levels predict the development of acute lung injury MESHD (ALI) and respiratory distress HP syndrome MESHD (ARDS), and correlate with poor clinical outcomes. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce MUC1 protein abundance. Our screen identified Fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia MESHD thrombocytopenia HP, as a repurposing candidate for the treatment of ALI. In vivo, Fostamatinib reduced MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by Fostamatinib promoted MUC1 removal from the cell surface. Our work reveals Fostamatinib as a repurposing drug candidate for ALI and provides the rationale for rapidly standing up clinical trials to test Fostamatinib efficacy in patients with COVID-19 lung injury MESHD.

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MeSH Disease
Human Phenotype

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