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    Renin-angiotensin system inhibitors and susceptibility to COVID-19 MESHD in patients with hypertension: a propensity score-matched cohort study in primary care

    Authors: Shamil Haroon; Anuradhaa Subramanian; Jennifer Cooper; Astha Anand; Krishna Gokhale; Nathan Byne; Samir Dhalla; Dionisio Acosta-Mena; Thomas Taverner; Kelvin Okoth; Jingya Wang; Joht Singh Chandan; Christopher Sainsbury; Dawit Tefra Zemedikun; G Neil Thomas; Dhruv Parekh; Tom Marshall; Elizabeth Sapey; Nicola J Adderley; Krishnarajah Nirantharakumar

    doi:10.1101/2020.09.17.20196469 Date: 2020-09-18 Source: medRxiv

    Introduction A significant proportion of patients with Coronavirus Disease-19 MESHD ( COVID-19 MESHD) have hypertension MESHD and are treated with renin-angiotensin system (RAS) inhibitors, namely angiotensin-converting enzyme I inhibitors (ACE inhibitors) or angiotensin II type-1 receptor HGNC blockers (ARBs). These medications have been postulated to influence susceptibility to Severe Acute Respiratory Syndrome Coronavirus-2 MESHD (SARS-CoV-2). The objective of this study was to assess a possible association between prescription of RAS inhibitors and the incidence of COVID-19 MESHD and all-cause mortality. Methods We conducted a propensity-score matched cohort study to assess the incidence of COVID-19 MESHD among patients with hypertension MESHD who were prescribed ACE HGNC inhibitors or ARBs compared to patients treated with calcium channel blockers (CCBs) in a large UK-based primary care database (The Health Improvement Network). We estimated crude incidence rates for confirmed/suspected COVID-19 MESHD among those prescribed ACE HGNC inhibitors, ARBs and CCBs. We used a Cox proportional hazards model to produce adjusted hazard ratios for COVID-19 MESHD comparing patients prescribed ACE HGNC inhibitors or ARBs to those prescribed CCBs. We further assessed all-cause mortality as a secondary outcome and a composite of accidents, trauma MESHD or fractures MESHD as a negative control outcome to assess for residual confounding. Results In the propensity score matched analysis, 83 of 18,895 users (0.44%) of ACE HGNC inhibitors developed COVID-19 MESHD over 8,923 person-years, an incidence rate of 9.3 per 1000 person-years. 85 of 18,895 (0.45%) users of CCBs developed COVID-19 MESHD over 8,932 person-years, an incidence rate of 9.5 per 1000 person-years. The adjusted hazard ratio for suspected/confirmed COVID-19 MESHD for users of ACE HGNC inhibitors compared to CCBs was 0.92 (95% CI 0.68 to 1.26). 79 out of 10,623 users (0.74%) of ARBs developed COVID-19 MESHD over 5010 person-years, an incidence rate of 15.8 per 1000 person-years, compared to 11.6 per 1000 person-years among users of CCBs. The adjusted hazard ratio for suspected/confirmed COVID-19 MESHD for users of ARBs compared to CCBs was 1.38 (95% CI 0.98 to 1.95). There were no significant associations between use of ACE HGNC inhibitors or ARBs and all-cause mortality, compared to use of CCBs. We found no evidence of significant residual confounding with the negative control analysis. Conclusion Current use of ACE HGNC inhibitors was not associated with the risk of suspected or confirmed COVID-19 MESHD whereas use of ARBs was associated with a statistically non-significant 38% relative increase in risk compared to use of CCBs. However, no significant associations were observed between prescription of either ACE HGNC inhibitors or ARBs and all-cause mortality during the peak of the pandemic.

    A trimeric human angiotensin-converting enzyme 2 HGNC as an anti-SARS-CoV-2 agent in vitro

    Authors: Jianming Lu; Rebecca I. Johnson; Lindsay G.A. McKay; Nadia Storm; Christy L. Lavine; Shen Lu; Brian D. Quinlan; Michael Farzan; Michael S. Seaman; Anthony Griffiths; Jingya Wang; Joht Singh Chandan; Christopher Sainsbury; Dawit Tefra Zemedikun; G Neil Thomas; Dhruv Parekh; Tom Marshall; Elizabeth Sapey; Nicola J Adderley; Krishnarajah Nirantharakumar; Ricardo Soto-Rifo; Fernando Valiente-Echeverría; Christian Caglevic; Mauricio Mahave; Carolina Selman; Raimundo Gazitúa; José Luis Briones; Franz Villarroel-Espindola; Carlos Balmaceda; Manuel A. Espinoza; Jaime Pereira; Bruno Nervi

    doi:10.1101/2020.09.18.301952 Date: 2020-09-18 Source: bioRxiv

    Effective intervention strategies are urgently needed to control the COVID-19 pandemic MESHD COVID-19 pandemic MESHD. Human angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) is a carboxypeptidase that forms a dimer and serves as the cellular receptor for SARS-CoV-2. It is also a key negative regulator of the renin HGNC-angiotensin system (RAS), conserved in mammals, which modulates vascular functions. We report here the properties of a trimeric ACE2 HGNC variant, created by a structure-based approach, with binding affinity of ~60 pM for the spike (S) protein PROTEIN of SARS-CoV-2, while preserving the wildtype peptidase activity as well as the ability to block activation of angiotensin II receptor type 1 HGNC in the RAS. Moreover, the engineered ACE2 HGNC potently inhibits infection of SARS-CoV-2 MESHD in cell culture. These results suggest that engineered, trimeric ACE2 HGNC may be a promising anti-SARS-CoV-2 agent for treating COVID-19 MESHD.

    Age-related expression of SARS-CoV-2 priming protease TMPRSS2 HGNC in the developing lung

    Authors: Bryce A Schuler; A Christian Habermann; Erin J Plosa; Chase J Taylor; Christopher S Jetter; Meghan E Kapp; John Benjamin; Peter Gulleman; David S Nichols; Lior Z Braunstein; Michael H Koval; Susan H Guttentag; Timothy S Blackwell; - Vanderbilt COVID-19 Consortium Cohort; Steven A Webber; Nicholas Banovich; Jonathan A Kropski; Jennifer MS Sucre; - HCA Lung Biological Network

    doi:10.1101/2020.05.22.111187 Date: 2020-05-23 Source: bioRxiv

    The SARS-CoV-2 novel coronavirus global pandemic ( COVID-19 MESHD) has led to millions of cases and hundreds of thousands of deaths around the globe. While the elderly appear at high risk for severe disease, hospitalizations and deaths due to SARS-CoV-2 among children have been relatively rare. Integrating single-cell RNA sequencing (scRNA-seq) of the developing mouse lung with temporally-resolved RNA-in-situ hybridization (ISH) in mouse and human lung tissue, we found that expression of SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD protein primer TMPRSS2 HGNC was highest in ciliated cells and type I alveolar epithelial MESHD cells ( AT1 HGNC), and TMPRSS2 HGNC expression was increased with aging in mice and humans. Analysis of autopsy tissue from fatal COVID-19 MESHD cases revealed SARS-CoV-2 RNA was detected most frequently in ciliated and secretory cells in the airway epithelium and AT1 HGNC cells in the peripheral lung. SARS-CoV-2 RNA was highly colocalized in cells expressing TMPRSS2 HGNC. Together, these data demonstrate the cellular spectrum infected by SARS-CoV-2 in the lung epithelium, and suggest that developmental regulation of TMPRSS2 HGNC may underlie the relative protection of infants and children from severe respiratory illness MESHD.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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