Match!

Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

Published on Apr 21, 2020in bioRxiv
· DOI :10.1101/2020.04.19.049254
Christoph Muus2
Estimated H-index: 2
(Broad Institute),
Malte D Luecken1
Estimated H-index: 1
+ 101 AuthorsChristopher Smillie15
Estimated H-index: 15
(Broad Institute)
Sources
Abstract
The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, creates an urgent need for identifying molecular mechanisms that mediate viral entry, propagation, and tissue pathology. Cell membrane bound angiotensin-converting enzyme 2 (ACE2) and associated proteases, transmembrane protease serine 2 (TMPRSS2) and Cathepsin L (CTSL), were previously identified as mediators of SARS-CoV2 cellular entry. Here, we assess the cell type-specific RNA expression of ACE2, TMPRSS2, and CTSL through an integrated analysis of 107 single-cell and single-nucleus RNA-Seq studies, including 22 lung and airways datasets (16 unpublished), and 85 datasets from other diverse organs. Joint expression of ACE2 and the accessory proteases identifies specific subsets of respiratory epithelial cells as putative targets of viral infection in the nasal passages, airways, and alveoli. Cells that co-express ACE2 and proteases are also identified in cells from other organs, some of which have been associated with COVID-19 transmission or pathology, including gut enterocytes, corneal epithelial cells, cardiomyocytes, heart pericytes, olfactory sustentacular cells, and renal epithelial cells. Performing the first meta-analyses of scRNA-seq studies, we analyzed 1,176,683 cells from 282 nasal, airway, and lung parenchyma samples from 164 donors spanning fetal, childhood, adult, and elderly age groups, associate increased levels of ACE2, TMPRSS2, and CTSL in specific cell types with increasing age, male gender, and smoking, all of which are epidemiologically linked to COVID-19 susceptibility and outcomes. Notably, there was a particularly low expression of ACE2 in the few young pediatric samples in the analysis. Further analysis reveals a gene expression program shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues, including genes that may mediate viral entry, subtend key immune functions, and mediate epithelial-macrophage cross-talk. Amongst these are IL6, its receptor and co-receptor, IL1R, TNF response pathways, and complement genes. Cell type specificity in the lung and airways and smoking effects were conserved in mice. Our analyses suggest that differences in the cell type-specific expression of mediators of SARS-CoV-2 viral entry may be responsible for aspects of COVID-19 epidemiology and clinical course, and point to putative molecular pathways involved in disease susceptibility and pathogenesis.
  • References (184)
  • Citations (18)
📖 Papers frequently viewed together
108 Citations
1 Citations
10 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References184
Newest
#1Elo MadissoonH-Index: 4
#1E. MadissoonH-Index: 1
Last. Kerstin B. MeyerH-Index: 19
view all 22 authors...
Background The Human Cell Atlas is a large international collaborative effort to map all cell types of the human body. Single-cell RNA sequencing can generate high-quality data for the delivery of such an atlas. However, delays between fresh sample collection and processing may lead to poor data and difficulties in experimental design.
23 CitationsSource
#1Yang LiH-Index: 1
#2Ruihong ZhaoH-Index: 3
Last. Fei YuH-Index: 16
view all 14 authors...
A woman with 2019 novel coronavirus disease in her 35th week of pregnancy delivered an infant by cesarean section in a negative-pressure operating room. The infant was negative for severe acute respiratory coronavirus 2. This case suggests that mother-to-child transmission is unlikely for this virus.
43 CitationsSource
#1Jianhua Xia (ZJU: Zhejiang University)H-Index: 2
#2Jianping Tong (ZJU: Zhejiang University)H-Index: 2
Last. Dongyu Guo (ZJU: Zhejiang University)H-Index: 2
view all 5 authors...
OBJECTIVE: This study aimed to assess the presence of novel coronavirus in tears and conjunctival secretions of SARS-CoV-2 infected patients. METHODS: A prospective interventional case series study was performed, and 30 confirmed novel coronavirus pneumonia (NCP) patients were selected at the First Affiliated Hospital of Zhejiang University from January 26, 2020 to February 9, 2020. At an interval of 2-3 days, tear and conjunctival secretions were collected twice with disposable sampling swabs f...
130 CitationsSource
#1Lili RenH-Index: 20
Last. Hui LiH-Index: 55
view all 36 authors...
BACKGROUND: Human infections with zoonotic coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, have raised great public health concern globally. Here, we report a novel bat-origin CoV causing severe and fatal pneumonia in humans. METHODS: We collected clinical data and bronchoalveolar lavage (BAL) specimens from five patients with severe pneumonia from Jin Yin-tan Hospital of Wuhan, Hubei province, China. Nucleic acids of ...
99 CitationsSource
#1Carly G.K. ZieglerH-Index: 1
#1Carly G K Ziegler (Ragon Institute of MGH, MIT and Harvard)H-Index: 1
Last. Jared Feldman (Ragon Institute of MGH, MIT and Harvard)H-Index: 1
view all 116 authors...
80 CitationsSource
#1Waradon SungnakH-Index: 1
#2Ni HuangH-Index: 19
Last. Fotios Sampaziotis (University of Cambridge)H-Index: 8
view all 13 authors...
108 CitationsSource
Guillain–Barre Syndrome with Covid-19 Five patients who had Guillain–Barre syndrome 5 to 10 days after the onset of Covid-19 are described. Three had severe weakness and an axonal pattern on electr...
75 CitationsSource
#1M. Hoffmann (DPZ: German Primate Center)H-Index: 1
#1Markus H. Hoffmann (DPZ: German Primate Center)H-Index: 20
Last. Andreas Nitsche (RKI: Robert Koch Institute)H-Index: 38
view all 13 authors...
Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SA...
1,081 CitationsSource
#1Julie Helms (UDS: University of Strasbourg)H-Index: 4
#2S. Kremer (UDS: University of Strasbourg)H-Index: 24
Last. Mickaël Ohana (UDS: University of Strasbourg)H-Index: 8
view all 12 authors...
Neurologic Features in SARS-CoV-2 Infection In a consecutive series of 64 patients with Covid-19 and ARDS, 58 of whom underwent neurologic examination, severe agitation and corticospinal signs were...
110 CitationsSource
#1Nathan R. TuckerH-Index: 14
#2Mark Chaffin (Broad Institute)H-Index: 12
Last. Roby P. Bhattacharyya (Harvard University)H-Index: 12
view all 13 authors...
Coronavirus disease 2019 (COVID-19) is a global pandemic caused by a novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). SARS-CoV-2 infection of host cells occurs predominantly via binding of the viral surface spike protein to the human angiotensin-converting enzyme 2 (ACE2) receptor. Hypertension and pre-existing cardiovascular disease are risk factors for morbidity from COVID-19, and it remains uncertain whether the use of angiotensin converting enzyme inhibitors (ACEi) or angi...
3 CitationsSource
Cited By18
Newest
#1Lydia Finney (Imperial College London)H-Index: 1
#2Nicholas GlanvilleH-Index: 11
Last. Patrick Mallia (Imperial College London)H-Index: 29
view all 13 authors...
Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is a new rapidly spreading infectious disease. Early reports of hospitalised COVID-19 cases have shown relatively low frequency of chronic lung diseases such as chronic obstructive pulmonary disease (COPD) but increased risk of adverse outcome. The mechanisms of altered susceptibility to viral acquisition and/or severe disease in at-risk groups are poorly understood. Inhaled corticosteroids (ICS) are widely used in the treatment of COPD bu...
Source
COVID-19, the disease caused by the novel coronavirus SARS-CoV-2 which was first reported in Wuhan, China in December 2019, is seen to have left its mark in the history with a global pandemic. As a novel member of the coronavirus family, SARS-CoV-2 represents a new kind of sickness in regard to viral pathogenesis and tissue changes. To comprehend the pathogenicity of the virus totally, one has to follow the pathways which a virus travels and inflicts damage through. What starts out as a simple f...
Source
#1Malte D Luecken (Helmholtz Zentrum München)H-Index: 1
#2Maren BüttnerH-Index: 6
Last. Maria Colomé-TatchéH-Index: 14
view all 11 authors...
Cell atlases often include samples that span locations, labs, and conditions, leading to complex, nested batch effects in data. Thus, joint analysis of atlas datasets requires reliable data integration. Choosing a data integration method is a challenge due to the difficulty of defining integration success. Here, we benchmark 38 method and preprocessing combinations on 77 batches of gene expression, chromatin accessibility, and simulation data from 23 publications, altogether representing >1.2 mi...
2 CitationsSource
#1Bryce A. Schuler (VUMC: Vanderbilt University Medical Center)H-Index: 1
#2A. Christian Habermann (VUMC: Vanderbilt University Medical Center)H-Index: 1
Last. Lior Z. Braunstein (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 6
view all 17 authors...
The emergence of the SARS-CoV-2 novel coronavirus has led to a global pandemic (COVID-19), with more than 5 million cases as of May 2020. Available data suggest that severe illness and death from COVID-19 are rare in the pediatric population. Integrating single-cell RNA sequencing of the developing mouse lung with temporally-resolved RNA-in-situ hybridization (ISH) in mouse and human lung tissue, we found expression of SARS-CoV-2 Spike protein primer TMPRSS2 was highest in ciliated cells and typ...
2 CitationsSource
#1Nicholas S. Hopkinson (Imperial College London)H-Index: 40
#2Niccolo' Rossi ('KCL': King's College London)H-Index: 1
Last. Sebastien Ourselin ('KCL': King's College London)H-Index: 62
view all 1 authors...
Background: The association between current tobacco smoking, the risk of developing COVID-19 and the severity of illness is an important information gap. Methods: UK users of the COVID Symptom Study app provided baseline data including demographics, anthropometrics, smoking status and medical conditions, were asked to log symptoms daily from 24th March 2020 to 23rd April 2020. Participants reporting that they did not feel physically normal were taken through a series of questions, including 14 p...
Source
#1Ilaria Liguoro (University of Udine)H-Index: 7
#1Ilaria LiguoroH-Index: 1
Last. Paola CogoH-Index: 26
view all 8 authors...
A recent outbreak of a novel Coronavirus responsible for a Severe Acute Respiratory Syndrome (SARS-CoV-2) is spreading globally. The aim of this study was to systematically review main clinical characteristics and outcomes of SARS-CoV-2 infections in pediatric age. An electronic search was conducted in PubMed database. Papers published between 1 January and 1 May 2020 including children aged 0–18 years were selected. Sixty-two studies and three reviews were included, with a total sample size of ...
4 CitationsSource
#1Roger Pique-Regi (WSU: Wayne State University)H-Index: 20
#2Robert Romero (WSU: Wayne State University)H-Index: 132
Last. Nardhy Gomez-Lopez (WSU: Wayne State University)H-Index: 26
view all 8 authors...
The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected over 3.8 million people, including pregnant women. To date, no consistent evidence of vertical transmission for SARS-CoV-2 exists. This new coronavirus canonically utilizes the angiotensin-converting enzyme 2 (ACE2) receptor and the serine protease TMPRSS2 for cell entry. Herein, building upon our previous study (Pique-Regi, 2019) and new placenta single-cel...
1 CitationsSource
#1Samir Kumar Patra (NITR: National Institute of Technology, Rourkela)H-Index: 18
#1Zofia Wicik (Medical University of Warsaw)
#2Ceren Eyileten (Medical University of Warsaw)H-Index: 4
Last. Marek Postula (Medical University of Warsaw)H-Index: 11
view all 6 authors...
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019; COVID-19) is associated with adverse outcome in patients with cardiovascular disease (CVD). Aim: To characterize the interaction between SARS-CoV-2 and Angiotensin Converting Enzyme 2 (ACE2) functional networks with focus on CVD. Methods: Using bioinformatic tools, network medicine approaches and publicly available datasets, we investigated ACE2 tissue expression and described ACE2 inter...
Source
#1Ali Hosseini Rad (University of Otago)
#2Alexander D. McLellan (University of Otago)H-Index: 29
The SARS-CoV-2 virus is a recently-emerged zoonotic pathogen already well adapted to transmission and replication in humans. Although the mutation rate is limited, recently introduced mutations in SARS-CoV-2 have the potential to alter viral fitness. In addition to amino acid changes, mutations could affect RNA secondary structure critical to viral life cycle, or interfere with sequences targeted by host miRNAs. We have analysed subsets of genomes from SARS-CoV-2 isolates from around the globe a...
Source