Evolution and Origins of SARS- Cov-2 and Related Coronaviruses Introduction to Evolution and Scientific Inquiry Spring 2020, Dr
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Evolution and origins of SARS- CoV-2 and related coronaviruses Introduction to Evolution and Scientific Inquiry Spring 2020, Dr. Spielman Zoonosis Image from April 2019 • Virus that normally infects one animal species infects a NEW/DIFFERENT species • Sometimes from a new mutation • Sometimes from an existing mutation • Sometimes no mutation at all – it just can infect multiple species Viruses bind host receptors or other cell-surface proteins https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000217 ACE2: Angiotension-converting enzyme 2 • ACE constricts blood flow • ACE inhibitors relax veins to improve blood flow. BRIEF COMMUNICATION Used to treat… https://doi.org/10.1038/s41591-020-0868-6 • Heart disease • Angiotension SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate • Diabetes immune genes • Migraines Waradon Sungnak! !1 , Ni Huang1, Christophe Bécavin! !2, Marijn Berg3,4, Rachel Queen5, Monika Litvinukova1,6, Carlos Talavera-López1, Henrike Maatz6, Daniel Reichart7, • Chronic kidney diseases Fotios Sampaziotis! !8,9,10, Kaylee B. Worlock11, Masahiro Yoshida! !11, Josephine L. Barnes11 and HCA Lung Biological Network* We investigated SARS-CoV-2 potential tropism by survey- associated with SARS-CoV-2 pathogenesis at cellular resolution, inghttps:// expressionwww.nature.com of viral entry-associated/articles/s41591 genes in single-cell using-020 single-cell-0868 RNA- 6sequencing (scRNA-seq) datasets from healthy RNA-sequencing data from multiple tissues from healthy donors generated by the Human Cell Atlas consortium and other human donors. We co-detected these transcripts in specific resources to inform and prioritize the use of precious, limited clinical respiratory, corneal and intestinal epithelial cells, potentially material that is becoming available from COVID-19 patients. explaining the high efficiency of SARS-CoV-2 transmission. We investigated gene expression of ACE2 in multiple scRNA-seq These genes are co-expressed in nasal epithelial cells with datasets from different tissues, including those of the respiratory genes involved in innate immunity, highlighting the cells’ tree, cornea, retina, esophagus, ileum, colon, heart, skeletal muscle, potential role in initial viral infection, spread and clearance. spleen, liver, placenta/decidua, kidney, testis, pancreas, prostate The study offers a useful resource for further lines of inquiry gland, brain, skin and fetal tissues. We note that studies may lack with valuable clinical samples from COVID-19 patients and we specific cell types due to their sparsity, the challenges associated provide our data in a comprehensive, open and user-friendly with isolation or analysis methodology. Moreover, expression may fashion at www.covid19cellatlas.org. be under-detected due to technical dropout effects. Thus, while The coronavirus disease 2019 (COVID-19) is caused by positive (presence) results are highly reliable, absence should be severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. interpreted with care. Detection of the virus was first reported in Wuhan2, China and has ACE2 expression was generally low in all analyzed datasets. since spread worldwide, emerging as a global pandemic3. Consistently with independent studies10,11, ACE2 was expressed in In symptomatic patients, nasal swabs have yielded higher viral cells from multiple tissues, including airways, cornea, esophagus, loads than throat swabs4. The same distribution was observed in an ileum, colon, liver, gallbladder, heart, kidney and testis (Fig. 1a; first asymptomatic patient4, implicating the nasal epithelium as a portal column). TMPRSS2 was highly expressed with a broader distribu- for initial infection and transmission. Cellular entry of coronavi- tion (Fig. 1a; second column), suggesting that ACE2, rather than ruses depends on the binding of the spike (S) protein to a specific TMPRSS2, may be a limiting factor for viral entry at the initial infec- cellular receptor and subsequent S protein priming by cellular tion stage. Cells from the respiratory tree, cornea, esophagus, ileum, proteases. Similarly to SARS-CoV5,6, SARS-CoV-2 employs ACE2 colon, gallbladder and common bile duct expressed both genes in as a receptor for cellular entry. The binding affinity of the S pro- the same cell (Fig. 1a; third column). We also assessed ACE2 and tein and ACE2 was found to be a major determinant of SARS-CoV TMPRSS2 expression in developmental datasets from fetal tissues, replication rate and disease severity4,7. Viral entry also depends on including liver, thymus, skin, bone marrow, yolk sac and lung, and TMPRSS2 protease activity and cathepsin B/L activity may be able found little to no expression of ACE2 in all but fetal liver and thymus to substitute for TMPRSS27. (Fig. 1a) where there was no co-expression with TMPRSS2 (data ACE2 and TMPRSS2 have been detected in both nasal and bron- not shown) except for a cluster of medullary thymic epithelial cells chial epithelium by immunohistochemistry8. Gene expression of ACE2 (Fig. 1a). ACE2 expression is noticeable in certain cell types in pla- and TMPRSS2 has been reported to occur largely in alveolar epithelial centa/decidua without TMPRSS2 (Fig. 1a). Additional fetal data type II cells9–11, which are central to SARS-CoV pathogenesis, whereas across relevant tissues and stages are needed to determine the gen- a different study reported the absence of ACE2 in the upper airway12. erality of these findings. To clarify the expression patterns of ACE2 and TMPRSS2, we ana- To further characterize specific epithelial cell types expressing lyzed their expression and the expression of other genes potentially ACE2, we evaluated ACE2 expression within the lung and airway 1Wellcome Sanger Institute, Cambridge, UK. 2Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis, France. 3Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands. 4Groningen Research Institute for Asthma and COPD, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands. 5Bioinformatics Core Facility, Newcastle University Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle-upon-Tyne, UK. 6Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. 7Department of Genetics, Harvard Medical School, Boston, MA, USA. 8Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. 9Department of Medicine, Addenbrookes Hospital, Cambridge, UK. 10Cambridge Liver Unit, Cambridge University Hospitals, Cambridge, UK. 11UCL Respiratory, Division of Medicine, University College London, London, UK. *A list of authors and their affiliations appears at the end of the paper. e-mail: [email protected]; [email protected] NATURE MEDICINE | www.nature.com/naturemedicine Structure of ACE2 bound to SARS-CoV-2 https://doi.org/10.1101/2020.02.19.956235 Recall “Red Queen Hypothesis” (Evolutionary Arms Race) “Now, here, you see, it takes all the running you can do, to keep in the same place.” -Lewis Caroll https://en.wikipedia.org/wiki/Red_Queen_hypothesis https://jvi.asm.org/content/90/7/3280 correspondence of laboratory escapes of SARS-CoV28. sequence helped reveal key RBD mutations Published online: 17 March 2020 We must therefore examine the possibility and the polybasic cleavage site. https://doi.org/10.1038/s41591-020-0820-9 of an inadvertent laboratory release of The genomic features described here SARS-CoV-2. may explain in part the infectiousness and References In theory, it is possible that SARS-CoV-2 transmissibility of SARS-CoV-2 in humans. 1. 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