Hot Topics: A brief update on coronaviruses

The new respiratory coronavirus from Wuhan in China is causing intense research activity in the world. Viruses are evidently associated with respiratory infections ranging in severity from the common cold to pneumonia and death. More than 200 viral types have been associated with the common cold, of which 50% of infections are rhinovirus, but also respiratory syncitial virus, influenza – and coronaviruses, particularly human coronavirus-229E (HCoV-229E), which is ‘relatively benign’. Monocytes are relatively resistant to HcoV-229E infection, but rapidly invades, replicates in, and kills dendritic cells within a few hours of infection (Mesel-Lemoine et al., 2012) [1]. Dendritic cells are the sentinel cells in the respiratory tract, and plasmacytoid dendritic cells are a crucial antiviral defence via interferon production. Thus, these viruses can impair control of viral dissemination and the formation of long-lasting immune memory. The cellular receptor for HcoV-229E is CD-13 (aminopeptidase-N).
The cellular receptors for coronaviruses are critical for cell entry. Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and HCoV-NL63, bind to angiotensin converting enzyme2, ACE2, on ciliated cells in the respiratory tract, the crystal structure is known (Song et al., 2018) [2]. The SARS-CoV spike (S) glycoprotein (with S1 and S2 sub-units) on the outer envelope binds to ACE2, fusing viral and cellular membranes, triggering conformational transformations. Cleavage of the S1/S2 subunits by proteases is critical. Indeed, Simmons et al (2005) [3] showed that SARS-CoV infection involved receptor binding, conformational changes receptor binding and subsequent cathepsin L (and type II transmembrane serine proteases) proteolysis within endosomes – with inhibitors of cathepsin L preventing viral entry. SARS-CoV may lead to markedly elevated cytokine levels, leading to tissue damage, pneumonitis, and acute respiratory distress syndrome (ARDS). The spike proteins in SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) are crucial for host specificity and jumping between species, e.g. from bats to humans (Lu et al., 2015) [4], and also the recent cross-over to swine acute diarrhoea syndrome coronavirus (SADS-CoV) to pigs (Zhou et al., 2018) [5]. There is intense interest in the complicated ways whereby coronaviruses engage with their target receptors, are activated and replicate. The rapid evolution of coronaviruses is critical as humans have little or no pre-existing immunity SARS- or MERS-CoV.

ACE2 has been identified as a potential receptor for the novel coronavirus that was identified as the cause of the respiratory disease outbreak in Wuhan in late 2019 (referred to as 2019 – nCoV by the WHO, or Wuhan coronavirus) [6,7 & 9]. 2019-nCoV is a betacoronavirus, and, in common with the SARS-CoV [8], the viral spike protein is postulated to engage ACE2 for viral entry [7]. The data presented by Letko and Munzter [7] is preliminary and has not been peer-reviewed, but a rapid pace of research is needed in the present circumstances. For example, in another recent, preliminary report, ACE2 receptor expression is highly expressed in type II alveolar cells (AT2) with much individual variation and the authors reported that the cells also expressed many genes involved in viral reproduction and transmission [10]. While these findings are preliminary, the rapid publications in bioRxiv and similar archives are crucial in what is now officially a global health emergency. This report is a hot topic in the IUPHAR/BPS Guide to PHARMACOLOGY (https://www.guidetopharmacology.org), and further underlines the importance of immunopharmacology and the IUPHAR Guide to IMMUNOPHARMACOLOGY (https://www.guidetoimmunopharmacology.org/immuno/index.jsp).

Comments by Prof. Michael Spedding, Spedding Reseach Solutions; Prof. Steve Alexander (@mqzspa), University of Nottingham; Dr. Elena Faccenda, University of Edinburgh; and Prof. Francesca Levi-Schaffer, The Hebrew University of Jerusalem.

Note from bioRxiv: bioRxiv is receiving many new papers on coronavirus 2019-nCoV.   A reminder: these are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information.

 

  1. Mesel-Lemoine M, Millet J, Vidalain PO, Law H, Vabret A, Lorin V, Escriou N, Albert ML, Nal B, Tangy F. A human coronavirus responsible for the common cold massively kills dendritic cells but not monocytes. J Virol. 2012 Jul;86(14):7577-87. doi: 10.1128/JVI.00269-12. Epub 2012 May 2. PubMed PMID: 22553325; PubMed Central PMCID: PMC3416289.
  2. Song W, Gui M, Wang X, Xiang Y. Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2. PLoS Pathog. 2018 Aug 13;14(8):e1007236. doi: 10.1371/journal.ppat.1007236. eCollection 2018 Aug. PubMed PMID: 30102747; PubMed Central PMCID: PMC6107290.
  3. Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL, Bates P. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11876-81. Epub 2005 Aug 4. PubMed PMID: 16081529; PubMed Central PMCID: PMC1188015.
  4. Lu R, Wang Y, Wang W, Nie K, Zhao Y, Su J, Deng Y, Zhou W, Li Y, Wang H, Wang W, Ke C, Ma X, Wu G, Tan W. Complete Genome Sequence of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) from the First Imported MERS-CoV Case in China. Genome Announc. 2015 Aug 13;3(4). pii: e00818-15. doi: 10.1128/genomeA.00818-15. PubMed PMID: 26272560; PubMed Central PMCID: PMC4536671.
  5. Zhou L, Sun Y, Lan T, Wu R, Chen J, Wu Z, Xie Q, Zhang X, Ma J. Retrospective detection and phylogenetic analysis of swine acute diarrhoea syndrome coronavirus in pigs in southern China. Transbound Emerg Dis. 2019 Mar;66(2):687-695. doi: 10.1111/tbed.13008. Epub 2019 Jan 9. PubMed PMID: 30171801.
  6. Gralinski LE, Menachery VD. Return of the Coronavirus: 2019-nCoV. Viruses. 2020 Jan 24;12(2). pii: E135. doi: 10.3390/v12020135. PubMed PMID: 31991541.
  7. Letko M, Munster V. Functional assessment of cell entry and receptor usage for lineage B β coronaviruses, including 2019-nCoV. bioRxiv 2020.01.22.915660; doi: 10.1101/2020.01.22.915660
  8. Li F, Li W, Farzan M, Harrison SC. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science. 2005 Sep 16;309(5742):1864-8. PubMed PMID: 16166518.
  9. Peng Z, Shi Z-L. (2020) Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin. bioRxiv 2020.01.22.914952; doi: 10.1101/2020.01.22.914952
  10. Yu Zhao, Zixian Zhao, Yujia Wang, Yueqing Zhou, Yu Ma, Wei Zuo.Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov bioRxiv 2020.01.26.919985 doi: 10.1101/2020.01.26.919985
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