COVID-19

COVID-19 (SARS-CoV-2), a novel coronavirus, which transferred to humans in late December 2019.  Originally, referred to as Wuhan Coronavirus as the first cases of patients seem to be associated with the Huanan seafood market or surrounding area in Wuhan, China.  This virus causes viral pneumonia with the most prominent symptoms being cough, fever and difficulty breathing¹.  The radiographs of most patients with the virus show invasive lesions in both lungs.  However, the symptoms can vary from mild to severe with some patients being asymptomatic.  The incubation period of the virus can last anywhere from 2-14 days, according to the CDC which is basing it off the MERS-CoV viruses¹.  The Wuhan Coronavirus was previously being referred to as 2019-nCoV, but is now being called COVID-19.

This virus is part of the family Coronaviridae.  The Coronaviridae family of viruses are normally seen in birds, bats, camels, masked palm civets, mice, dogs and cats.  Normally, these viruses are kept within the avian or mammalian species it infects.  However, occasionally, a spillover event occurs in which the virus is transferable to humans.  Of the coronaviruses that are pathogenic to humans, most are either mild or asymptomatic².  The exceptions to these are SARS, Severe acute respiratory syndrome, and MERS, Middle East respiratory syndrome.  SARS was identified in November 2002, Guangdong, China³.  SARS causes severe respiratory illness and during the 2002-2003 outbreak, infected over 8000 people and caused 774 deaths³.  MERS was identified in Saudia Arabia in 2012.  The symptoms of MERS cover a full spectrum of cases from severe disease, to mild, to asymptomatic⁴.  Symptoms can include fever, runny nose, cough, with the common factor being viral pneumonia.

This leads us to our new novel finding of the Wuhan Coronavirus, COVID-19.  COVID-19 has been identified to be in the same family, Coronaviridae, as SARS and MERS.  We are still discovering new properties of this novel virus, but let’s take a look at what we do know.  The Coronaviridae family of viruses are enveloped, single-stranded, positive-sense RNA viruses.  They are subdivided into four groups: alpha, beta, gamma and delta, of which SARS, MERS and COVID-19 fall into the beta group.  They contain very large genomes for an RNA virus, approximately 30 kilobases (kb).  Coronaviridae’s virion structure is spherical with diameters about 125nm.  The clublike projections that protrude from the surface give the viruses a solar corona appearance, leading to the name coronavirus.  These viruses contain an envelope with a nucleocapsid inside.  The nucleocapsids for these viruses are symmetrical which is uncharacteristic of positive-sense strand RNA viruses, this a common feature for negative-sense strand RNA viruses.  There are four main structural proteins found in these viruses, encoded for on the 3’ end of their genome:  spike (S), membrane (M), envelope (E), and nucleocapsid (N)⁵.  Inside the nucleocapsid is where you would find the protected genome of the virus. 

For a coronavirus to enter into a cell, it requires the S protein to come into contact with its receptor⁵.  The S protein/receptor binding is a key component in the ability of the coronavirus to infect a host, and it also determines what cell type(s) it can infect. Once bound to its receptor, the virus must gain access into the cell’s cytosol.  This occurs through a series of cleavages of the S protein, which allows the virus and cellular membranes to fuse. Following this fusion, the viral genome is released into the cell’s cytoplasm

Once the viral genome has entered into the cytoplasm, the next step is for the replicase gene to be translated from the genome. Once this gene is translated, many cleavages occur that result in the formation of the replicase-transcriptase complex (RTC) which is responsible for RNA replication and transcription.  After replication and transcription of the viral particles occurs, assembly and release can follow.  The M protein is responsible for directing most of the protein-protein interaction in the virus construction.  It has been suggested that the M protein together with the E protein are responsible for producing the coronavirus envelopes^5,6.  Once the virions have finished assembly, they are transported to the cell surface in vesicles and released by exocytosis.  It has been suggested that the E protein is not only involved in viral assembly, but also in viral release⁷.  (*All of these processes’ have been simplified and are much more complex involving various other steps.  If you would like to read more about it please see paper #5 in the Bibliography). 

What receptor is COVID-19 using to infect cells?  Recently, it has been shown that COVID-19 is using ACE2 receptors to attach to and infect primary host lung cells^8,9.  Since COVID-19 seems to use ACE2 receptors to enter into the host cell, it is of interest to know which cells contain these receptors.  Knowing where these receptors are expressed and distributed, would give some insight into the infection routes of the virus.  One location where ACE2 receptors are highly expressed is type II alveolar cells, which are found in the lungs^11-13.  Other cells with ACE2 highly expressed are cells in the esophagus (upper and stratified), absorptive enterocytes in the ileum and colon¹³, cholangiocytes (bile duct), myocardial cells, kidney proximal tubule cells and bladder and urothelial cells¹¹.  In addition, Xu et al., just recently discovered that ACE2 is expressed in the oral cavity epithelial cells, with higher expression in the tongue than buccal and gingival tissues¹⁰.

The best way to prevent the spread of COVID-19 is to make sure your hands are washed, avoid touching your face and avoiding contact with others that may be sick.   Those who are more at risk include immune comprised, older adults and those who may have underlying health conditions, such as diabetes, heart or lung disease.

Bibliography

1. CDC website: https://www.cdc.gov/coronavirus/2019-ncov/about/symptoms.html

2. Su S, Wong G, Shi W, et al. Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol 2016; 24: 490–502.

3. Peiris JS, Guan Y, Yuen KY. Severe acute respiratory syndrome. Nat Med 2004; 10 (suppl 12): S88–97.

4.  Hui DS, Azhar EI, Kim Y-J, Memish ZA, Oh M-d, Zumla A. Middle East respiratory syndrome coronavirus: risk factors and determinants of primary, household, and nosocomial transmission. The Lancet Infectious Diseases. 2018;18(8):e217-e27.

5. Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol. 2015;1282:1–23. doi:10.1007/978-1-4939-2438-7_1

6. Bos EC, Luytjes W, van der Meulen HV, Koerten HK, Spaan WJM. The production of recombinant infectious DI-particles of a murine coronavirus in the absence of helper virus. Virology. 1996; 218:52–60.

7.  Ye Y, Hogue BG. Role of the coronavirus E viroporin protein transmembrane domain in virus assembly. Journal of virology. 2007; 81(7):3597–3607.

8.  Yushun Wan, Jian Shang, Rachel Graham, Ralph S. Baric, Fang Li.  Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS.  Journal of Virology Jan 2020, JVI.00127-20; DOI: 10.1128/JVI.00127-20

9. Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. https://doi.org/10.1038/s41586-020-2012-7 (2020).

10. Xu, H., Zhong, L., Deng, J. et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci 12, 8 (2020). https://doi.org/10.1038/s41368-020-0074-x

11. Zou, X. et al. The single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to Wuhan 2019-nCoV infection. Front. Med. http://journal.hep.com.cn/fmd/EN/ 10.1007/s11684-020-0754-0 (2020).

12. Zhao, Y. et al. Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov. Preprint at https://www.biorxiv.org/content/10.1101/ 2020.01.26.919985v1 (2020).

13. Zhang, H. et al. The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. Preprint at https:// http://www.biorxiv.org/content/10.1101/2020.01.30.927806v1 (2020).