SARS-CoV2

SARS-CoV2

    After looking briefly into coronaviruses in general (see previous post), I have turned to SARS-CoV2, the virus responsible for the current pandemic of the respiratory infection called COVID-19.

Interesting aspect at this stage in the pandemic include:

• Important biochemical and biological differences between SARS-CoV2 and SARS-CoV viruses.
• Hight infectivity; 100 or 1000 times higher than SARS-CoV.
• Why are 30-40% of infected  'carriers' symptom-free?

Difference between SARS-CoV2 and SARS-CoV(1) that might cause higher infectivity.

    SARS-CoV2 is said to be 1000 time more infectious than SARS-CoV1; a pretty loose statement, but there is some biochemistry to investigate. Is this high infectivity due to:  

a.    different, more accessible or numerous, targets on host;

b.    tighter binding to target; 

c.     epidemiological factors like shedding before or without symptoms, or more coughing and sneezing; 

d.    better evasion of host responses. 

[a] Target on host

    The host receptor for both SARS-CoV and SARS-CoV2  seems to be the dimeric membrane-bound protease called ACE2 (for Angiotensin Converting Enzyme 2). There is a small mystery here, as the first investigators found very little ACE2 protein, or mRNA, in human lung tissue, though lots in arteries, gut, kidney, testes and elsewhere [1]. Yet SARS-CoV2  seems to attack the lower respiratory tract (as well as gut, blood-cells, kidney, etc). This was so important that the question was re-examined and some ACE2 was found in lung tissue, particularly around arterioles [2].  (It is notable, however, that SARS-CoV2  can cause diarrhoea and kidney damage [3].) Other coronaviruses act primarily as gut pathogens (See previous blog). I worried that the polyclonal antibody used by Hamming to test the presence of ACE2 (which was reared against a stretch of 19 amino acids distinctive to ACE2) might cross-react and mislead. However, it seems to be universally accepted that the receptor for SARS-CoV2  is ACE2.

[b] Tighter binding of Spike to Target.

    The spike protein is not highly conserved; the opposite rather, and it seems likely that mutations, deletions and insertions in spike can affect host range; possibly infectivity as well. There are distinctive features in the spike protein of SARS-CoV2 not found in SARS-CoV spike.  Thus, there is an insert of 4 amino acids (PRRA) into the sequence, which generates a cleavage site absent from the spike protein of SARS-CoV and several other coronaviruses (but present in MERS!). 
                                                                                ↓            
            SARS-CoV2: CASYQTQTNSPRRARSVASQSI
            SARS-CoV  : CASYQTQTNS­­– – – –RSVASQSI
Cleavage is effected by a host protease present cytoplasmically throughout the body. It is a 'subtilisin-type' calcium-dependent protease (called furin), which cleaves after the marked serine residue, but the cleavage site is flagged by the paired basic amino acids (–R+R+–). The furin enzyme is obviously present to service host proteins. But SARS-CoV2 is not unique among viruses in using it for pathologicial purposes, for furin also operates in the activation of: HIV, influenza, dengue fever, Marburg virus, papillomavirus, and even anthrax toxin. It is suggested that processing of progeny virions before release may facilitate the spread of virus (c.f. SARS-CoV)[4]. 
    The spike protein of SARS-CoV2 operates as two peptides (S1 and S2) formed into a trimeric "clove-like" structure.  Tai et al. (2020) were able to compare the binding (to human ACE2) of SARS-CoV2 spike with that of SARS-CoV spike, and found it bound 9 time more tightly. (Interestingly, it bound even more tightly to bat ACE2). [5] 

[c] Epidemiological factors.

     It is important to distinguish pre-symptomatic from truly a-symptomatic carriers; both categories of infected subjects experience no symptoms, but in the former case they eventually develop symptoms, while in the latter they never do. When I use the term 'asymtomatic' in this post it will always mean that the subject did not develop sysmptoms, in at least 4 weeks. Both categories can spread the disease.
    Compared with SARS-CoV of 2003, SARS-CoV2 causes more cases with mild (or very mild) symptoms, and larger numbers stayed at home in the community. There was also twice as long incubation period before the appearance of symptoms (4–12 days). Similarly relevant for the spread of the disease, the new strain can shed infective particles as soon as symptoms appear; or even before (see above). And they can continue shedding for 3 weeks [6].   Susan Lee et al. [7] mentions a family in Anyang (China) where an asymptomatic carrier tested positive for the virus and infected 5 family members. 
    Other factors of obvious relevance to infectivity are propensity to cough or sneeze. 

[d] Evasion of host defences.

    Two recent well referenced summaries are by Indwiani Astuti and Ysrafil [8] and Swatantra Kumar et al. [9]

 References

[1] Donoghue, M., Hsieh, F. et al. (2000) Circulation Research. 87:e1–e9; "A Novel Angiotensin-Converting Enzyme–Related Carboxypeptidase (ACE2) Converts Angiotensin I to Angiotensin 1-9".
[2] Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H.  (2004)"Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis." J Pathol.; 203:631-637. doi:10.1002/path.1570
[3] Martinez-Rojas, M.A. et al. (2020) "Is the kidney a target of SARS-CoV-2?"; Am J Physiol Renal Physiol.; 318:F1454-F1462.
[4] Coutard, B., Valle, C. et al  (2020)
Antiviral Res.; 176: 104742. "The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade."
[5] Tai, W-B. He L.,  Zhang, X-J. et.al. (2020) Cellular & Molecular Immunology volume 17, 613–620. "Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine"
[6] Petersen, E., Koopmans, M. et al (2020).Lancet, Infectious Diseases, https://doi.org/10.1016/ S1473-3099(20)30484-9 "Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics.".
[7] Lee S, Meyler P, Mozel M, Tauh T, Merchant R. "Asymptomatic carriage and transmission of SARS-CoV-2: What do we know?"  Can J Anaesth. 2020;1-7. doi:10.1007/s12630-020-01729-x
[8]  Indwiani Astuti & Ysrafil, (2020) Diabetes Metab Syndr. 2020 July-August; 14(4): 407–412.
Published online 2020 Apr 18. doi: 10.1016/j.dsx.2020.04.020 "Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): An overview of viral structure and host response"
[9]  Kumar S., Nyodu R., Maurya V.K., Saxena S.K. (2020) Host Immune Response and Immunobiology of Human SARS-CoV-2 Infection. In: Saxena S. (eds) Coronavirus Disease 2019 (COVID-19). Medical Virology: From Pathogenesis to Disease Control. Springer, Singapore. Published online 2020 Apr 30. doi: 10.1007/978-981-15-4814-7_5