SARS-CoV-2
Of the 7 coronaviruses known to infect human, only 3 of them, SARS-CoV-2, MERS-CoV and SARS-CoV cause severe disease in humans. SARS-CoV-2 infections spread rapidly and are more fatal.
What is the difference between them? [1]
1. Affinity if RBD for ACE2 (Angiotensin Converting Enzyme 2)
The receptor-binding domain (RBD) has a higher affinity fir ACE2 than the RBDs from other coronaviruses. The higher the affinity, the more its ability to infect cells. Higher affinity may be because of a mutation in the RBD.
2. Polybasic furin cleavage site
SARS-CoV-2 has a polybasic cleavage site at the junction of two subunits (S1 and S2) which in turn enhances cell-cell fusion without affecting viral entry. This might have an impact on its transmissibility and pathogenesis.
3. Cytokine profile
Cytokine profiles are often perturbed during viral infections. In individuals with SARS-CoV-2 infection, the level of inflammatory cytokines was significantly higher than normal. In addition, there was significant correlation between cytokine levels and severity of the disease. The severe cytokine storm is reflected in the severity of the symptoms.
Classification of Covid-19 Severity [2]
Stage I (mild)
People often feel non-specific symptoms such as malaise, fever and a dry cough. SARS-CoV-2 binds to its target, angiotensin-converting enzyme 2 (ACE2) receptor, that ubiquitous present on human lung, small intestine epithelium and the vascular endothelium as well. Treatment at this stage is to relieve the symptoms. There has been increasing viral load in patient’s blood.
Stage II (moderate)
In this stage, patients develop a viral pneumonia with cough, fever, and possibly hypoxia. Treatments include anti-viral therapies (there are no drugs available specifically to eradicate SARS-CoV-2, however we could use other potential drugs that have mechanisms against SARS-CoV-2) such as chloroquine, hydroxychloroquine, remdesivir (now Gilead conduct phase 3 trial of Remdesivir) and supportive therapies.
Stage III (severe)
Only several patients develop into this stage which manifests as an extra-pulmonary systemic hyperinflammation syndrome. Therapies for this stage include anti-viral, immunomodulator, anti-infammation, supportive therapies. In addition, corticosteroid can also be used as cytokine inhibitorsincluding tocilizumab (IL-6 inhibitor) or anakinra (IL-1 receptor antagonist)
Scheme for SARS-CoV-2 Viral Life cycle
SARS-CoV-2 is a single stranded RNA-enveloped virus which binds to the angiotensin-converting enzyme 2 (ACE2) receptor through the virus's spike. A host type 2 transmembrane serine protease (TMPRSS2) facillitates cell entry via the S protein. When the virus already inside the cell, viral polyproteins are synthesise that encode for the replicase-transcriptase complex. RNA-dependent RNA polymerase then initiates the production of viral RNA[3].
SARS-CoV-2 prompted conformational changes in Spike (S) glycoprotein result in proteolysis of cathepsin L through intercellular proteases and activating the membrane fusion mechanism.
To be continued.
REFERENCES
[1] Andersen, K. G., Rambaut, A., Lipkin, W. I., Holmes, E. C., & Garry, R. F. (2020). The proximal origin of SARS-CoV-2. Nature medicine, 26(4), 450-452.
[2] Siddiqi, H. K., & Mehra, M. R. (2020). COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal. The Journal of Heart and Lung Transplantation, 39(5), 405.
[3] Sanders, J. M., Monogue, M. L., Jodlowski, T. Z., & Cutrell, J. B. (2020). Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. Jama, 323(18), 1824-1836.
[4] InvivoGen, 2020, Spotlight on COVID-19 : Infection cycle of SARS-CoV-2, https://medschool.vanderbilt.edu/bret/2020/03/31/spotlight-on-covid-19-infection-cycle-of-sars-cov-2/