Pathophysiology and Infection Cycle of SARS-CoV-2
SARS-Cov-2 is a novel coronavirus that causes an acute respiratory disease that is known as covid-19. This disease is now a pandemic affecting and threatening the global pandemic. This article covers the main steps in the SARS-C0V-2 infection cycle.
SARS-CoV-2 is an enveloped positive sense single stranded RNA virus. This virus belongs to a family of coronaviridae.
SARS-CoV-2 infection cycle
The SARS-CoV-2 infection cycle involves these steps:
- Direct cytopathic effects
- Dysregulated immune response
The angiotensin converting enzyme 2 has been identified as the binding site for SARS-CoV-2 virus. This enzyme is found on the surface epithelium of the human lungs and has a role in catalyzing the conversion of angiotensin II.
Here the spike glycoprotein is cleaved into S1 and S2 by a cell derived protease. The S1 glycoprotein binds to the angiotensin converting enzyme 2. The S2 glycoprotein is activated by the host Transmembrane serine protease known as TMPRSS2.
This activation results in membrane fusion which then enables the virion to enter the cells through endosomes.
Once the virus gains entry into the cell, its viral components are replicated via the use of viral enzymes like RNA polymerase. These enzymes are virally induced by endosomal viral RNA release.
While the SARS-CoV-2 virion is in the human cell it hijacks the host machinery so as to transcribe, replicate and translate its RNA genome and structural proteins before reassembly and encapsulation and release of the virions from the infected human cell.
The 5’ two thirds of the viral genome encodes polyproteins PP1a and PP1ab These two polyproteins are known as replicases.
These replicases PP1a and PP1ab are cleaved by 3C- like protease known as 3CLPro and a parpain-like protease (PLPro) into sixteen non-structural proteins. The important of these non-structural protein are an RNA dependent RNA polymerase (RdRp) forming a replication complex.
This replication complex carries out the transcription of full-length negative strand.
The 3’ end of the viral genome then encodes four structural proteins known as spike protein (S) envelope (E) protein, nucleocapsid (N) protein and matrix/membrane (M) protein together with set of accessory proteins.
When transcription and replication of viral RNA genome and accessory proteins is over, there is trafficking of the newly synthesized viral protein from the endoplasmic reticulum to the golgi apparatus then the assembly of mature virions in a budding vessicle follows. Lastly the mature virion os released via exocytosis process.
Direct cytopathic effects
This virus produces a direct damage into alveolar epithelium in the lungs. In some severe cases there is a damage to multiple organs causing multi organ failure.
Dysregulated immune response
SARS-CoV-2 viral antigen is then presented to the specialized type of cells known as host antigen presenting cells (APCs) which then produce a number of inflammatory mediators known as cytokines.
Most important of these inflammatory mediators or cytokines that are produced are interleukin-1 (IL-1), interleukin-6 (IL-6), CXCL-10 and tumor necrosis factor alpha (TNF-alpha).
These cytokines cause an enhanced and dysregulated devastating pro-inflammatory response known as cytokine storm to the host.
Cytokine storm syndrome is an excessive immune response that damages a healthy lung tissue leading to development of acute respiratory distress and multiorgan failure.
The understanding of the infectious cycle has enabled research on interleukin-6 inhibitors use to ameliorate some damage to lung tissue caused by cytokine release in patients with severe COVID-19 disease. These drugs include Sarilimab and Tocilizumab.
Hydroxychloroquine has also shown to be effective in controlling cytokine release syndrome.