# Changing Dynamics of SARS-CoV-2: A Global Challenge
## 3 Immunopathology of SARS-CoV-2  
Throughout the evolution of SARS-CoV-2, it has been observed that mutations and the response of the immune system towards those mutations have become the controlling factors of the pathogenicity of this virus. The host cell membrane has the protein receptor ACE-2, which influences the virus's passage into the cell [25; 26]. The virus enters the host cell by fusion of spike glycoprotein with the ACE-2 receptor on the cell membrane [27]. This induces conformational alteration in the plasma membrane and facilitates receptor-mediated endocytosis (Figure 4) [28]. Once uncoating is performed inside the cell, all proteins are removed and viral RNA is released into the cytoplasm. Then, spike glycoproteins inhibit ACE-2 and downregulate it. The downregulation of ACE-2 leads to the compensatory increase in ACE-1 and causes the excessive production of angiotensin-II, consequently enhancing pulmonary vascular permeability [29; 30]. Once the cell is infected by the virus, it stimulates the production of interferon \(\alpha\) in infected cells, which alerts the adjacent cells to stimulate the antiviral program. This leads to the production of interferon \(\gamma\) in the immune cells, which, in turn, triggers the immune system to destroy the infected cells. Virus-infected cells lose surface MHC I expression, which leads to a reduced inhibitory signal in NK cells. Additionally, cellular stress due to the viral infection upregulates the activating receptors of NK cells leading to the elimination of infected cells. Simultaneously, cytotoxic T cells are alerted when a fragment of viral protein is transported onto the cell's surface by MHC I, which presents antigens from the virus  
Figure 4: The entry and immunopathology of SARS-CoV-2 in the human body. Adapted from “Mechanism of SARS-CoV-2 Viral Entry, Acute Respiratory Distress Syndrome (ARDS), Adaptive Immunity and Interferons”, by biorender.com (accessed on 5 January 2022). Retrieved from [[https://app.biorender.com/biorender-templates](https://app.biorender.com/biorender-templates)]([https://app.biorender.com/biorender-templates](https://app.biorender.com/biorender-templates)); image for “memory cell and IFN gamma” from <[[https://reactome.org/PathwayBrowser/#/R-HSA-168256&SEL=R-HSA-1280218](https://reactome.org/PathwayBrowser/#/R-HSA-168256&SEL=R-HSA-1280218)]([https://reactome.org/PathwayBrowser/#/R-HSA-168256&SEL=R-HSA-1280218](https://reactome.org/PathwayBrowser/#/R-HSA-168256&SEL=R-HSA-1280218))> and image for “ACE2” from [[https://reactome.org/PathwayBrowser/#/R-HSA-2022377&SEL=R-HSA-2022344&PATH=R-HSA-392499,R-HSA-2980736&FLG=Q9](https://reactome.org/PathwayBrowser/#/R-HSA-2022377&SEL=R-HSA-2022344&PATH=R-HSA-392499,R-HSA-2980736&FLG=Q9) BYF1]([https://reactome.org/PathwayBrowser/#/R-HSA-2022377&SEL=R-HSA-2022344&PATH=R-HSA-392499,R-HSA-2980736&FLG=Q9](https://reactome.org/PathwayBrowser/#/R-HSA-2022377&SEL=R-HSA-2022344&PATH=R-HSA-392499,R-HSA-2980736&FLG=Q9) BYF1). Reactome, (all accessed on 30 December 2021). within the cell [29]. Dendritic cells present antigens on their surface, which interacts with T cells and B cells to produce antigen-specific antibodies (Figure 4). Additionally, phagocytes play a significant role in innate immunity by ingesting the free virus particles and contribute to adaptive immunity by presenting antigens to lymphocytes. Simultaneously, certain chemokines, such as CXCL10 and CCL2, are released in order to guide immune cells towards the infected region and, hence, destroy the infected cells [31; 32]. Studies report that the failure of switching between innate to adaptive responses disables the formation of memory cells, which increases the risk of recurring infections. Alluding to the above mechanism, the human body is well designed to protect itself against pathogens. Yet, SARS-CoV-2 successfully escapes and disrupts the immune response by generating various viral proteins, such as 3b and M, which inhibits the natural processes of the cell.