Implications of the Immune Polymorphisms of the Host and the Genetic Variability of SARS-CoV-2 in the Development of COVID-19

Abstract

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current pandemic affecting almost all countries in the world. SARS-CoV-2 is the agent responsible for coronavirus disease 19 (COVID-19), which has claimed millions of lives around the world. In most patients, SARS-CoV-2 infection does not cause clinical signs. However, some infected people develop symptoms, which include loss of smell or taste, fever, dry cough, headache, severe pneumonia, as well as coagulation disorders. The aim of this work is to report genetic factors of SARS-CoV-2 and host-associated to severe COVID-19, placing special emphasis on the viral entry and molecules of the immune system involved with viral infection. Besides this, we analyze SARS-CoV-2 variants and their structural characteristics related to the binding to polymorphic angiotensin-converting enzyme type 2 (ACE2). Additionally, we also review other polymorphisms as well as some epigenetic factors involved in the immunopathogenesis of COVID-19. These factors and viral variability could explain the increment of infection rate and/or in the development of severe COVID-19.

Keywords: ACE2 overexpression; SARS-CoV-2 variant; genetic susceptibility; immune polymorphism; severe COVID-19.

Figure 1

Interaction between SARS-CoV-2 and host cell. The SARS-CoV-2 virion is composed of 4 structural proteins, spike protein (S), membrane protein (M), envelope protein (E), and nucleocapsid protein (N), associated with single-stranded RNA (ssRNA) of the virion. S protein interacts with the host cell ACE2 protein and is activated by TMPRSS2 as part of the infection mechanism.

Figure 2

Main mutations in S glycoprotein that regulate viral transmissibility and neutralization. Structure of the S glycoprotein in a trimeric conformation (PDB: 6VXX); each monomer is shown in a different shade of gray, mutation sites are only shown for one monomer (light grey), and the colors used are to visualize one mutation for another.

Figure 3

SARS-CoV-2 variants modify their binding capability to angiotensin converting enzyme 2 (ACE2). Variants of SARS-CoV-2 with altered glycoprotein S can modify their interaction with the viral receptor ACE2 by increasing its binding capacity (variant N501Y, E484K, or L452R) or inhibiting it (variant K417N) during infection.

Figure 4

Angiotensin-converting enzyme 2 (ACE2) structure. (A) Schematic representation of the ACE2 protein. Peptidase domain (PD) and collectrin-like domain (CLD) are also shown. The N-glycosylation sites are shown as arrows for each amino acid residue, indicating their relative position in PD and CLD. (B) Structure of ACE2. According to panel A, the domains and motifs are shown, except the intracellular segment (PDB: 6M17).

Figure 5

ACE2-RBD (S) complex. (A) Structure of a monomer of the S protein in lateral view of the open conformation and Spike trimer; also, the top view (PDB: 6VYB). The receptor binding domain (RBD) and receptor binding motif (RBM) are shown in red and cyan, respectively. (B) Structure of the ACE2-RBD complex, in which the amino acids of the RBM and the amino acids of the PD subdomain 1 of ACE2 interact (PDB: 6M17).

Figure 6

ACE2 polymorphisms modify their binding capability to SARS-CoV-2 glycoprotein S. ACE2 polymorphisms can also increase or decrease their binding affinity with SARS-CoV-2 glycoprotein S. Several ACE2 polymorphisms are shown interacting with SARS-CoV-2 wild type (WT). K26R and T29I ACE2 polymorphisms show a higher binding affinity to S glycoprotein. E37K and K31R ACE2 polymorphisms show a lower binding affinity to S glycoprotein, suggesting a lower infectivity to people with this last polymorphism.