Molecular Understanding of ACE-2 and HLA-Conferred Differential Susceptibility to COVID-19: Host-Directed Insights Opening New Windows in COVID-19 Therapeutics

Abstract

The genetic variants of HLAs (human leukocyte antigens) play a crucial role in the virus-host interaction and pathology of COVID-19. The genetic variants of HLAs not only influence T cell immune responses but also B cell immune responses by presenting a variety of peptide fragments of invading pathogens. Peptide cocktail vaccines produced by using various conserved HLA-A2 epitopes provoke substantial specific CD8+ T cell responses in experimental animals. The HLA profiles vary among individuals and trigger different T cell-mediated immune responses in COVID-19 infections. Those with HLA-C*01 and HLA-B*44 are highly susceptible to the disease. However, HLA-A*02:01, HLA-DR*03:01, and HLA-Cw*15:02 alleles show resistance to SARS infection. Understanding the genetic association of HLA with COVID-19 susceptibility and severity is important because it can help in studying the transmission of COVID-19 and its physiopathogenesis. The HLA-C*01 and B*44 allele pathways can be studied to gain insight into disease transmission and physiopathogenesis. Therefore, integrating HLA testing is suggested in the ongoing pandemic, which will help in the rapid identification of highly susceptible populations worldwide and possibly acclimate vaccine development. Therefore, understanding the correlation between HLA and SARS-CoV-2 is critical in opening new insights into COVID-19 therapeutics, based on previous studies conducted.

Keywords: ACE-2; COVID-19; HLA; antiviral immunity; disease severity; genetic susceptibility; pandemic.

Figure 1

The attachment of SARS-CoV-2 virus on human ACE-2.

Figure 2

The role of immunogenetics in SARS-CoV-2 infection.

Figure 3

Schematic representation of cellular and molecular pathophysiology of SARS- CoV-2 (COVID-19).SARS-CoV-2 interacts with the ACE-2 receptor resulting in membrane fusion and cytoplasmic entry. 2 and 3: Proteasomal degradation of SARS-CoV-2 in the endolysosome results in antigen generation. 4 and 5: Further processing of the peptide antigens through interaction with HLA class 1 and complexing with the endoplasmic reticulum leads to its presentation on the cell surface. 6 and 7: The processed antigen is further represented by the APC through its β2M receptor, which activates T cells when they encounter the T cell receptors, leading to induced apoptosis. Adapted from “Acute Immune Responses to Coronaviruses”, by BioRender.com (2022). https://app.biorender.com/biorender-templates (accessed on 6 December 2022).

Figure 4

Cell entry of SARS-CoV-2 with ACE-2-mediation and virus infection inhibition by recombinant soluble ACE-2 protein. SARS-CoV-2 penetrates host cells via angiotensin-converting enzyme 2 (ACE-2), which subsequently results in the fusion of viral and cellular membranes.

Figure 5

The cytokines secreted from the innate immune system counterparts and the interferons further trigger adaptive immunity leading to the expression of many types of antiviral proteins. Genes that play a key role include chemokines and their related receptors along with members of the IFN pathway. Dysregulated neutrophil extracellular traps (NET) formations persuade immune coagulation and intensify inflammation in the lungs of patients with COVID-19.

Figure 6

B cell receptor (BCR) proteins are present at B cells receptors, while T cell receptor (TCR) proteins are only found on the surface of T cells. When the TCR identifies the HLA molecule complex bonded with the foreign peptide, it activates the immune system to be aware of the presence of a foreign protein. Activated T cells can kill infected cells, or activate B cells, which produce antibodies in response to an infection.

Figure 7

Schematic structure of HLA class I and class II molecules. The peptide-binding groove in class I and class II molecules are important for functional aspects of HLA molecule. Class I antigens consist of two chains: a glycoprotein heavy chain and a β2-microglobulin molecule. Class II consists of two structurally similar α- and β-glycoprotein chains, each chain has two amino acid domains, of which the outermost domain contains the variable region of class II alleles.

Figure 8

Schematic representation of individuals harboring susceptible and tolerant HLA variants. Created with BioRender.com (2022). Susceptible organisms have higher chances of COVID-19 infection and the tolerant have fewer chances.