Relevance between COVID-19 and host genetics of immune response

Abstract

The outbreak of coronavirus disease 2019 (COVID-19) was caused by the newly emerged corona virus (2019-nCoV alias SARS-CoV-2) that resembles the severe acute respiratory syndrome virus (SARS-CoV). SARS-CoV-2, which was first identified in Wuhan (China) has spread globally, resulting in a high mortality worldwide reaching ∼4 million deaths to date. As of first week of July 2021, ∼181 million cases of COVID-19 have been reported. SARS-CoV-2 infection is mediated by the binding of virus spike protein to Angiotensin Converting Enzyme 2 (ACE2). ACE2 is expressed on many human tissues; however, the major entry point is probably pneumocytes, which are responsible for synthesis of alveolar surfactant in lungs. Viral infection of pneumocytes impairs immune responses and leads to, apart from severe hypoxia resulting from gas exchange, diseases with serious complications. During viral infection, gene products (e.g. ACE2) that mediate viral entry, antigen presentation, and cellular immunity are of crucial importance. Human leukocyte antigens (HLA) I and II present antigens to the CD8 + and CD4 + T lymphocytes, which are crucial for immune defence against pathogens including viruses. HLA gene variants affect the recognition and presentation of viral antigenic peptides to T-cells, and cytokine secretion. Additionally, endoplasmic reticulum aminopeptidases (ERAP) trim antigenic precursor peptides to fit into the binding groove of MHC class I molecules. Polymorphisms in ERAP genes leading to aberrations in ERAP’s can alter antigen presentation by HLA class I molecules resulting in aberrant T-cell responses, which may affect susceptibility to infection and/or activation of immune response. Polymorphisms from these genes are associated, in global genetic association studies, with various phenotype traits/disorders some of which are related to the pathogenesis and progression of COVID-19; polymorphisms from various genes are annotated in genotype-tissue expression data as regulating the expression of ACE2, HLA’s and ERAP’s. We review such polymorphisms and illustrate variations in their allele frequencies in global populations. These reported findings highlight the roles of genetic modulators (e.g. genotype changes in ACE2 , HLA ’s and ERAP ’s leading to aberrations in the expressed gene products or genotype changes at other genes regulating the expression levels of these genes) in the pathogenesis of viral infection.

Predictive Factors and ACE-2 Gene Polymorphisms in Susceptibility to Long COVID-19 Syndrome

“…The ACE-2 gene acts as a receptor on the surface of cells, and it is through this interaction that the SARS-CoV-2 virus enters in human cells [20]. The relationship between COVID-19 susceptibility and severity has been of great interest [49][50][51], and previous studies have suggested that higher levels of ACE-2 expression may be associated with greater ease of viral entry and, thus, greater severity of COVID-19, and this may be the result of a complex interaction between multiple factors, including the host immune response [52,53].…”

Influence of polymorphic variations of IFNL, HLA, and IL-6 genes in severe cases of COVID-19

“…87,88 Among the various HLA molecules, those of classes I and II are the most important, with the former inducing the cytotoxic action of CD8+ T cells by inducing programmed cell death of infected cells 89 and the latter characterized by their high specificity in binding and presenting antigens to CD4+ T cells (Figure 2). 90 The process of binding to antigens is mediated by interaction in the peptide-binding grooves of the complex proteins, followed by proteolysis of the epitopes and finally their presentation. 87 The extensive number of polymorphisms in HLA genes characterize a large variability in the immune response produced, making possible genotypes strong markers that impact susceptibility to viral infections.…”

Circular RNAs as emerging regulators in COVID-19 pathogenesis and progression

“…The ability to activate CD4+ T cells is restricted to antigen-presenting cells that are endocytosed and processed in lysosomes for presentation on MHC class II molecules, which can transduce signals required for B-cell activation. Moreover, MHC class II antigen presentation by B lymphocytes is a multistep process involving in the presentation of MHC II-peptide complexes to CD4+ T cells ( 44 – 47 ). Although the host’s innate immune system works against the virus particles in this process, a small number of viruses still escape, and the RNAs released by these viruses are captured and identified by toll-like receptors (TLRs).…”