Variants in ACE2; potential influences on virus infection and COVID-19 severity

Abstract

The third pandemic of coronavirus infection, called COVID-19 disease, was first detected in November 2019th. Various determinants of disease progression such as age, sex, virus mutations, comorbidity, lifestyle, host immune response, and genetic background variation have caused clinical variability of COVID-19. The causative agent of COVID-19 is an enveloped coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that invades host cells using an endocytic pathway. The SARS-CoV-2 spike protein is the main viral protein that contributes to the fusion of the virus particle to the host cell through angiotensin-converting enzyme 2 (ACE2). The highly conserved expression of ACE2 is found in various animals, which indicates its pivotal physiological function. The ACE2 has a crucial role in vascular, renal, and myocardial physiology. Genetic factors contributing to the outcome of SARS-CoV-2 infection are unknown; however, variants in the specific sites of ACE2 gene could be regarded as a main genetic risk factor for COVID-19. Given that ACE2 is the main site for virus landing on host cells, the effect of amino acid sequences of ACE2 on host susceptibility to COVID-19 seems reasonable. It would likely have a substantial role in the occurrence of a wide range of clinical symptoms. Several ACE2 variants can affect the protein stability, influencing the interaction between spike protein and ACE2 through imposing conformational changes while some other variants are known to cause a decrease or an increase in the ligand-receptor affinity. The other variations are located at the proteolytic cleavage site, which can influence virus infection; because soluble ACE2 can act as a decoy receptor for virus and decrease virus intake by cell surface ACE2. Notably, polymorphisms of regulatory and non-coding regions such as promoter in ACE2, can play crucial role in different expression levels of ACE2 among different individuals. Many studies should be performed to investigate the involvement of ACE2 polymorphism with susceptibility to COVID-19. Herein, we discuss some reported associations between variants of ACE2 and COVID-19 in details. In addition, the mode of action of ACE2 and its role in SARS-CoV-2 infection are highlighted which is followed by addressing the effects of several ACE2 variants on its protein stability, viral tropism or ligand-receptor affinity, secondary and tertiary structure or protein conformation, proteolytic cleavage site, and finally inter-individual clinical variability in COVID-19. The polymorphisms of regulatory regions of ACE2 and their effect on expression levels of ACE2 are also provided in this review. Such studies can improve the prediction of the affinity of mutant ACE2 variations with spike protein, and help the biopharmaceutical industry to design effective approaches for recombinant hACE2 therapy and vaccination of COVID-19 disease.

The SARS-CoV-2/Receptor Axis in Heart and Blood Vessels: A Crisp Update on COVID-19 Disease with Cardiovascular Complications

“…Intriguingly, there are several hypotheses that support the symptomless nature of the disease, which are speculated to be determined by the host factors in terms of susceptibility to infection and the virus-related factors in terms of the degree of virulence. The host associated factors might include (i) insufficient expression of ACE2 receptors on nasopharynx or salivary glands, which could terminate in very feeble infection and could be unnoticed; (ii) polymorphisms in ACE2 gene, causing alteration in affinity binding region and spike protein processing [ 252 ]; (iii) polymorphism affecting TMPRSS2 structure and function; (iv) role of sex hormones, as women develop lesser complications than men [ 253 ]; (v) type of blood group, as people with A blood group are at higher risk compared to the people with O blood group [ 254 ]; (vi) alleles of major histocompatibility complex (MHC) class I, where the human leukocyte antigen (HLA)-B*46:01 tend to load fewer peptides and might increase the susceptibility to infection in comparison to HLA-B*15:03 that enhance T cell immunity [ 255 ]; duration of antibodies production [ 256 ]. Likewise, the deletion of 15–30 bp in the S1/S2 cleavage site region decreases the virulence of the SARS-CoV-2 virus [ 257 , 258 ].…”

High rate of mutational events in SARS-CoV-2 genomes across Brazilian geographical regions, February 2020 to June 2021

“…The SARS-CoV-2 single stranded RNA is 29.9 kb in size and has positive coding orientation, encoding four major structural proteins on its 3’ end: spike (S), envelope (E), membrane (M) and nucleocapsid (N). These proteins are essential to virus entry into cells and virus particle formation (Bakhshandeh et al, 2021; Souza et al, 2021).…”

“…The mutation rate in SARS-CoV-2 is about 10^4 replacement of base pairs per year, and possible variations may appear in each replication cycle. In the context of investigating evolutionary events it is possible to compare single-nucleotide polymorphisms (SNPs) in RNA sequences because mutations in coronaviruses occur from RdRp mistakes during viral genome replication (Bakhshandeh et al, 2021; Domingo et al, 1997; Ma et al, 2015).…”

SARS-CoV-2 as a betacoronavirus comprises five structural proteins?

“…We read with interest a review article by Bakhshandeh et al ( Bakhshandeh et al, 2021 ). The authors considered hemagglutinin esterase (HE) as one of the structural proteins of SARS-CoV-2 ( Bakhshandeh et al, 2021 ).…”

“…We read with interest a review article by Bakhshandeh et al ( Bakhshandeh et al, 2021 ). The authors considered hemagglutinin esterase (HE) as one of the structural proteins of SARS-CoV-2 ( Bakhshandeh et al, 2021 ). Although, scientific evidences show that the genome of SARS-CoV-2 lacks the HE gene and it has no hemagglutinin-esterase glycoprotein ( Kumar et al, 2020 ; Anastasopoulou and Mouzaki, 2020 ; Crawford et al, 2020 ; Zhang et al, 2020 ).…”