ACE2 receptor polymorphism in humans and animals increases the risk of the emergence of SARS-CoV-2 variants during repeated intra- and inter-species host-switching of the virus

Abstract

Like other coronaviruses, SARS-CoV-2 has ability to spread through human-to-human transmission and to circulate from humans to animals and from animals to humans. A high frequency of SARS-CoV-2 mutations has been observed in the viruses isolated from both humans and animals, suggesting a genetic fitness under positive selection in both ecological niches. The most documented positive selection force driving SARS-CoV-2 mutations is the host-specific immune response. However, after electrostatic interactions with lipid rafts, the first contact between the virus and host proteins is the viral spike-cellular receptor binding. Therefore, it is likely that the first level of selection pressure impacting viral fitness relates to the virus’s affinity for its receptor, the angiotensin I converting enzyme 2 (ACE2). Although sufficiently conserved in a huge number of species to support binding of the viral spike with enough affinity to initiate fusion, ACE2 is highly polymorphic both among species and within a species. Here, we provide evidence suggesting that when the viral spike-ACE2 receptor interaction is not optimal, due to host-switching, mutations can be selected to improve the affinity of the spike for the ACE2 expressed by the new host. Notably, SARS-CoV-2 is mutation-prone in the spike receptor binding domain (RBD), allowing a better fit for ACE2 orthologs in animals. It is possibly that this may also be true for rare human alleles of ACE2 when the virus is spreading to billions of people. In this study, we present evidence that human subjects expressing the rare E329G allele of ACE2 with higher allele frequencies in European populations exhibit a improved affinity for the SARS-CoV-2 spike N501Y variant of the virus. This may suggest that this viral N501Y variant emerged in the human population after SARS-CoV-2 had infected a human carrying the rare E329G allele of ACE2. In addition, this viral evolution could impact viral replication as well as the ability of the adaptive humoral response to control infection with RBD-specific neutralizing antibodies. In a shifting landscape, this ACE2-driven genetic drift of SARS-CoV-2 which we have named the ‘boomerang effect’, could complicate the challenge of preventing COVID with a SARS-CoV-2 spike-derived vaccine.

Possible contribution of rare alleles of human ACE2 in the emergence of SARS-CoV-2 variants escaping the immune response

“…Notably, the N 501 Y variant of concern (B1.1.7), emerged in the UK ( 24 ). Very recently, we reported structural evidence that the E 329 G substitution in ACE2 is much more favorable to interaction with the mutated spike protein N 501 Y than it is with E 329 , a physical contact (hydrogen bond) being established between N 501 Y and Q 325 for ACE2 with E 329 G, whereas this contact does not appear for ACE2 with E 329 ( 25 ).…”

Predicting Antibody and ACE2 Affinity for SARS-CoV-2 BA.2.86 and JN.1 withIn SilicoProtein Modeling and Docking

“…A mutation in the vital RBD region can affect the efficiency of this crucial viral-cell binding event (12). With the emergence of novel SARS-CoV-2 variants featuring mutations within the RBD domain, we have observed an increased affinity for binding to the ACE2 receptor in XBB.1.5 (12). This enhanced affinity of RBD and ACE2 has contributed to the rapid person-toperson transmissibility of viruses such as Omicron B.1.1.529 and XBB.1.5, which became predominant within the population (13).…”

“…Since antibodies primarily target the viral S protein’s RBD (9), it is considered a region of particular interest in the viral genome. More-over, mutations in this vital RBD region can affect the efficiency of crucial viral-cell binding events (10), impacting the virus’ ability to bind to the human angiotensin converting enzyme 2 (ACE2) receptor. For instance, the emergence of novel SARS-CoV-2 variants, featuring RBD mutations, has been associated with an increased affinity for binding to the ACE2 receptor in XBB.1.5 (10).…”

“…More-over, mutations in this vital RBD region can affect the efficiency of crucial viral-cell binding events (10), impacting the virus’ ability to bind to the human angiotensin converting enzyme 2 (ACE2) receptor. For instance, the emergence of novel SARS-CoV-2 variants, featuring RBD mutations, has been associated with an increased affinity for binding to the ACE2 receptor in XBB.1.5 (10). This heightened RBD and ACE2 affinity has been linked to the accelerated person-to-person transmissibility observed in viruses like Omicron B.1.1.529 and XBB.1.5, leading to their predominance within the population (11).…”

“…The ACE2 receptor serves as the primary point of interaction between human cells and SARS-CoV-2. A mutation in the vital RBD region can affect the efficiency of this crucial viral-cell binding event (12). With the emergence of novel SARS-CoV-2 variants featuring mutations within the RBD domain, we have observed an increased affinity for binding to the ACE2 receptor in XBB.1.5 (12).…”