COVID-19 is heavily linked to the genetic production of both host and virus, say researchers

A recent study by a team of international scientists has revealed that the infectivity and pathogenicity of coronary respiratory syndrome 2 (SARS-CoV-2) is largely dependent on the genetic background of both viruses. and the guest. The study is currently available on the bioRxiv* preprint server.

Background

Since its outbreak in December 2019, SARS-CoV-2, the causative pathogen of the 2019 coronavirus outbreak (COVID-19), has received more than 13,000 mutations, most of which have occurred in the viral spike protein, indicating that the virus grows rapidly in nature to increase fitness, survival and maintenance within host cells. To date, two major mutations have been observed in SARS-CoV-2, both of which cause a significant increase in viral infections. In January 2020, the genetic variation of SARS-CoV-2 by spike D614G mutation has been shown to rapidly degrade the original form and become a major one. Subsequently, in December 2020, another infectious variant with N501Y spike mutation appeared in England, indicating potential for further spread of COVID-19 pandemic.

Studies regarding the interaction with virus host have shown that the spike protein on the surface of SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) receptor of human cells to initiate viral induction. Proteolytic use and activation of the spike protein by proteins of the respiratory tract, such as TMPRSS2, is another important step necessary for their viral entry. In addition, TMPRSS2-mediated use of ACE2 is known to increase viral entry size.

Although the majority of COVID-19 patients are still asymptomatic or slightly symptomatic, some factors including age, gender, ethnicity, and the presence of comorbidity have been shown to increase the risk of comorbidity. COVID-19 development hard. Given the individual variation in disease depth, it is possible that some individuals are genetically predisposed to developing severe COVID-19-related complications.

Routine study design

The study was designed to study host-pathogen interactions by considering both human and viral genetic changes. In particular, the scientists have studied the kinetics of interactions between SARS-CoV-2 spike proteins and ACE2 or TMPRSS2 hosts using in silico modeling.

Important comments

The new “RA variant” of SARS-CoV-2 contains 7 mutations found mainly in the viral spike protein. Of the mutations, N501Y found in the receptor binding (RBD) -Receptor binding domain (RBM) of the spike protein is known to increase viral susceptibility.

In the present study, the scientists noted that mutation of N501Y significantly increases spike protein affinity for ACE2 compared with wildtype spike protein without this simulation. In addition, they have found that the K26R variant of ACE2, which has a higher affinity for wildtype spike, significantly less affinity for mutant N501Y, indicating that the magnitude of the spike mutation effects. dependent on the genetic make-up of ACE2.

Regarding the D614G mutation, the scientists have hypothesized that the effects may be mediated through interaction with TMPRSS2. In addition, they have found that the mutation alters the secondary structure of the spike protein and increases the flexibility of the area. Further computational studies have shown that mutation of D614G significantly increases the affinity of spike proteins for TMPRSS2 wildtype. Regarding the interaction between D614- or G614-harboring spike protein and the wild or polymorphic forms of TMPRSS2, significant changes in the interaction pattern were observed between the polymorphic forms of TMPRSS2 and the wildtype or mutated spike protein. These observations again point to the involvement of host genetic make-up in determining the extent of viral infection.

In the latest version of SARS-CoV-2 with N501Y mutation, D614G mutation is present with other single amino acid by-products. These amino acid compounds have been found to increase spike protein affinity for TMPRSS2 wildtype. In addition, a diverse range of specific substituents were observed for polymorphic modifications of TMPRSS2. However, the combination of these by-products in the N501Y version of SARS-CoV-2 has been shown to increase the spike affinity for TMPRSS2 modifications, but not for the TMPRSS2 wildtype. Taken together, these observations indicate that the increased susceptibility of the newer SARS-CoV-2 differential is largely due to N501Y mutation in the RBD-RBM spike and the effect of other mutations largely depends on the genetic make-up of the host.

Overall, the findings of the study show that, in addition to viral genetic changes, a host’s genetic background is equally important in determining the susceptibility and pathogenicity of SARS-CoV-2.

* Important message

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be seen as final, guiding health-related clinical / behavioral practice, or treated as fixed information.