Severe COVID-19 linked to genetic make-up of both host and virus, say researchers

A recent study conducted by a team of international scientists has revealed that the infectivity and pathogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strongly depend on the genetic background of both the virus and the host. The study is currently available on the bioRxiv* preprint server.

Background

Since its emergence in December 2019, SARS-CoV-2, the causative pathogen of coronavirus disease 2019 (COVID-19) pandemic, has already acquired more than 13,000 mutations, and the majority of these mutations have occurred in the viral spike protein, indicating that the virus is rapidly evolving in nature to increase fitness, to survive and to sustain inside host cells. So far, two major mutations have been noticed in SARS-CoV-2, both causing a significant increase in viral infectivity. In January 2020, the genetic variant of SARS-CoV-2 with spike D614G mutation has been shown to rapidly displace the original form and become the predominant one. Afterward, in December 2020, another highly infectious variant with spike N501Y mutation has emerged in England, signifies the possibility of further expansion of the COVID-19 pandemic.     

Studies regarding the virus-host interaction have shown that the spike protein on the surface of SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptor of human cells to initiate the process of viral entry. The proteolytic cleavage and activation of the spike protein by proteases of the respiratory tract, such as TMPRSS2, is another important step necessary for the viral entry. Moreover, TMPRSS2-mediated cleavage of ACE2 is known to increase the magnitude of viral entry.

Although the majority of COVID-19 patients remain asymptomatic or mildly symptomatic, certain factors including age, sex, ethnicity, and presence of comorbidity have been shown to increase the risk of developing severe COVID-19. Given the individual variation in disease severity, it is possible that certain individuals are genetically predisposed to develop serious COVID-19-related complications.

Current study design

The study was designed to investigate the host-pathogen interaction by considering both human and viral genetic variations. Specifically, the scientists have investigated the kinetics of interaction between the SARS-CoV-2 spike protein and host ACE2 or TMPRSS2 using in silico modelling.

Important observations

The newly emerged “UK variant” of SARS-CoV-2 contains 7 mutations mostly found in the viral spike protein. Of the mutations, N501Y found in the receptor binding domain (RBD)-Receptor binding motif (RBM) of the spike protein is known to increase the viral infectivity.

In the current study, the scientists observed that N501Y mutation significantly increases the affinity of spike protein for ACE2 compared to that of the wildtype spike protein without this mutation. Furthermore, they have observed that the K26R variant of ACE2, which has higher affinity for wildtype spike, has significantly less affinity for the N501Y mutant, indicating that the magnitude of effects of spike mutation depends on the genetic makeup of ACE2.

Regarding D614G mutation, the scientists have hypothesized that the effects are probably mediated via interaction with TMPRSS2. Moreover, they have observed that the mutation alters the secondary structure of the spike protein and increases the flexibility of the region. Further computational analyses revealed that D614G mutation significantly increases the affinity of spike protein for wildtype TMPRSS2. Regarding the interaction between D614- or G614-harboring spike protein and the wildtype 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 signify the involvement of host genetic makeup in determining the magnitude of viral infection.

In the newer variant of SARS-CoV-2 with N501Y mutation, D614G mutation is present with other single amino acid substitutions. These amino acid substitutions have been found to increase the affinity of spike protein for wildtype TMPRSS2. Moreover, a varied range of affinities of specific substitutions have been observed for polymorphic variants of TMPRSS2. However, the combination of these substitutions in N501Y variant of SARS-CoV-2 has been shown to increase the spike affinity for TMPRSS2 variants, but not for the wildtype TMPRSS2. Taken together, these observations suggest that the increased infectivity of newer SARS-CoV-2 variant is primarily due to N501Y mutation in the spike RBD-RBM and that the effects of other mutations mostly depend on the genetic makeup of the host.

Overall, the study findings indicate that besides viral genetic variations, the genetic background of host is equally important in determining the infectivity and pathogenicity of SARS-CoV-2.  

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.