COVID-19 Research: Italian And French Study Shows That Genetics Of Both Human Host And Virus Strains Influences Disease Severity

COVID-19 Research: Scientist from the University of Salento-Italy and the  University of Paris-France in a new study have found that the infectivity and pathogenicity of SARS-CoV-2 strongly depend on the genetic background of both the SARS-CoV-2 virus strain and that of the human host.


 
Variants of SARS-CoV-2 have been identified rapidly after the beginning of the COVID-19 pandemic. One of them, involving the spike protein and called D614G, represents a substantial percentage of currently isolated strains. While research on this variant was ongoing worldwide, on December 20th 2020 the European Centre for Disease Prevention and Control reported a Threat Assessment Brief describing the emergence of a new variant of SARS-CoV-2, named B.1.1.7, harboring multiple mutations mostly affecting the Spike protein. This viral variant has been recently associated with a rapid increase in COVID-19 cases in South East England, with alarming implications for future virus transmission rates. Specifically, of the nine amino acid replacements that characterize the Spike in the emerging variant, four are found in the region between the Fusion Peptide and the RBD domain (namely the already known D614G, together with A570D, P681H, T716I), and one, N501Y, is found in the Spike Receptor Binding Domain-Receptor Binding Motif (RBD-RBM).
 
The study team by utilizing in silico biology provides evidence that these amino acid replacements have dramatic effects on the interactions between SARS-CoV-2 Spike and the host ACE2 receptor or TMPRSS2, the protease that induces the fusogenic activity of Spike.
 
Importantly, the team demonstrates that these effects are strongly dependent on ACE2 and TMPRSS2 polymorphism, suggesting that dynamics of pandemics are strongly influenced not only by virus variation but also by host genetic background.
 
The study findings are published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.01.12.426365v1
 
Ever since the emergence of SARS-CoV-2 in December 2019, the virus has already acquired more than 13,000 mutations, and the majority of these mutations have occurred in the viral spike protein, indicating that the novel coronavirus is rapidly evolving in nature to increase fitness, to survive and to sustain inside host cells.
 
To date two major mutations have been noticed in SARS-CoV-2, both causing a significant increase in viral infectivity.
 
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.
 
However 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.     
 
Research regarding the virus-host interaction has 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-medi ated cleavage of ACE2 is known to increase the magnitude of viral entry.
 
Though 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.
 
This new research 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.
 
Tit has been found that 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.
 
The study team observed that N501Y mutation significantly increases the affinity of spike protein for ACE2 compared to that of the wildtype spike protein without this mutation.
 
Also the team has 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.
 
Pertaining to the D614G mutation, the study team have hypothesized that the effects are probably mediated via interaction with TMPRSS2.
 
Furthermore the study team has observed that the mutation alters the secondary structure of the spike protein and increases the flexibility of the region.
 
Follow up 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 proteins 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 new observations again signify the involvement of host genetic makeup in determining the magnitude of viral infection.
 
It was also found that 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.
 
It should also be noted that 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.
 
The study findings overall 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 human host.
 
In summary the study findings indicate that besides viral genetic variations, the genetic background of human host is equally important in determining the infectivity and pathogenicity of SARS-CoV-2.  
 
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