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The burning question is how novel viruses acquire the ability to recognize, bind to and enter human cells for the first time – whether this is dependent only on viral proteins recognizing host cell proteins, or adaptations in other viral processes that allow replication in a human host.
The current COVID-19 pandemic demonstrates the vast unknown of virology, which continues to challenge the ability of humanity to remain healthy when faced with pathogens. While most known microbes have restricted affinity for specific species, continuing to adapt with the host species, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has crossed over from an unknown animal reservoir, like the preceding SARS and MERS coronaviruses, to infect human cells. Such viruses are typically more readily infective and cause more severe disease, as they have not yet adapted fully to the target host.
Novel Coronavirus SARS-CoV-2 Colorized scanning electron micrograph of an apoptotic cell (green) heavily infected with SARS-COV-2 virus particles (purple), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
Acquiring Potential for Human Infection
This issue is discussed by researchers at the University of Calgary in a new study published on the preprint server bioRxiv* in June 2020. The spike protein is the most well known of the SARS-CoV-2 proteins, and its binding to ACE2 receptors on the host cell is responsible for viral entry into the target cell. The human ACE2 (hACE2) has some rare variants which make the host more vulnerable to infection. Similarly, the spike protein of this virus has a greater affinity for the receptor than the previous SARS virus, which is another possible explanation for the increased infective potential of the current virus.
The Study: Origin of ACE2 Binding Affinity
The current study examines the origin of this spike protein variant with its affinity for hACE2, using molecular dynamics (MD) simulations along with sequence reconstruction to identify the adaptation pathway of the virus. The result is a preliminary phylogenetic analysis that agrees with earlier studies – the virus is 96% similar to the bat coronavirus (RaTG13) genome and 90% similar to the Pangolin-CoV genome.
The next step was to carry out a more detailed analysis of 479 sequences collected from December 30, 2019, to March 20, 2020, where they found 16 variants. Of these, 11 were missense mutations occurring in 5% or more of cases, and each had its own phylogenetic route.
The researchers then tried to recreate the ancestral sequence for the spike-RBD region, so that they could identify the important mutations that specifically drive its recent adaptation to the human host. They reconstructed the hypothetical common ancestor spike-RBD sequence for all human SARS-CoV-2 cases, called N1, and for the common ancestor with the closest animal virus, called N2.
N1 is identical to the sequence in the SARS-CoV-2 reference sequence, but the N0 sequence is unique, which shows that this virus has originated uniquely. The two differ at 4 positions. The ancestral protein gave rise to various descendants, one of which is the RaTG13. Since this was around in 2013, the researchers conclude that the ancestral strain existed as early as that year, at least. In other words, the N0-N1 branch has been evolving for at least 7 years.
Ancestral Sequence Had Higher Binding Affinity
What are the functional differences between N0 and current spike-RBD sequences? The researchers used MD simulations of the spike-RBD-hACE2 complex, beginning with the X-ray crystal structures. The model showed that the free binding energy for this complex decreased as N0 changed to N1. Thus, this actually reduced the binding affinity both in the simulations and in vitro.
However, two of the changes were associated with more significant decreases than the other. This shows that the N0 strain had, unexpectedly, greater binding affinity than the N1 strain. This is the first study to show that the common ancestor of both SARS-CoV-2 and the RaTG13…
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Michael Novakhov – SharedNewsLinks℠