OmniVira

Evolution at Spike protein position 519 in SARS-CoV-2 facilitated adaptation to humans.

C Cereghino1,2 K Michalak3 S DiGiuseppe3 J Guerra3 D Yu3 A Faraji3 A K Sharp4 A M Brown4,5 L Kang3,6,7 J Weger-Lucarelli8,9 P Michalak10,11,12
Affiliations 12 institutions
  1. Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA, USA.
  2. Center for Emerging, Zoonotic and Arthropod-borne Pathogens, Virginia Tech, Blacksburg, VA, USA.
  3. Department of Biomedical Research, Edward Via College of Osteopathic Medicine, Monroe, LA, USA.
  4. Department of Biochemistry, Virginia Tech, Blacksburg, VA, USA.
  5. Research and Informatics, University Libraries, Virginia Tech, Blacksburg, VA, USA.
  6. College of Pharmacy, University of Louisiana Monroe, Monroe, LA, USA.
  7. Center for One Health Research, VA-MD College of Veterinary Medicine, Blacksburg, VA, USA.
  8. Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA, USA. [email protected].
  9. Center for Emerging, Zoonotic and Arthropod-borne Pathogens, Virginia Tech, Blacksburg, VA, USA. [email protected].
  10. Department of Biomedical Research, Edward Via College of Osteopathic Medicine, Monroe, LA, USA. [email protected].
  11. Center for One Health Research, VA-MD College of Veterinary Medicine, Blacksburg, VA, USA. [email protected].
  12. Institute of Evolution, University of Haifa, Haifa, Israel. [email protected].
PMID40295673 DOI10.1038/s44298-024-00036-2 Year2024 Journal Npj viruses Npj Viruses Languageeng Statusepublish

Abstract

As the COVID-19 pandemic enters its fourth year, the pursuit of identifying a progenitor virus to SARS-CoV-2 and understanding the mechanism of its emergence persists, albeit against the backdrop of intensified efforts to monitor the ongoing evolution of the virus and the influx of new mutations. Surprisingly, few residues hypothesized to be essential for SARS-CoV-2 emergence and adaptation to humans have been validated experimentally, despite the importance that these mutations could contribute to the development of effective antivirals. To remedy this, we searched for genomic regions in the SARS-CoV-2 genome that show evidence of past selection around residues unique to SARS-CoV-2 compared with closely related coronaviruses. In doing so, we identified a residue at position 519 in Spike within the receptor binding domain that holds a static histidine in human-derived SARS-CoV-2 sequences but an asparagine in SARS-related coronaviruses from bats and pangolins. In experimental validation, the SARS-CoV-2 Spike protein mutant carrying the putatively ancestral H519N substitution showed reduced replication in human lung cells, suggesting that the histidine residue contributes to viral fitness in the human host. Structural analyses revealed a potential role of Spike residue 519 in mediating conformational transitions necessary for Spike prior to binding with ACE2. Pseudotyped viruses bearing the putatively ancestral N519 also demonstrated significantly reduced infectivity in cells expressing the human ACE2 receptor compared to H519. ELISA data corroborated that H519 enhances Spike binding affinity to the human ACE2 receptor compared to the putatively ancestral N519. Collectively, these findings suggest that the evolutionary transition at position 519 of the Spike protein played a critical role in SARS-CoV-2 emergence and adaptation to the human host. Additionally, this residue presents as a potential drug target for designing small molecule inhibitors tailored to this site.

Supporting text Virus Host Location

Evidence records

2 total
Functional Mechanism
2 records · 2 evidence types
Evidence type Receptor Usage
1 records
OVE9108 Receptor Usage
Key finding

SARS-CoV-2 Spike residue H519 enhances viral binding and infectivity through the human ACE2 receptor compared with the ancestral N519 variant.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
human Homo sapiens Experimental system
Location
Not specified
Supporting text

Pseudotyped viruses bearing the putatively ancestral N519 demonstrated significantly reduced infectivity in cells expressing the human ACE2 receptor compared to H519. ELISA data corroborated that H519 enhances Spike binding affinity to the human ACE2 receptor compared to the putatively ancestral N519.

Method
pseudovirus infectivity assay | ELISA receptor-binding assay
Receptors
human ACE2 receptor
Evidence type Molecular Adaptation
1 records
OVE9107 Molecular Adaptation
Key finding

The histidine residue at Spike position 519 enhances SARS-CoV-2 replication fitness and receptor binding to human ACE2 compared with the ancestral N519 variant.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
Not specified
Location
Not specified
Supporting text

In experimental validation, the SARS-CoV-2 Spike protein mutant carrying the putatively ancestral H519N substitution showed reduced replication in human lung cells, and pseudotyped viruses bearing N519 exhibited significantly reduced infectivity and ACE2 binding, indicating the histidine residue contributes to viral adaptation to humans.

Genes or proteins
Spike protein
Receptors
ACE2
Host factors
human lung cells
Mutations
H519N
Mechanism types
receptor binding | host-range expansion | replication adaptation | transmission fitness