Wednesday, April 2, 2025
4/2/2025
Functional Viromics of Betacoronavirus Entry - PROJECT SUMMARY/ABSTRACT After the severe acute respiratory coronavirus (SARS-CoV) emerged in China in 2002, the virus was traced back to animal markets and several genetically related viruses were identified in bats. This early work into coronavirus zoonosis and the concomitant rise of next generation sequencing technologies in the early 2000’s helped initiate global research efforts to identify viruses circulating in wildlife. The genomes for tens of thousands of novel animal viruses have now been sequenced and deposited in online repositories. Coronaviruses are abundant in mammals and birds and comprise approximately 25% of all bat viruses discovered to date. The highly pathogenic human coronaviruses, SARS-CoV, and middle east respiratory syndrome coronavirus (MERS-CoV) are only representative members of their respective sarbeco- and merbeco- subgenera, which encompass hundreds of related viruses found in bats and other wildlife, worldwide. Unfortunately, because there are few tools available for researchers to study uncharacterized animal viruses, virus discovery studies rarely isolate viruses under laboratory conditions or perform experiments beyond genetic sequencing, leaving some of the most essential questions about these viruses – including if they have the potential to infect humans – unanswered. An improved understanding for what species these viruses can infect and how they invade the cells of their hosts is essential for future pandemic preparedness. The most significant species barrier for the coronaviruses that have transmitted to humans is at the level of cell entry and studies have shown that overcoming this barrier allows for coronaviruses to replicate in cells from diverse species. To invade cells, the “spike” glycoprotein on the surface of viral particles binds to host cell receptor molecules. The receptor binding domain (RBD) is a small region on the distal tip of the spike protein, capable of folding independently of spike and contains all amino acids that contact the host receptor. We previously developed “SarbecoType” – a BSL2-compatible, viral pseudotype-based platform to functionally screen the cell entry properties of the RBD from any sarbecovirus. This approach is highly cost- efficient and scalable, requiring synthesis of only a small portion of the spike gene, and has allowed us to characterize the cell entry phenotypes of approximately 95% of all published sarbecoviruses. This dataset identified multiple clades of sarbecovirus RBDs that vary in their zoonotic properties for humans, and has formed a foundational basis for ongoing universal sarbecovirus design. Therefore, we hypothesize uncharacterized coronaviruses pose a threat to humans. Here we propose to functionally screen the much larger and diverse group of merbecoviruses with similar methods (I.e., “MerbecoType”) and use this entry data to predict the entry capabilities of novel sarbeco- and merbeco-virus sequences.
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