RAISE: A computational tool for evaluating sarbecovirus spillover potential.

Area of Science:

• Virology
• Computational Biology
• Epidemiology

Background:

• Animal sarbecoviruses, related to SARS-CoV and SARS-CoV-2, present a significant zoonotic risk due to their potential to bind the human ACE2 receptor.
• Evaluating the zoonotic potential of these viruses is challenging, necessitating advanced predictive tools.

Purpose of the Study:

• To develop and validate a computational framework, RAISE (Receptor binding domain-hACE2 Interaction Scoring Evaluation), for assessing the zoonotic threat of animal sarbecoviruses.
• To categorize sarbecoviruses based on their potential to bind the human ACE2 receptor and identify viruses with intermediate binding capabilities.

Main Methods:

• RAISE integrates structural predictions with interaction scoring to evaluate the binding affinity of sarbecovirus receptor-binding domains to the human ACE2 receptor.
• The framework categorizes viruses into high potential (hACE2-binding), negligible potential (hACE2-nonbinding), and a "poised" intermediate state.
• Mutation screening was performed on "hACE2-poised" sarbecoviruses (PDF-2370, Khosta-1) to identify mutations enhancing hACE2 utilization.

Main Results:

• RAISE successfully categorized sarbecoviruses based on their hACE2 interaction potential.
• Mutation screening identified specific mutations (e.g., T498Y/W) that conferred or enhanced human ACE2 utilization in previously non-binding or weakly binding sarbecoviruses.
• The model demonstrated generalizability by accurately assessing merbecoviruses, indicating broad applicability across coronavirus lineages.

Conclusions:

• The RAISE framework provides a reliable method for preemptively assessing zoonotic threats posed by animal sarbecoviruses.
• It enables the prioritization of viruses for further investigation and guides pandemic preparedness efforts by identifying viruses with the potential to evolve hACE2 binding.
• RAISE is a valuable tool for virologists and public health officials in monitoring and mitigating future zoonotic spillover events.