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Coronavirus protein interaction mapping in bat and human cells identifies molecular and genetic switches for immune evasion and replication

ABSTRACT: Coronaviruses, including SARS-CoV-2, can cause severe disease in humans, whereas reservoir hosts like Rhinolophus bats appear to remain asymptomatic for reasons that are not well-recognized. To understand how host-specific protein-protein interactions (PPIs) shape infection outcomes, we generated comparative PPI maps for SARS-CoV-2 and its close bat-originating relative, RaTG13, using affinity purification-mass spectrometry (AP-MS) in human and Rhinolophus ferrumequinum (RFe) bat cells. Our analysis revealed both conserved as well as virus- and host-specific PPIs, pointing to key interactions that regulate infection dynamics across species. SARS-CoV-2 required a non-synonymous mutation at the RNA-binding domain of the viral N protein to replicate in the RFe bat cells. Moreover, comparative analysis of the viral protein Orf9b revealed differential interactions with the human and bat mitochondrial proteins Tom70 and MTARC2, and modulating virus replication. A single residue in SARS-CoV-2 Orf9b serves as a molecular switch between these interactions, with a T72I substitution weakening Tom70 binding and reducing its ability to counteract innate immune activation. These findings demonstrate how a single-residue substitution can reshape virus-host interactions and contribute to immune evasion and host adaptation.

ORGANISM(S): Rhinolophus ferrumequinum Homo sapiens

PROVIDER: GSE302357 | GEO | 2026/05/13

REPOSITORIES: GEO

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