A Sweep of Earth's Virome Reveals Host-Guided Viral Protein Structural Mimicry and Points to Determinants of Human Disease

Viruses deploy genetically encoded strategies to coopt host machinery and support viral replicative cycles. Here, we use protein structure similarity to scan for molecular mimicry, manifested by structural similarity between viral and endogenous host proteins, across thousands of cataloged viruses and hosts spanning broad ecological niches and taxonomic range, including bacteria, plants and fungi, invertebrates, and vertebrates. This survey identified over 6,000,000 instances of structural mimicry; more than 70% of viral mimics cannot be discerned through protein sequence alone. We demonstrate that the manner and degree to which viruses exploit molecular mimicry varies by genome size and nucleic acid type and identify 158 human proteins that are mimicked by coronaviruses, providing clues about cellular processes driving pathogenesis. Our observations point to molecular mimicry as a pervasive strategy employed by viruses and indicate that the protein structure space used by a given virus is dictated by the host proteome. A record of this paper's transparent peer review process is included in the Supplemental Information. Virally encoded factors resembling host factors hijack host molecular machines in a phenomenon called molecular mimicry. Lasso et al. use 3D protein structural information to identify over 6,000,000 instances of structural mimicry, >70% of which cannot be discerned through protein sequence alone. Their work provides the first systematic analysis of molecular mimicry across the earth's virome.