Natural genus-exclusive four-position VP24 configuration in Bundibugyo virus links host interferon tone to a testable cell-type ordering

Abstract Bundibugyo virus (BDBV) causes outbreaks with lower case-fatality than Ebola virus (EBOV); its VP24 carries the only BDBV-specific functional difference mapped to date. That difference was defined in an engineered virus. Here, we integrate a sequence census, a human cell-type expression atlas, and a reanalysis of public infection data to connect the natural BDBV VP24 configuration to host interferon (IFN) tone and derive a testable cell-type ordering of post-entry IFN-mediated restriction. All 31 full-length BDBV VP24 records and all 36 complete 2026 outbreak genomes carried S83/Q135/H140/A141; none of the other five orthoebolavirus species assessed carried the complete set. Two consensus-only single-position departures occurred among 860 callable copies in the surveillance data. Δ, a baseline IFN-tone score, tracks the IFN-stimulated level attained by a cell and predicts the strength of IFN-mediated suppression of viral RNA accumulation in cells infected with BDBV carrying the VP24 defect: high Δ denotes stronger suppression, low Δ weaker. Across 154 human cell types, Δ was higher in surface epithelia and circulating myeloid cells (enterocytes 1.28; monocytes 1.00) than in retinal and testicular cells (retinal pigment epithelium − 1.02; Sertoli cells − 0.68). A competing importin-α model predicted exemption in the 47 cell types with high Δ but low importin-α, including enteric epithelium and hepatocytes. In the HIV-1 restriction panel, Δ discriminated restricted from permissive cells (area under the curve (AUC) 0.87), whereas importin-α was at chance (AUC 0.47–0.50); functional data therefore descriptively support Δ.