Decoding the blueprint of receptor binding by filoviruses through large-scale binding assays and machine learning

Lasso E, Grodus M, Valencia E, DeJesus V, Liang E, Delwel I, Bortz RH III, Lupyan D, Ehrlich HY, Castellanos AA, Gazzo A, Wells HL, Wacharapluesadee S, Tremeau-Bravard A, Seetahal JFR, Hughes T, Lee J, Lee M, Sjodin AR, Geldenhuys M, Mortlock M, Navarrete-Macias I, Gilardi K, Willig MR, Nava AFD, Loh EH, Asrat M, Smiley-Evans T, Magesa WS, Zikankuba S, Wolking D, Suzán G, Ojeda-Flores R, Carrington CVF, Islam A, Epstein JH, Markotter W, Johnson CK, Goldstein T, Han BA, Mazet JAK, Jangra RK, Chandran K. Decoding the blueprint of receptor binding by filoviruses through large-scale binding assays and machine learning. Cell Host Microbe. 2025. In press.

[doi: 10.1016/j.chom.2024.12.016] [Full text]

ABSTRACT

Evidence suggests that bats are important hosts of filoviruses, yet the specific species involved remain largely unidentified. Niemann-Pick C1 (NPC1) is an essential entry receptor, with amino acid variations influencing viral susceptibility and species-specific tropism. Herein, we conducted combinatorial binding studies with seven filovirus glycoproteins (GPs) and NPC1 orthologs from 81 bat species. We found that GP-NPC1 binding correlated poorly with phylogeny. By integrating binding assays with machine learning, we identified genetic factors influencing virus-receptor-binding and predicted GP-NPC1-binding avidity for additional filoviruses and bats. Moreover, combining receptor-binding avidities with bat geographic distribution and the locations of previous Ebola outbreaks allowed us to rank bats by their potential as Ebola virus hosts. This study represents a comprehensive investigation of filovirus-receptor binding in bats (1,484 GP-NPC1 pairs, 11 filoviruses, and 135 bats) and describes a multidisciplinary approach to predict susceptible species and guide filovirus host surveillance.