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

Lasso G 1 , Grodus M 2 , Valencia E 3 , DeJesus V 3 , Liang E 2 , Delwel I 3 Show all authors , Bortz RH 3 , Lupyan D 4 , Ehrlich HY 5 , Castellanos AA 6 , Gazzo A 7 , Wells HL 8 , Wacharapluesadee S 9 , Tremeau-Bravard A 5 , Seetahal JFR 10 , Hughes T 11 , Lee J 11 , Lee MH 11 , Sjodin AR 12 , Geldenhuys M 13 , Mortlock M 13 , Navarrete-Macias I 8 , Gilardi K 5 , Willig MR 14 , Nava AFD 15 , Loh EH 16 , Asrat M 8 , Smiley-Evans T 5 , Magesa WS 17 , Zikankuba S 17 , Wolking D 5 , Suzán G 18 , Ojeda-Flores R 18 , Carrington CVF 19 , Islam A 20 , Epstein JH 21 , Markotter W 13 , Johnson CK 5 , Goldstein T 22 , Han BA 6 , Mazet JAK 5 , Jangra RK 23 , Chandran K 24 , Anthony SJ 25

Affiliations 

  • 1 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA. Electronic address: gorka.lasso@gmail.com
  • 2 Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
  • 3 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
  • 4 Schrödinger Inc., Cambridge, MA 02142, USA
  • 5 One Health Institute, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
  • 6 Cary Institute of Ecosystem Studies, Millbrook, NY 12545, USA
  • 7 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
  • 8 Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
  • 9 Thai Red Cross Emerging Infectious Diseases Clinical Center, King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand
  • 10 Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66502, USA
  • 11 Conservation Medicine, 47000 Sungai Buloh, Selangor, Malaysia; EcoHealth Alliance, New York, NY 10018, USA
  • 12 Department of Ecology and Evolutionary Biology, University of Connecticut, Storrs, CT 06269, USA
  • 13 Centre for Viral Zoonoses, Department of Medical Virology, University of Pretoria, Pretoria 0001, South Africa
  • 14 Department of Ecology and Evolutionary Biology, University of Connecticut, Storrs, CT 06269, USA; Center for Environmental Sciences and Engineering, Institute of the Environment, University of Connecticut, Storrs, CT 06269, USA
  • 15 Fundação Oswaldo Cruz-Fiocruz, Instituto Leônidas & Maria Deane, Laboratório de Ecologia de Doenças Transmissíveis na Amazônia - EDTA, Manaus 69.057-070, AM, Brazil
  • 16 Division of Natural Sciences and Mathematics, Transylvania University, Lexington, KY 40508, USA
  • 17 College of Veterinary Medicine and Biomedical Sciences, Sokoine University of Agriculture, P.O. Box 3021, Morogoro, Tanzania
  • 18 Laboratorio de Ecología de Enfermedades y Una Salud, Departamento de Etología, Fauna Silvestre y Animales de Laboratorio, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Ciudad de México, 04510, Mexico
  • 19 Department of Preclinical Sciences, Faculty of Medical Sciences, The University of the West Indies, St. Augustine, Republic of Trinidad and Tobago
  • 20 Gulbali Research Institute, Charles Sturt University, Wagga Wagga, NSW 2678, Australia
  • 21 EcoHealth Alliance, New York, NY 10018, USA
  • 22 One Health Institute, Colorado State University, Fort Collins, CO 80523, USA
  • 23 Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Center of Excellence for Emerging Viral Threats, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA. Electronic address: rohit.jangra@lsuhs.edu
  • 24 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA. Electronic address: kartik.chandran@einsteinmed.edu
  • 25 Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. Electronic address: sjanthony@ucdavis.edu
Cell Host Microbe, 2025 Jan 15.
PMID: 39818205 DOI: 10.1016/j.chom.2024.12.016

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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