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

Gorka Lasso¹, Michael Grodus², Estefania Valencia³, Veronica DeJesus³, Eliza Liang², Isabel Delwel³, Rob H Bortz 3rd³, Dmitry Lupyan⁴, Hanna Y Ehrlich⁵, Adrian A Castellanos⁶, Andrea Gazzo⁷, Heather L Wells⁸, Supaporn Wacharapluesadee⁹, Alexandre Tremeau-Bravard⁵, Janine F R Seetahal¹⁰, Tom Hughes¹¹, Jimmy Lee¹¹, Mei-Ho Lee¹¹, Anna R Sjodin¹², Marike Geldenhuys¹³, Marinda Mortlock¹³, Isamara Navarrete-Macias⁸, Kirsten Gilardi⁵, Michael R Willig¹⁴, Alessandra F D Nava¹⁵, Elisabeth H Loh¹⁶, Makda Asrat⁸, Tierra Smiley-Evans⁵, Walter S Magesa¹⁷, Sijali Zikankuba¹⁷, David Wolking⁵, Gerardo Suzán¹⁸, Rafael Ojeda-Flores¹⁸, Christine V F Carrington¹⁹, Ariful Islam²⁰, Jonathan H Epstein²¹, Wanda Markotter¹³, Christine K Johnson⁵, Tracey Goldstein²², Barbara A Han⁶, Jonna A K Mazet⁵, Rohit K Jangra²³, Kartik Chandran²⁴, Simon J Anthony²⁵

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.

PMID: 39818205
PMCID: PMC11825280 (available on 2026-02-12)
DOI: 10.1016/j.chom.2024.12.016

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

Gorka Lasso et al. Cell Host Microbe. 2025.

. 2025 Feb 12;33(2):294-313.e11.

doi: 10.1016/j.chom.2024.12.016. Epub 2025 Jan 15.

Authors

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.

PMID: 39818205
PMCID: PMC11825280 (available on 2026-02-12)
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.

Keywords: NPC1; bat; binding avidity; filovirus; glycoprotein; host; machine learning; protein-protein interaction; susceptibility; virus.

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Conflict of interest statement

Declaration of interests D.L. is employed by Schrodinger Inc. and holds company stocks. K.C. holds shares in Integrum Scientific, LLC, and Eitr Biologics Inc.

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

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

Authors

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Abstract

Conflict of interest statement

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