Abstract
Delivery of the viral genome into host cells is a critical step in successful viral infection. Alphaviruses achieve this step by fusing the viral and endosomal membranes under acidic conditions. This process requires significant structural changes in the alphavirus glycoprotein organization. Structural characterization of acidic pH-induced conformational changes in alphavirus virions has remained elusive due to the rapid, transient nature of these states, conformational heterogeneity, and particle aggregation. Antibody binding studies conducted at elevated temperatures or under acidic pH conditions have further revealed the presence of transitional epitopes that are inaccessible on alphaviruses at room temperature or neutral pH. In this report, we present structural snapshots of the conformational changes in the glycoproteins and nucleocapsid core of a prototypical alphavirus, Eastern equine encephalitis virus, caused by exposure to 40 °C or pH 5.6. These findings provide insights into the structural transitions that occur prior to viral fusion with the endosomal membrane. This approach has also allowed us to define the molecular basis for recognition of a pan-alphavirus epitope by a patient-derived human antibody.
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Acknowledgements
We thank R. Nargi, R. Kidwell, C. Gainza, J. Rodriguez, L. Handal, S. Monroig, J. Martinez, E. Villalobos, S. Rutherford, J. Reidy, R. Irving, R. Troseth, and L. Myers for technical support. We thank G. DeBellis, K. Moton, T. Martin, T. Hendy, H. Darling, A. Bunnell, B. Haseltine, N. Lee, N. Suazo, and J. Mitchell for administrative assistance. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817). We thank the Purdue cryo-EM facility and the Vanderbilt Center for Structural Biology for equipment access and support.
Funding
L.E.W. was supported by the NIH grants T32 HL069765 and F31 AI145189. This project received support from the NIAID grants R01 AI095366-10 (R.J.K.), U19 AI142790 (R.J.K. and J.E.C.), R01 AI172156 (J.E.C.), U19AI181960 (J.E.C, R.J.K, and L.E.W).
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L.E.W. has served as a consultant for BigHat Biosciences. J.E.C. is a former member of the Scientific Advisory Boards of Gigagen (Grifols) and BTG International, has consulted for Moderna and Merck, is founder of IDBiologics and receives royalties from UpToDate. The laboratory of J.E.C. received unrelated sponsored research agreements from IDBiologics during the conduct of the study. The remaining authors declare no competing interests.
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Bandyopadhyay, A., Williamson, L.E., Buchman, C.D. et al. Asymmetric structural transitions in the icosahedral organization of Eastern equine encephalitis virus. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73197-8
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DOI: https://doi.org/10.1038/s41467-026-73197-8
