Structural Insights into Human Bocaparvoviruses.
Bocaparvoviruses are emerging pathogens of theParvoviridaefamily. Human bocavirus 1 (HBoV1) causes severe respiratory infections and HBoV2 to HBoV4 cause gastrointestinal infections in young children. Recent reports of life-threatening cases, lack of direct treatment or vaccination, and a limited understanding of their disease mechanisms highlight the need to study these pathogens on a molecular and structural level for the development of therapeutics. Toward this end, the capsid structures of HBoV1, HBoV3, and HBoV4 were determined to a resolution of 2.8 to 3.0 Å by cryo-electron microscopy and three-dimensional image reconstruction. The bocaparvovirus capsids, which display different tissue tropisms, have features in common with other parvoviruses, such as depressions at the icosahedral 2-fold symmetry axis and surrounding the 5-fold symmetry axis, protrusions surrounding the 3-fold symmetry axis, and a channel at the 5-fold symmetry axis. However, unlike other parvoviruses, densities extending the 5-fold channel into the capsid interior are conserved among the bocaparvoviruses and are suggestive of a genus-specific function. Additionally, their major viral protein 3 contains loops with variable regions at their apexes conferring capsid surface topologies different from those of other parvoviruses. Structural comparisons at the strain (HBoV) and genus (bovine parvovirus and HBoV) levels identified differences in surface loops that are functionally important in host/tissue tropism, pathogenicity, and antigenicity in other parvoviruses and likely play similar roles in these viruses. This study thus provides a structural framework to characterize determinants of host/tissue tropism, pathogenicity, and antigenicity for the development of antiviral strategies to control human bocavirus infections.IMPORTANCEHuman bocaviruses are one of only a few members of theParvoviridaefamily pathogenic to humans, especially young children and immunocompromised adults. There are currently no treatments or vaccines for these viruses or the related enteric bocaviruses. This study obtained the first high-resolution structures of three human bocaparvoviruses determined by cryo-reconstruction. HBoV1 infects the respiratory tract, and HBoV3 and HBoV4 infect the gastrointestinal tract, tissues that are likely targeted by the capsid. Comparison of these viruses provides information on conserved bocaparvovirus-specific features and variable regions resulting in unique surface topologies that can serve as guides to characterize HBoV determinants of tissue tropism and antigenicity in future experiments. Based on the comparison to other existing parvovirus capsid structures, this study suggests capsid regions that likely control successful infection, including determinants of receptor attachment, host cell trafficking, and antigenic reactivity. Overall, these observations could impact efforts to design antiviral strategies and vaccines for HBoVs.
Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA.
Mario
M
Mietzsch
Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA.
Shweta
S
Kailasan
Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA.
Jamie
J
Garrison
Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA.
Maria
M
Ilyas
Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA.
Paul
P
Chipman
Department of Virology, University of Helsinki, Helsinki, Finland.
Kalle
K
Kantola
Department of Chemistry and Biochemistry and Division of Biological Sciences, University of California-San Diego, San Diego, California, USA.
Mandy E
ME
Janssen
Biological Science Imaging Resource, Department of Biological Sciences, The Florida State University, Tallahassee, Florida, USA.
John
J
Spear
Biological Science Imaging Resource, Department of Biological Sciences, The Florida State University, Tallahassee, Florida, USA.
Duncan
D
Sousa
Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA.
Robert
R
McKenna
Virus Reference Department, National Infection Service, Public Health England, London, United Kingdom.
Kevin
K
Brown
Department of Virology, University of Helsinki, Helsinki, Finland.
Maria
M
Söderlund-Venermo
Department of Chemistry and Biochemistry and Division of Biological Sciences, University of California-San Diego, San Diego, California, USA.
Timothy
T
Baker
Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA mckenna@ufl.edu.
Mavis
M
Agbandje-McKenna
D052660:Bocavirus / Q000737:chemistry; D002213:Capsid / Q000737:chemistry* / Q000648:ultrastructure*; D036022:Capsid Proteins / Q000032:analysis; D020285:Cryoelectron Microscopy; D056661:Human bocavirus / Q000737:chemistry* / Q000648:ultrastructure*; D006801:Humans; D021621:Imaging, Three-Dimensional; D014764:Viral Proteins; D056189:Viral Tropism
D036022:Capsid Proteins; D014764:Viral Proteins
HBoV; capsid; cryo-EM; gastrointestinal infection; human bocaviruses; parvovirus; respiratory infection