title: Intracerebral Inoculation of Mouse-Passaged Saffold Virus Type 3 Affects Cerebellar Development in Neonatal Mice.
abstract: Saffold virus (SAFV), a human cardiovirus, is occasionally detected in infants with neurological disorders, including meningitis and cerebellitis. We recently reported that SAFV type 3 isolates infect cerebellar glial cells, but not large neurons, in mice. However, the impact of this infection remained unclear. Here, we determined the neuropathogenesis of SAFV type 3 in the cerebella of neonatal ddY mice by using SAFV passaged in the cerebella of neonatal BALB/c mice. The virus titer in the cerebellum increased following the inoculation of each of five passaged strains. The fifth passaged strain harbored amino acid substitutions in the VP2 (H160R and Q239R) and VP3 (K62M) capsid proteins. Molecular modeling of the capsid proteins suggested that the VP2-H160R and VP3-K62M mutations alter the structural dynamics of the receptor binding surface via the formation of a novel hydrophobic interaction between the VP2 puff B and VP3 knob regions. Compared with the original strain, the passaged strain showed altered growth characteristics in human-derived astroglial cell lines and greater replication in the brains of neonatal mice. In addition, the passaged strain was more neurovirulent than the original strain, while both strains infected astroglial and neural progenitor cells in the mouse brain. Intracerebral inoculation of either the original or the passaged strain affected brain Purkinje cell dendrites, and a high titer of the passaged strain induced cerebellar hypoplasia in neonatal mice. Thus, infection by mouse-passaged SAFV affected cerebellar development in neonatal mice. This animal model contributes to the understanding of the neuropathogenicity of SAFV infections in infants.IMPORTANCESaffold virus (SAFV) is a candidate neuropathogenic agent in infants and children, but the neuropathogenicity of the virus has not been fully elucidated. Recently, we evaluated the pathogenicity of two clinical SAFV isolates in mice. Similar to other neurotropic picornaviruses, these isolates showed mild infectivity of glial and neural progenitor cells, but not of large neurons, in the cerebellum. However, the outcome of this viral infection in the cerebellum has not been clarified. Here, we examined the tropism of SAFV in the cerebellum. We obtained anin vivo-passaged strain from the cerebella of neonatal mice and examined its genome and its neurovirulence in the neonatal mouse brain. The passaged virus showed high infectivity and neurovirulence in the brain, especially the cerebellum, and affected cerebellar development. This unique neonatal mouse model will be helpful for elucidating the neuropathogenesis of SAFV infections occurring early in life.
authors: Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.|Department of Virology and Viral Infections, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, Japan.
authors: Osamu
authors: O
authors: Kotani
authors: Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Tadaki
authors: T
authors: Suzuki
authors: Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Masaru
authors: M
authors: Yokoyama
authors: Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Naoko
authors: N
authors: Iwata-Yoshikawa
authors: Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Noriko
authors: N
authors: Nakajima
authors: Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Hironori
authors: H
authors: Sato
authors: Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Hideki
authors: H
authors: Hasegawa
authors: Department of Virology and Viral Infections, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, Japan.
authors: Fumihiro
authors: F
authors: Taguchi
authors: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
authors: Hiroyuki
authors: H
authors: Shimizu
authors: Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan nnagata@niid.go.jp.
authors: Noriyo
authors: N
authors: Nagata