title: Cytomegalovirus initiates infection selectively from high-level β1 integrin-expressing cells in the brain.
abstract: Cytomegalovirus (CMV) is a prevalent pathogen in intrauterine infections that causes congenital anomalies such as CMV encephalitis, which is characterized by the focal areas of reactive gliosis, reactive mononuclear cells, microglial nodules, and ventriculoencephalitis. To elucidate the mechanisms of CMV susceptibility in the developing brain, cell tropism and the infectious dynamics of CMV infection were investigated. We evaluated intraventricular and intravascular infections from the perspective of the distribution of CMV and its receptor (β1 integrin) in the earliest phase of infection. Murine CMV (MCMV) immediate early 1-positive cells were colocalized mainly with meninges and choroid plexus (after intraventricular infection) or with endothelial cells and pericytes (after intravascular infection). Using green fluorescent protein-expressing recombinant MCMV particles and fluorescent microbeads (100 to 300 nm), we revealed that CMV particle size is the primary factor determining the initial CMV distribution. β1 Integrin inhibition using a shRNA and functional blocking antibody significantly reduced MCMV infection. IHC analysis, flow cytometric, and brain slice analyses strongly support that high-level β1 integrin-expressing cells (eg, endothelial cells, pericytes, meninges, choroid plexus, and neural stem progenitor cells) are the first targets of MCMV. Therefore, our data demonstrate that the initial distributions of MCMV particles and β1 integrin determine the distinct pattern of infection in the brain in the acute phase.
authors: Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address: gloria@hama-med.ac.jp.
authors: Hideya
authors: H
authors: Kawasaki
authors: Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors: Isao
authors: I
authors: Kosugi
authors: First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors: Makiko
authors: M
authors: Sakao-Suzuki
authors: Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors: Shiori
authors: S
authors: Meguro
authors: Department of Pathology, Seirei Hamamatsu General Hospital, Shizuoka, Japan.
authors: Yoshifumi
authors: Y
authors: Arai
authors: Faculty of Health Science, Tokoha University, Hamamatsu, Japan.
authors: Yoshihiro
authors: Y
authors: Tsutsui
authors: Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors: Toshihide
authors: T
authors: Iwashita
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D004195:Disease Models, Animal; D004660:Encephalitis / Q000378:metabolism / Q000821:virology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006566:Herpesviridae Infections / Q000378:metabolism / Q000821:virology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D019012:Integrin beta1 / Q000096:biosynthesis*; D051379:Mice; D008813:Mice, Inbred ICR; D018146:Muromegalovirus / Q000472:pathogenicity
chemical_list: D019012:Integrin beta1