Integrative systems biology characterizes immune-mediated neurodevelopmental changes in murine Zika virus microcephaly
Kimino Fujimura,
Amanda J. Guise,
Tojo Nakayama,
Christoph N. Schlaffner,
Anais Meziani,
Mukesh Kumar,
Long Cheng,
Dylan J. Vaughan,
Andrew Kodani,
Simon Van Haren,
Kenneth Parker,
Ofer Levy,
Ann F. Durbin,
Irene Bosch,
Lee Gehrke,
Hanno Steen,
Ganeshwaran H. Mochida,
Judith A. Steen
Affiliations
Kimino Fujimura
F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA; Division of Genetics and Genomics and The Manton Center for Orphan Disease, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan; Department of Pediatrics, Shin-Yurigaoka General Hospital, Kanagawa, Japan
Amanda J. Guise
F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Tojo Nakayama
Division of Genetics and Genomics and The Manton Center for Orphan Disease, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Christoph N. Schlaffner
F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Anais Meziani
F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Mukesh Kumar
F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Long Cheng
F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Dylan J. Vaughan
Division of Genetics and Genomics and The Manton Center for Orphan Disease, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Andrew Kodani
Center for Pediatric Neurological Disease Research and Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
Simon Van Haren
Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Kenneth Parker
SimulTOF Systems, Marlborough, MA, USA
Ofer Levy
Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
Ann F. Durbin
Department of Microbiology, Harvard Medical School, Boston, MA, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA
Irene Bosch
Department of Microbiology, Harvard Medical School, Boston, MA, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA
Lee Gehrke
Department of Microbiology, Harvard Medical School, Boston, MA, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA
Hanno Steen
Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Ganeshwaran H. Mochida
Division of Genetics and Genomics and The Manton Center for Orphan Disease, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Corresponding author
Judith A. Steen
F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA; Corresponding author
Summary: Characterizing perturbation of molecular pathways in congenital Zika virus (ZIKV) infection is critical for improved therapeutic approaches. Leveraging integrative systems biology, proteomics, and RNA-seq, we analyzed embryonic brain tissues from an immunocompetent, wild-type congenital ZIKV infection mouse model. ZIKV induced a robust immune response accompanied by the downregulation of critical neurodevelopmental gene programs. We identified a negative correlation between ZIKV polyprotein abundance and host cell cycle-inducing proteins. We further captured the downregulation of genes/proteins, many of which are known to be causative for human microcephaly, including Eomesodermin/T-box Brain Protein 2 (EOMES/TBR2) and Neuronal Differentiation 2 (NEUROD2). Disturbances of distinct molecular pathways in neural progenitors and post-mitotic neurons may contribute to complex brain phenotype of congenital ZIKV infection. Overall, this report on protein- and transcript-level dynamics enhances understanding of the ZIKV immunopathological landscape through characterization of fetal immune response in the developing brain.
