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

doi:10.1016/j.isci.2023.106909

Integrative systems biology characterizes immune-mediated neurodevelopmental changes in murine Zika virus microcephaly

iScience. 2023 May 19;26(7):106909. doi: 10.1016/j.isci.2023.106909. eCollection 2023 Jul 21.

Authors

Kimino Fujimura^{1

2

3

4}, Amanda J Guise¹, Tojo Nakayama², Christoph N Schlaffner¹, Anais Meziani¹, Mukesh Kumar¹, Long Cheng¹, Dylan J Vaughan², Andrew Kodani⁵, Simon Van Haren⁶, Kenneth Parker⁷, Ofer Levy^{6

8}, Ann F Durbin^{9

10}, Irene Bosch^{9

10}, Lee Gehrke^{9

10}, Hanno Steen^{6

11}, Ganeshwaran H Mochida^{2

12}, Judith A Steen¹

Affiliations

¹ F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
² 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.
³ Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
⁴ Department of Pediatrics, Shin-Yurigaoka General Hospital, Kanagawa, Japan.
⁵ Center for Pediatric Neurological Disease Research and Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
⁶ Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
⁷ SimulTOF Systems, Marlborough, MA, USA.
⁸ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
⁹ Department of Microbiology, Harvard Medical School, Boston, MA, USA.
¹⁰ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹¹ Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹² Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.

Abstract

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.

Keywords: Developmental neuroscience; Immunology; Virology.

Abstract

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