Reduced-beclin1-expressing mice infected with zika-R103451 and viral-associated pathology during pregnancy

Mohan Kumar Muthu Karuppan, Chet Raj Ojha, Myosotys Rodriguez, Jessica Lapierre, M. Javad Aman, Fatah Kashanchi, Michal Toborek, Madhavan Nair, Nazira El-Hage

Research output: Contribution to journalArticle

Abstract

Here, we used a mouse model with defective autophagy to further decipher the role of Beclin1 in the infection and disease of Zika virus (ZIKV)-R103451. Hemizygous (Becn1+/-) and wild-type (Becn1+/+) pregnant mice were transiently immunocompromised using the anti-interferon alpha/beta receptor subunit 1 monoclonal antibody MAR1-5A3. Despite a low mortality rate among the infected dams, 25% of Becn1+/- offspring were smaller in size and had smaller, underdeveloped brains. This phenotype became apparent after 2-to 3-weeks post-birth. Furthermore, the smaller-sized pups showed a decrease in the mRNA expression levels of insulin-like growth factor (IGF)-1 and the expression levels of several microcephaly associated genes, when compared to their typical-sized siblings. Neuronal loss was also noticeable in brain tissues that were removed postmortem. Further analysis with murine mixed glia, derived from ZIKV-infected Becn1+/- and Becn1+/+ pups, showed greater infectivity in glia derived from the Becn1+/- genotype, along with a significant increase in pro-inflammatory molecules. In the present study, we identified a link by which defective autophagy is causally related to increased inflammatory molecules, reduced growth factor, decreased expression of microcephaly-associated genes, and increased neuronal loss. Specifically, we showed that a reduced expression of Beclin1 aggravated the consequences of ZIKV infection on brain development and qualifies Becn1 as a susceptibility gene of ZIKV congenital syndrome.

Original languageEnglish (US)
Article number608
JournalViruses
Volume12
Issue number6
DOIs
StatePublished - Jun 2020

Keywords

  • Autophagy-defective mouse-model
  • Beclin1
  • Congenital syndrome
  • Growth factor
  • Inflammatory molecules
  • Microcephaly
  • Zika virus

ASJC Scopus subject areas

  • Infectious Diseases
  • Virology

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    Karuppan, M. K. M., Ojha, C. R., Rodriguez, M., Lapierre, J., Aman, M. J., Kashanchi, F., Toborek, M., Nair, M., & El-Hage, N. (2020). Reduced-beclin1-expressing mice infected with zika-R103451 and viral-associated pathology during pregnancy. Viruses, 12(6), [608]. https://doi.org/10.3390/v12060608