Reduced-Beclin1-Expressing Mice Infected with Zika-R103451 and Viral-Associated Pathology during Pregnancy.
Mohan Kumar Muthu KaruppanChet Raj OjhaMyosotys RodriguezJessica LapierreM Javad AmanFatah KashanchiMichał ToborekMadhavan NairNazira El-HagePublished in: Viruses (2020)
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.
Keyphrases
- zika virus
- wild type
- dengue virus
- growth factor
- poor prognosis
- aedes aegypti
- monoclonal antibody
- binding protein
- mouse model
- oxidative stress
- genome wide
- cell death
- cerebral ischemia
- endoplasmic reticulum stress
- white matter
- signaling pathway
- high fat diet induced
- resting state
- sars cov
- magnetic resonance imaging
- type diabetes
- pregnant women
- insulin resistance
- cardiovascular disease
- multiple sclerosis
- cardiovascular events
- gestational age
- metabolic syndrome
- case report
- coronary artery disease
- functional connectivity
- dendritic cells
- adipose tissue
- transcription factor
- magnetic resonance
- high fat diet
- diffusion weighted imaging
- skeletal muscle
- copy number
- blood brain barrier
- pi k akt
- data analysis
- extracorporeal membrane oxygenation