Molecular Mechanism(s) of Zika virus infection and associated neuropathogenesis

Authors

Chet Raj OjhaFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Biomedical Sciences

First Advisor's Name

Nazira El-Hage

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Madhavan Nair

Second Advisor's Committee Title

Committee Member

Third Advisor's Name

Ajeet Kaushik

Third Advisor's Committee Title

Committee Member

Fourth Advisor's Name

Tomas Guilarte

Fourth Advisor's Committee Title

Committee Member

Fifth Advisor's Name

Fatah Kashanchi

Fifth Advisor's Committee Title

Committee Member

Keywords

Zika virus, Astrocytes, Entry receptor, ER stress, Toll-like receptor 3, Autophagy, Microcephaly

Date of Defense

5-28-2019

Abstract

Zika virus (ZIKV), a mosquito-borne flavivirus, is known to induce various neurodevelopmental disorders including microcephaly and growth retardation in newborns from infected mothers. However, the exact mechanism of ZIKV-associated neurodevelopmental disorders is still unknown. The study was aimed at identifying the molecular mechanism(s) of ZIKV infection using in-vitro and in vivo methods. Using three isolated strains of ZIKV (MR766, R103451, and PRVABC59), we show that the Asian strains of ZIKV are more infective and toxic to glial cells and neurons compared to the African strain. Infection by PRVABC59 induces markedly higher release of inflammatory molecules; IP10, RANTES, IL-6, and IFN-β. ZIKV cellular entry in glial cells is primarily mediated by Axl receptor irrespective of the viral strains. We show that ZIKV induces unfolded protein response (UPR), toll-like receptor (TLR) and autophagy pathways in the glial cells. Exploring the role of these pathways in ZIKV infection, we report that pharmacological and genetic inhibition of TLR3 causes a marked decrease in ZIKV titers and the viral-induced inflammatory response in infected glial cells, while Beclin1, an autophagy protein having a crucial role in the initiation of autophagosome formation, controls the ZIKV-induced host inflammatory responses. We further investigated the role of Beclin1 in the development of neuropathology in-utero using ZIKV-exposed fetus. ZIKV-infected timed-pregnant wild-type C57BL/6J and Beclin1 deficient (Atg6^+/-) mice showed that the Beclin1 protein plays a protective role in both growth and embryonic brain development in the fetus. Mechanistically, deficiency of Beclin1 causes the reduction in microcephaly related genes (MCPH1, ASPM, CASC5, and WDR62) in the fetal brain, which correlate with the overt congenital malformations and growth impairment in fetus and pups born from Atg6^+/- mice. Since viral protein (NS1and Env) were detected in pup’s brain in the absence of ZIKV genome, we reason that viral proteins transmigrated from the placenta to the fetus by a yet unknown mechanism, probably the secretory autophagy, might be the causal factors for the neurodevelopmental disorder detected in pups born from infected mice.

Identifier

FIDC007764

ORCID

0000-0002-6816-8892

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Recommended Citation

Ojha, Chet Raj, "Molecular Mechanism(s) of Zika virus infection and associated neuropathogenesis" (2019). FIU Electronic Theses and Dissertations. 4269.
https://digitalcommons.fiu.edu/etd/4269