Abstract
Zika virus (ZIKV) is a neurotropic flavivirus that causes several diseases including birth defects such as microcephaly. Intrinsic immunity is known to be a frontline defense against viruses through host anti-viral restriction factors. Limited knowledge is available on intrinsic immunity against ZIKV in brains. Amyloid precursor protein (APP) is predominantly expressed in brains and implicated in the pathogenesis of Alzheimer's diseases. We have found that ZIKV interacts with APP, and viral infection increases APP expression via enhancing protein stability. Moreover, we identified the viral peptide, HGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL, which is capable of en-hancing APP expression. We observed that aging brain tissues with APP had protective effects on ZIKV infection by reducing the availability of the viruses. Also, knockdown of APP expression or blocking ZIKV-APP interactions enhanced ZIKV replication in human neural progenitor/stem cells. Finally, intracranial infection of ZIKV in APP-null neonatal mice resulted in higher mortality and viral yields. Taken together, these findings suggest that APP is a restriction factor that protects against ZIKV by serving as a decoy receptor, and plays a protective role in ZIKV-mediated brain injuries.
Highlights
Zika virus (ZIKV) belongs to Flaviviridae and the genus Flavivirus, and is related to the dengue, West Nile, and other flaviviruses
Because ZIKV has a limited effect on adult mouse brains, aging mouse brain tissues may have a protective effect on other susceptible cells by binding and trapping the virus (Fig. 2e)
The interacting domain in Amyloid precursor protein (APP) is probably located around the Beta-secretase 1 (BACE1)-binding site based on findings that the single-chain variable fragment (scFv) of antibody BSC1 could affect both ZIKV binding as well as viral replication in cells (Figs. 2h and 5)
Summary
Using information about the ZIKV virion structure [32, 33], we applied protein structure alignment methods, such as SSM [34] and TM-alignment [35], to screen structurally homologous proteins to ZIKV virion and E protein.
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