Zika viruses encode 5' upstream open reading frames affecting infection of human brain cells.

Area of Science:

• Virology
• Molecular Biology
• Neuroscience

Background:

• Zika virus (ZIKV), a mosquito-borne flavivirus, is linked to severe congenital neurological issues.
• Understanding ZIKV's gene expression is crucial for explaining its neurotropic potential.

Purpose of the Study:

• To investigate novel gene expression mechanisms in ZIKV strains.
• To identify potential pathological correlates of ZIKV neurotropism.

Main Methods:

• RNA sequencing and ribosome profiling were employed to analyze ZIKV gene expression.
• Reverse genetics was used to create and study mutant ZIKV strains with altered uORFs.

Main Results:

• Unrecognized upstream open reading frames (uORFs) were identified in the ZIKV genome's 5' region.
• Asian/American ZIKV strains exhibit uORF1 and uORF2, while African strains have a fused African uORF.
• Expression of African uORF and Asian/American uORF1 modulated ZIKV growth and tropism in human neuronal models.
• uORFs did not significantly impact ZIKV transmission in mosquito vectors.

Conclusions:

• ZIKV uORFs represent a novel layer of gene regulation impacting neurotropism.
• These findings offer new insights into ZIKV's infection of human brain cells.
• The existence of uORFs in other neurotropic flaviviruses warrants further investigation.