Zika and dengue viruses differentially modulate host mRNA processing factors defining its virulence

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Global climate change is increasing vector populations, leading to more vector-borne flavivirus infections.
• Flaviviruses like Zika virus (ZIKV) and Dengue virus (DENV) pose risks to human-derived biologics, including cell and gene therapies.
• Understanding host-pathogen interactions is crucial for mitigating flavivirus threats.

Purpose of the Study:

• To investigate the molecular mechanisms underlying Zika virus (ZIKV) and Dengue virus (DENV) virulence.
• To identify host cellular factors involved in flavivirus replication and host defense.
• To compare the pathogenic differences between ZIKV and DENV infections.

Main Methods:

• Time-course transcriptomic (RNA-seq) and proteomic analyses were performed on infected host cells.
• Differential gene expression and protein degradation pathways were analyzed.
• Host nuclear transport requirements for viral replication were assessed.

Main Results:

• ZIKV demonstrated greater virulence and cytopathic effects compared to DENV.
• ZIKV infection led to the degradation of host nonsense-mediated RNA decay (NMD) factors, unlike DENV.
• Accumulation of host intronic transcripts and requirement of active nuclear transport were observed in ZIKV-infected cells.

Conclusions:

• ZIKV induces early host cell damage through targeted degradation of essential host proteins, particularly NMD factors.
• ZIKV's unique mechanism of host factor manipulation contributes to its heightened virulence.
• These findings pave the way for developing novel transcriptomics- and proteomics-based strategies for flavivirus detection in biologics.