Altered m⁶A Modification of Specific Cellular Transcripts Affects Flaviviridae Infection

Area of Science:

• Molecular Biology
• Virology
• Epigenetics

Background:

• N⁶-methyladenosine (m⁶A) is a prevalent mRNA modification influencing gene expression and cellular processes.
• Flaviviridae family viruses (DENV, ZIKV, WNV, HCV) are significant human pathogens.
• Understanding host-pathogen interactions at the molecular level is crucial for developing antiviral strategies.

Purpose of the Study:

• To investigate the impact of viral infection on m⁶A modification patterns across the host transcriptome.
• To identify specific cellular transcripts whose m⁶A levels are altered during infection.
• To elucidate the functional consequences of these m⁶A changes on viral replication and host response.

Main Methods:

• Transcriptome-wide analysis of m⁶A modification in cells infected with DENV, ZIKV, WNV, and HCV.
• Quantitative analysis of m⁶A levels in specific host transcripts, including RIOK3 and CIRBP.
• Assessment of the functional roles of m⁶A modifications in RIOK3 translation and CIRBP splicing during infection.
• Investigation of the link between viral-induced signaling pathways (innate immunity, ER stress) and m⁶A alterations.

Main Results:

• Viral infection by DENV, ZIKV, WNV, and HCV alters m⁶A modification of specific host transcripts, notably RIOK3 and CIRBP.
• m⁶A addition to RIOK3 enhances its translation, while m⁶A loss in CIRBP promotes alternative splicing.
• Innate immune sensing and ER stress responses activated during infection contribute to altered m⁶A levels in RIOK3 and CIRBP, respectively.
• Host proteins encoded by infection-altered m⁶A transcripts, including RIOK3 and CIRBP, influence viral replication.

Conclusions:

• Cellular signaling pathways activated during viral infection induce changes in host mRNA m⁶A modification.
• These m⁶A alterations play a regulatory role in modulating viral infection outcomes.
• Targeting m⁶A modification pathways could represent a novel therapeutic strategy against Flaviviridae infections.