Reduced Nucleoprotein availability impairs negative-sense RNA virus replication and promotes host recognition
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ABSTRACT:
PROVIDER: PRJNA694127 | ENA |
REPOSITORIES: ENA
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Project description:Negative-sense RNA viruses (NSVs) rely on prepackaged viral RNA-dependent RNA polymerases (RdRp) to replicate and transcribe their viral genomes. Their replication machinery consists of an RdRp bound to viral RNA which is wound around a nucleoprotein (NP) scaffold, forming a viral ribonucleoprotein complex. NSV NP is known to regulate transcription and replication of genomic RNA, however its role in maintaining and protecting the viral genetic material is unknown. Here, we exploited host microRNA expression to target NP of influenza A virus and Sendai virus to ascertain how this would impact genomic levels and the host response to infection. We find that in addition to inducing a drastic decrease in genome replication, the antiviral host response in the absence of NP is dramatically enhanced. Additionally, our data shows that insufficient levels of NP prevent the replication machinery of these NSVs to process full-length genomes, resulting in aberrant replication products which form pathogen-associated molecular patterns in the process. These dynamics facilitate immune recognition by cellular pattern recognition receptors leading to a strong host antiviral response. Moreover, we observe that the consequences of limiting NP levels are universal amongst NSVs including Ebola virus, Lassa virus and Measles virus. Overall, these results provide new insights into viral genome replication of negative-sense RNA viruses and highlight novel avenues towards developing effective antiviral strategies, adjuvants, and/or live-attenuated vaccines.
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Project description:Anti-sense transcription originating upstream of mammalian protein-coding genes is a well-documented phenomenon, but remarkably little is known about the function or regulation of these anti-sense promoters or the non-coding RNAs they generate. Here we define at nucleotide resolution the divergent transcription start sites (TSSs) near mouse mRNAs. We find that coupled sense and anti-sense TSSs form the boundaries of an evolutionarily conserved and nucleosome-depleted regulatory region with dramatically enriched transcription factor (TF) occupancy. Notably, as the distance between sense and anti-sense TSSs increases, so does the level of TF binding and signal-dependent gene activation. We further discover a cluster of anti-sense TSSs in macrophages with an enhancer-like chromatin signature. Remarkably, this signature identifies promoters that are selectively and rapidly activated during immune challenge. We conclude that anti-sense TSSs can serve as potent, local enhancers of sense-strand gene expression by facilitating TF binding and deposition of activating histone modifications.
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