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Viral N6-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus

ABSTRACT: N6-methyladenosine (m6A) is the most prevalent internal modification of mRNAs in most eukaryotes. Likewise, viral RNAs may acquire m6A methylation during replication within these cells. Here we show that RNAs of human respiratory syncytial virus (RSV), a medically important non-segmented negative-sense (NNS) RNA virus, are modified by m6A within discreet regions and that these modifications enhance viral replication and pathogenesis. Overexpression of m6A binding proteins significantly enhanced RSV replication and gene expression. Knockdown of m6A methyltransferases decreased viral replication and gene expression whereas knockdown of m6A demethylases had the opposite effect. The G gene contained the most abundant m6A modifications. Recombinant RSV expressing a G gene lacking different m6A sites, resulted in RSVs with various degrees of defects in replication in A549 cells, primary well differentiated human airway epithelial (HAE) cultures, upper and lower respiratory tract of cotton rats, and were also less pathogenic to the lungs of cotton rats. One of the m6A-deficient rgRSVs, rgRSV-G12, was completely attenuated yet retained high immunogenicity in cotton rats. Moreover, a small molecule that inhibits S-adenosyl-L-homocysteine (SAH) hydrolase, thereby reducing the cellular SAH pool and viral RNA m6A, also inhibited RSV replication in HAE cells. Collectively, our results demonstrate viral m6A methylation upregulates RSV replication and pathogenesis and identify viral m6A methylation as a target for rational design of live attenuated vaccine candidates and for novel antiviral therapeutic agents for RSV.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125803 | GEO | 2019/09/10

REPOSITORIES: GEO

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Project description:Numerous studies have elucidated the neuroprotective effect of 6-gingerol in central nervous system diseases. However, the potential role and mechanism of 6-gingerol on early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains poorly understood. Here, we report that 6-gingerol exerts a neuroprotective effect on SAH-induced EBI through the GBP2/PI3K/AKT pathway. A SAH rat model was established by injecting femoral artery blood into the cisterna magna. 6-gingerol or vehicle was injected intraperitoneally one hour post-SAH induction. We found that the neurological function score and brain edema of SAH rats were significantly improved after 6-gingerol treatment, as well as neuronal apoptosis was attenuated in SAH rats by Nissl staining assay and TUNEL assay. To further explore potential molecular mechanisms associated with 6-gingerol, RNA sequencing was implemented to investigate the differences in transcriptomes between SAH rats with and without 6-gingerol treatment; and found that the expression of guanylate-binding protein 2 (GBP2) evidently was suppressed with 6-gingerol treatment compared to vehicle group. In addition, dual immunofluorescence was also employed to investigate changes in neurons, astrocytes, and microglia after 6-gingerol treatment. The results showed that GBP2 was expressed in neurons but not astrocytes or microglia. Western blotting analysis results demonstrated that the PI3K/AKT pathway was activated in the SAH rats treated with 6-gingerol. Furthermore, recombinant GBP2 protein and LY294002 (PI3K inhibitor) treatment reversed the effects of 6-gingerol treatment in SAH rats. These results indicate that 6-gingerol suppressed the expression of GBP2 to activate the PI3K/AKT pathway, improve neurologic outcomes, reduce brain edema and neuronal apoptosis. In summary, our findings suggest that 6-gingerol could attenuate EBI post-SAH in rats, and 6-gingerol may serve as a novel candidate neuroprotective drug for SAH-induced EBI.

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Viral N6-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus

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