MIR155HG Plays a Bivalent Role in Regulating Innate Antiviral Immunity by Encoding Long Noncoding RNA-155 and microRNA-155-5p.

MIR155HG encodes a precursor RNA of microRNA-155 (miRNA-155). We previously identified this RNA also as a long noncoding RNA (lncRNA) that we call lncRNA-155. To define the functions of miRNA-155 and lncRNA-155, we generated miRNA-155 knockout (KO) mice lacking only 19 bp of the miRNA-155 core sequence without affecting the expression of lncRNA-155. Surprisingly, compared with the miRNA-155KO mice, previously generated lncRNA-155KO mice were more susceptible to both influenza virus (RNA virus) and pseudorabies virus (DNA virus) infection, as characterized by lower survival rate, higher body weight loss, and higher viral load. We found that miRNA-155-5p enhanced antiviral responses by positively regulating activation of signal transducer and activator of transcription 1 (STAT1), but the STAT1 activity differed greatly in the animals (lncRNA-155KO < miRNA-155KO < wild type). In line with this, expression levels of several critical interferon-stimulated genes (ISGs) were also significantly different (lncRNA-155KO < miRNA-155KO < wild type). We found that lncRNA-155 augmented interferon beta (IFN-ß) production during the viral infection, but miRNA-155 had no significant effect on the virus-induced IFN-ß expression. Furthermore, we observed that lncRNA-155 loss in mice resulted in dramatic inhibition of virus-induced activation of interferon regulatory factor 3 compared to both miRNA-155KO and wild-type (WT) animals. Moreover, lncRNA-155 still significantly suppressed the viral infection even though the miRNA-155 derived from lncRNA-155 was deleted or blocked. These results reveal that lncRNA-155 and miRNA-155 regulate antiviral responses through distinct mechanisms, indicating a bivalent role for MIR155HG in innate immunity. IMPORTANCE Here, we found that lncRNA-155KO mice lacking most of the lncRNA-155 sequences along with pre-miRNA-155, were more susceptible to influenza virus or pseudorabies virus infection than miRNA-155KO mice lacking only 19 bp of the miRNA-155 core sequence without affecting the expression of lncRNA-155, as evidenced by faster body weight loss, poorer survival, and higher viral load, suggesting an additional role of lncRNA-155 in regulating viral pathogenesis besides via processing miRNA-155. Congruously, miRNA-155-deleted lncRNA-155 significantly attenuated the viral infection. Mechanistically, we demonstrated miRNA-155-5p potentiated antiviral responses by promoting STAT1 activation but could not directly regulate the IFN-ß expression. In contrast, lncRNA-155 enhanced virus-induced IFN-ß production by regulating the activation of interferon regulatory factor 3. This finding reveals a bivalent role of MIR155HG in regulating antiviral responses through encoding lncRNA-155 and miRNA-155-5p and provides new insights into complicated mechanisms underlying interaction between virus and host innate immunity.

Effects of Anterior Borderzone Angle Grading on Predicting the 90-Day Prognosis After Recanalization of Acute Middle Cerebral Artery Occlusion.

Objective: This work explores collateral circulation metrics, such as the anterior borderzone angle grading (ABZA-grading), as a predictor of the prognosis in patients with acute middle cerebral artery occlusion (MCAO) following endovascular treatment (EVT). Methods: Clinical data from 108 patients with acute MCAO, treated by EVT, were retrospectively analyzed. In patients with MCAO, ABZA is the angle between the median line of the sagittal sinus and the borderzone of the pial arterioles of ACA and MCA, and the ABZA/23.0° was rounded to obtain the corresponding collateral circulation score (ABZA-grading). In parallel, the primary outcome was defined as the 90-day clinical outcome by modified ranking scale score (mRS). Univariate analysis and logistic regression were used to analyze the independent predictors of the 90-day clinical outcome (mRS). Receiver operating characteristic curve (ROC) analysis was used to judge the predictive value of ABZA. Results: Univariate analysis and logistic regression analysis showed that ABZA-grading > 2 and age were independent predictors of the 90-day clinical outcome after EVT in patients with acute MCAO. The ROC analysis showed that ABZA alone could predict a favorable 90-day clinical outcome with an area under the curve (AUC) of 0.868. Using an ABZA of >57.8° (the corresponding ABZA-grading of >2) as the cut-off value, the predictive sensitivity and specificity were 75.7 and 88.7%, respectively. Contingency table analysis showed a statistical difference in mRS score between ABZA-grading subgroups, and ABZA-grading between stroke caused by large artery atherosclerosis (LAA) and cardiogenic embolism (CE). Conclusion: The ABZA-grading is an easy and objective assessment of collateral circulation that is independently associated with short-time clinical outcome after EVT in patients with acute MCAO. Therefore, it may guide selection of patients with acute ischemic stroke (AIS) suitable for EVT. The ABZA-grading of collateral circulation can be a supplemental metric to help differentiate stroke by LAA and CE.