Interleukin 11 Involves In The Molecular Mechanism Of Hepatitis C Virus Replication And Its Innate Immunity To Host Cells

According to institutional statistics,the number of Hepatitis C Virus infection is about170 million people worldwide,accounting for 3%of the world population.Acute HCV infection is usually asymptomatic,with highly chronic rate of 80%,so it is one of the most common causes leading to end-stage liver disease such as cirrhosis and liver cancer.Because the classic treatment method by pegylated interferon combined with ribavirin treatment cause adverse reactions,sustained low virological response rate and treatment effect is affected by patient's health status and HCV genotype,the current guideline preferred to direct antiviral drugs(DAAs)such as sofosbuvir,dacarbavir or Combined treatment of sofosbuvir/detopavir,with a cure rate of 95%or more,which is more effective,safer and more tolerable than classic therapies,greatly reducing death risk of liver cancer and liver Hardened.However,the high mutability of HCV also makes the resistance barrier of small-molecule inhibitors low,and no effective vaccine is available so far.After HCV infection,host cells can suppress virus replication by activating innate immunity,and the virus also maintains the relative homeostasis with host cell immune factors through a series of complex mechanisms,leading to the chronicity of infection.Previously,we performed gene expression profiling by a microarray and the detection of protein level in HCV-infected Huh7 cells.We found that HCV infection significantly promoted up-regulation of TXNIP expression in Huh7 cells.And in my study,we also show that TXNIP has an important effect on HCV replication using RNA interference technology.In addition,on the homogenous cell strains with significantly different susceptibility to HCV,Huh7 and Huh7.5.1,the previous literature considered that the intrinsic immune function loss caused by the RIG-I mutation is the main reason for the enhanced replication of HCV in Huh7.5.1 cells,but the recognition mechanism is still controversial.Recent reports have show that MDA5 is also involved in the identification of HCV,and we also show the differential expression of TXNIP in the two cell lines is also an important cause for the susceptibility of Huh7.5.1 to HCV.In order to explore the interaction mechanism of HCV and innate immunity and find out more evidence that HCV utilize host factors to evade the innate immunity,we treat CD81~-Huh7 cells with HCV-infected Huh7 and Huh7.5.1 cell culture supernatants and find that a soluble factor up-regulate the expression of TXNIP.Through transcriptome sequencing analysis of Huh7 cells infected with HCV for 12h,36h,and 60h,we confirm significantly up-regulated cytokines IL-11 and TNF-?.Then treated with exogenous cytokines in Huh7 cells,we also find IL-11 significantly up-regulate TXNIP in Huh7 cells,while TNF-?significantly inhibit TXNIP expression with the detection of mRNA and protein levels.At the same time,treatment of Huh7 cells with IL-11 inhibitors show a significant decrease in TXNIP expression levels and HCV RNA.On the other hand,Huh7.5.1 cells are found to have significantly higher IL-11 expression levels than Huh7cells.These results suggest that differential expression of IL-11 is also one of the important factors for the susceptibility of HCV to Huh7.5.1 cells.In addition,stimulating the interferon pathway signaling molecules RIG-I and MDA5,we confirm that the MDA5signaling pathway in Huh7.5.1 cells is also insufficient and stimulation of MDA5 in Huh7cells can up-regulate TXNIP expression,which is a strategy for HCV infection to escape cell innate immunity.In view of the fact that TXNIP plays an important role in normal physiological functions and stress conditions of cells,and there have been no reports in the literature yet that IL-11,which is a negative immunoregulatory factor that can be induced by HCV infection,interact with HCV replication and HCV escaping from innate immunity.Our study reveals for the first time the important role of IL-11 in the induction of high TXNIP expression in HCV infection.We tentatively describe the mechanism of their interaction,and provide new clues for the two cell lines Huh7 and Huh7.5.1 differentially supporting for HCV infection,and we also provide a reference for discovering new targets of anti-HCV drugs.