MicroRNA-155 controls Toll-like receptor 3- and hepatitis C virus-induced immune responses in the liver

ABSTRACTHepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States, with the majority of patients becoming chronically infected and a subset (20%) progressing to cirrhosis and hepatocellular carcinoma. Individual variations in immune responses may help define successful resistance to infection with HCV. We have compared the immune response in primary macrophages from patients who have spontaneously cleared HCV (viral load negative [VL−],n= 37) to that of primary macrophages from HCV genotype 1 chronically infected (VL+) subjects (n= 32) and found that macrophages from VL− subjects have an elevated baseline expression of Toll-like receptor 3 (TLR3). Macrophages from HCV patients were stimulatedex vivothrough the TLR3 pathway and assessed using gene expression arrays and pathway analysis. We found elevated TLR3 response genes and pathway activity from VL− subjects. Furthermore, macrophages from VL− subjects showed higher production of beta interferon (IFN-β) and related IFN response genes by quantitative PCR (Q-PCR) and increased phosphorylation of STAT-1 by immunoblotting. Analysis of polymorphisms in TLR3 revealed a significant association of intronic TLR3 polymorphism (rs13126816) with the clearance of HCV and the expression of TLR3. Of note, peripheral blood mononuclear cells (PBMCs) from the same donors showed opposite changes in gene expression, suggesting ongoing inflammatory responses in PBMCs from VL+ HCV patients. Our results suggest that an elevated innate immune response enhances HCV clearance mechanisms and may offer a potential therapeutic approach to increase viral clearance.

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Enhanced immune responses, PI3K/AKT and JAK/STAT signaling pathways following hepatitis C virus eradication by direct-acting antiviral therapy among Egyptian patients: a case control study

Pathogens and Disease ◽

10.1093/femspd/ftab008 ◽

2021 ◽

Author(s):

Haidi Karam-Allah Ramadan ◽

Gamal Badr ◽

Nancy K Ramadan ◽

Aml Sayed

Keyword(s):

Immune Response ◽

Liver Cirrhosis ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Immune Responses ◽

Signaling Pathways ◽

Liver Diseases ◽

Stat Signaling ◽

Chronic Hcv ◽

Direct Acting

Abstract The use of direct-acting antivirals (DAAs) therapy for the treatment of hepatitis C virus (HCV) results in a high sustained virological response (SVR) and subsequently alters liver immunologic environment. However, hepatocellular carcinoma (HCC) may occur after DAAs treatment. We aimed to clarify changes of immune responses, PI3K/AKT and JAK/STAT signaling pathways in HCV-induced liver diseases and HCC following DAAs treatment. Four cohorts are classified as chronic HCV patients, HCV-related cirrhosis without HCC, HCV-related cirrhosis and HCC, and healthy control group. The patient groups were further divided into treated or untreated with DAAs with SVR12. Increased percentages of CD3, CD8 and CD4, decreased CD4/FoxP3/CD25, CD8/PD-1 and CD19/PDL-1 were found in DAAs-treated patients in the three HCV groups. Following DAAs therapy, the levels of ROS, IL-1β, IL-6, IL-8 and TNF-α were significantly decreased in the three HCV groups. Treated HCV patients showed up regulation of p-AKT and p-STAT5 and down regulation of p-STAT3, HIF-1α and COX-2. In conclusion, DAAs enhance the immune response in chronic HCV and liver cirrhosis, hence our study is the first to show change in PI3K/AKT and JAK/STAT signaling pathways in different HCV-induced liver diseases after DAAs. In chronic HCV, DAAs have better impact on the immune response while in liver cirrhosis not all immune changes were prominent.

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Multiple Fixed Drug Eruption Mimicking Parapsoriasis en Plaque in a Patient with Hepatitis C Virus Infection

Case Reports in Dermatology ◽

10.1159/000505477 ◽

2020 ◽

Vol 12 (1) ◽

pp. 25-32 ◽

Cited By ~ 1

Author(s):

Michie Katsuta ◽

Akihiko Asahina ◽

Tetsuo Shiohara

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Immune Responses ◽

Drug Eruption ◽

Hcv Rna ◽

Fixed Drug Eruption ◽

Cutaneous Manifestations ◽

Fixed Drug ◽

Per Se ◽

Multiple Drugs

Although hepatitis C virus (HCV) infection is often associated with extrahepatic cutaneous manifestations such as lichen planus, it is unclear whether HCV per se or HCV-specific immune responses play a pathophysiological role in the development of HCV-related cutaneous diseases. We recently treated a patient who developed parapsoriasis en plaque-like lesions after ingestion of various drugs. She showed hypersensitivity to multiple drugs after interferon therapy. Her clinical course was complicated by flares of parapsoriasis-like lesions which returned at precisely the same sites. The flares had begun within hours of ingesting nicardipine hydrochloride, amlodipine besilate, candesartan cilexetil and atenolol for the first time despite showing a low level of HCV RNA. Interestingly, the flares gradually subsided during continued treatment with these drugs while her HCV RNA level paradoxically increased: thus, there was an inverse correlation between flares and HCV RNA level. The eruptions were eventually diagnosed as fixed drug eruption, although the clinical manifestations mimicked parapsoriasis en plaque. Our results suggest that multiple drug hypersensitivity could be induced by antiviral immune responses that are cross-reactive to multiple drugs, but not by HCV per se.

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Hepatitis C Virus Induces Toll-Like Receptor 4 Expression, Leading to Enhanced Production of Beta Interferon and Interleukin-6

Journal of Virology ◽

10.1128/jvi.80.2.866-874.2006 ◽

2006 ◽

Vol 80 (2) ◽

pp. 866-874 ◽

Cited By ~ 131

Author(s):

Keigo Machida ◽

Kevin T. H. Cheng ◽

Vicky M.-H. Sung ◽

Alexandra M. Levine ◽

Steven Foung ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cells ◽

Immune Responses ◽

Interleukin 6 ◽

Innate Immune ◽

Hcv Infection ◽

Innate Immune Responses ◽

Altered Expression ◽

Beta Interferon

ABSTRACT Hepatitis C virus (HCV) induces inflammatory signals, leading to hepatitis, hepatocellular carcinomas, and lymphomas. The mechanism of HCV involvement in the host's innate immune responses has not been well characterized. In this study, we analyzed expression and regulation of the entire panel of toll-like receptors (TLRs) in human B cells following HCV infection in vitro. Among all of the TLRs (TLRs 1 to 10) examined, only TLR4 showed an altered expression (a three- to sevenfold up-regulation) after HCV infection. Peripheral blood mononuclear cells from HCV-infected individuals also showed a higher expression level of TLR4 compared with those of healthy individuals. HCV infection significantly increased beta interferon (IFN-β) and interleukin-6 (IL-6) secretion from B cells, particularly after lipopolysaccharide stimulation. The increased IFN-β and IL-6 production was mediated by TLR4 induction, since the introduction of the small interfering RNA against TLR4 specifically inhibited the HCV-induced cytokine production. Among all of the viral proteins, only NS5A caused TLR4 induction in hepatocytes and B cells. NS5A specifically activated the promoter of the TLR4 gene in both hepatocytes and B cells. In conclusion, HCV infection directly induces TLR4 expression and thereby activates B cells, which may contribute to the host's innate immune responses.

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