title: Impaired toll-like receptor 3-mediated immune responses from macrophages of patients chronically infected with hepatitis C virus.
abstract: Hepatitis 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 stimulated ex vivo through 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.
authors.affiliation: Section of Rheumatology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Bolen
authors.forename: Chunxia
authors.initials: C
authors.lastname: Jing
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Erol
authors.initials: E
authors.lastname: Fikrig
authors.forename: R Douglas
authors.initials: RD
authors.lastname: Bruce
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Montgomery
mesh_terms: D000328:Adult; D005260:Female; D015870:Gene Expression; D005838:Genotype; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology; D006801:Humans; D007249:Inflammation; D016899:Interferon-beta / Q000096:biosynthesis; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D008297:Male; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000235:genetics* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D019562:Viral Load; D000095022:Interferon Lambda
chemical_list: D016899:Interferon-beta; D007372:Interferons; D007378:Interleukins; D050794:STAT1 Transcription Factor; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494079:STAT1 protein, human; C495344:TLR3 protein, human