title: Elevation of Alanine Aminotransferase Activity Occurs after Activation of the Cell-Death Signaling Initiated by Pattern-Recognition Receptors ‎but before Activation of Cytolytic Effectors in NK or CD8+ T Cells in the Liver During Acute HCV Infection.
abstract: Pattern-recognition receptors (PRRs) promote host defenses against HCV infection by binding to their corresponding adapter molecules leading to the initiation of innate immune responses including cell death. We investigated the expression of PRR genes, biomarkers of liver cell-death, and T cell and NK cell activation/inhibition-related genes in liver and serum obtained from three experimentally infected chimpanzees with acute HCV infection, and analyzed the correlation between gene expression levels and clinical profiles. Our results showed that expression of hepatic RIG-I, TLR3, TLR7, 2OAS1, and CXCL10 mRNAs was upregulated as early as 7 days post-inoculation and peaked 12 to 83 days post-inoculation. All of the three HCV infected chimpanzees exhibited significant elevations of serum alanine aminotransferase (ALT) activity between 70 and 95 days after inoculation. Elevated levels of serum cytokeratin 18 (CK-18) and caspases 3 and 7 activity coincided closely with the rise of ALT activity, and were preceded by significant increases in levels of caspase 3 and caspase 7 mRNAs in the liver. Particularly we found that significant positive auto-correlations were observed between RIG-I, TLR3, CXCL10, 2OAS1, and PD-L1 mRNA and ALT activity at 3 to 12 days before the peak of ALT activity. However, we observed substantial negative auto-correlations between T cell and NK cell activation/inhibition-related genes and ALT activity at 5 to 32 days after the peak of ALT activity. Our results indicated cell death signaling is preceded by early induction of RIG-I, TLR3, 2OAS1, and CXCL10 mRNAs which leads to elevation of ALT activity and this signaling pathway occurs before the activation of NK and T cells during acute HCV infection. Our study suggests that PRRs and type I IFN response may play a critical role in development of liver cell injury related to viral clearance during acute HCV infection.
authors: Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors: Youkyung H
authors: YH
authors: Choi
authors: Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America.
authors: Nancy
authors: N
authors: Jin
authors: Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors: Fiona
authors: F
authors: Kelly
authors: Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
authors: SenthilKumar K
authors: SK
authors: Sakthivel
authors: Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America.
authors: Tianwei
authors: T
authors: Yu
mesh_terms: D000208:Acute Disease; D000410:Alanine Transaminase / Q000378:metabolism*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D054357:Chemokine CXCL10 / Q000097:blood; D016174:Hepacivirus / Q000235:genetics; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D002679:Pan troglodytes; D061026:Programmed Cell Death 1 Receptor / Q000097:blood; D015398:Signal Transduction
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D007370:Interferon Type I; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000410:Alanine Transaminase