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

• Published in: PloS one 2016-10, Vol.11 (10), p.e0165533-e0165533
• Main Authors: Choi, Youkyung H, Jin, Nancy, Kelly, Fiona, Sakthivel, SenthilKumar K, Yu, Tianwei
• Format: Article
• Language: English
• Subjects: Acute Disease; Adapters; Alanine; Alanine transaminase; Alanine Transaminase - metabolism; Amino acids; Analysis; Animals; Apoptosis; Bioindicators; Bioinformatics; Biology and Life Sciences; Biomarkers; Caspase; Caspase-3; Caspase-7; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell activation; Cell death; Cell injury; Chemokine CXCL10 - blood; Chimpanzees; Correlation; Correlation analysis; CXCL10 protein; Cytokeratin; Cytokines; Disease control; Disease prevention; Drug dosages; Gastroenterology; Gene expression; Genes; Hepacivirus - genetics; Hepatitis; Hepatitis C - immunology; Hepatitis C virus; Hepatocytes; Hepatology; Humans; Immune clearance; Immune response; Infection; Infections; Inhibition; Innate immunity; Inoculation; Interferon; Interferon Type I - metabolism; Keratin; Killer cells; Killer Cells, Natural - immunology; Laboratory animals; Ligands; Liver; Liver - immunology; Liver - pathology; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Medicine and health sciences; Messenger RNA; Mortality; Natural killer cells; Nutrition research; Pan troglodytes; Pattern recognition; PD-L1 protein; Programmed Cell Death 1 Receptor - blood; Public health; Receptors; Signal Transduction; Signaling; T cells; TLR3 protein; TLR7 protein; Toll-like receptors; Transcription activation; Tumor necrosis factor-TNF; Viral infections; Virology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0165533

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.