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.

Cellular metabolism dictates T cell effector function in health and disease

“…These include production of α-ketoglutarate (α-KG) from glutamate during which alanine is produced from glycolytic pyruvate by alanine aminotransferase (ALT). 48 The product α-KG may further be converted to citrate in the tricarboxylic acid (TCA) cycle during which citrate is shunted out of the mitochondrion to support cytosolic acetyl co-enzyme A (AcCoA) levels. AcCoA is a substrate for lipogenesis and mevalonate metabolism as well as cholesterol synthesis.…”

“…Conversion of glutamine to glutamate is pivotal for proliferating cells in general, as it supports a number of metabolic pathways. These include production of α‐ketoglutarate (α‐KG) from glutamate during which alanine is produced from glycolytic pyruvate by alanine aminotransferase (ALT) 48 . The product α‐KG may further be converted to citrate in the tricarboxylic acid (TCA) cycle during which citrate is shunted out of the mitochondrion to support cytosolic acetyl co‐enzyme A (AcCoA) levels.…”

Biological roles and potential applications of immune cell‐derived extracellular vesicles

“…After entry into the target cell cytosol, granzyme B activates initiator caspases (such as caspases‐8, ‐9, ‐10) and then promotes apoptosis through two main pathways. First, granzyme B can directly process effector caspases‐3 and ‐7 to promote apoptosis [139,140,142,143]. Second, granzyme B‐mediated proteolysis of the BH3‐only protein BID exposes a myristolyation signal that induces the oligomerization of BAX and/or BAK in the mitochondrial outer membrane.…”

“…DISC activates the initiator caspases (e.g. caspase‐8, ‐10) and subsequently can induce the death signals in two directions: (a) direct activation of effector caspases‐9, ‐3 and ‐7, without the involvement of mitochondria; (b) formation of apoptosomes (mitochondrial proteins, dATP and Apaf‐1), leading to activation of effector caspases‐3 and ‐7 [143], consequently, dismantling the target cells.…”

Humanized Mice as an Effective Evaluation System for Peptide Vaccines and Immune Checkpoint Inhibitors

“…Viral infections do not always enhance PD-L1 expression, because similar PD-L1 levels are detected in individuals not infected with viruses [61][62][63][64]. Increased PD-L1 levels are related to specific viruses, such as the following: Epstein-Barr virus (EBV) [65][66][67][68], hepatitis B virus (HBV) [69][70][71], hepatitis C virus (HCV) [72][73][74][75], human immunodeficiency virus (HIV) [63,[76][77][78][79], human papilloma virus (HPV) [68,[80][81][82][83], Merkel cell polyomavirus (MCPyV) [84], bovine leukemia virus (BLV) [85], and Kaposi sarcoma-associated herpes virus (KSHV) [86]. The pathobiological mechanisms by which viruses trigger the expression of PD-L1 have been elucidated.…”