IRF3-mediated pathogenicity in a murine model of human hepatitis A

Abstract

HAV-infected Ifnar1-/- mice recapitulate many of the cardinal features of hepatitis A in humans, including serum alanine aminotransferase (ALT) elevation, hepatocellular apoptosis, and liver inflammation. Previous studies implicate MAVS-IRF3 signaling in pathogenesis, but leave unresolved the role of IRF3-mediated transcription versus the non-transcriptional, pro-apoptotic activity of ubiquitylated IRF3. Here, we compare the intrahepatic transcriptomes of infected versus naïve Mavs-/- and Ifnar1-/- mice using high-throughput sequencing, and identify IRF3-mediated transcriptional responses associated with hepatocyte apoptosis and liver inflammation. Infection was transcriptionally silent in Mavs-/- mice, in which HAV replicates robustly within the liver without inducing inflammation or hepatocellular apoptosis. By contrast, infection resulted in the upregulation of hundreds of genes in Ifnar1-/- mice that develop acute hepatitis closely modeling human disease. Upregulated genes included pattern recognition receptors, interferons, chemokines, cytokines and other interferon-stimulated genes. Compared with Ifnar1-/- mice, HAV-induced inflammation was markedly attenuated and there were few apoptotic hepatocytes in livers of infected Irf3S1/S1Ifnar1-/- mice in which IRF3 is transcriptionally-inactive due to alanine substitutions at Ser-388 and Ser-390. Although transcriptome profiling revealed remarkably similar sets of genes induced in Irf3S1/S1Ifnar1-/- and Ifnar1-/- mice, a subset of genes was differentially expressed in relation to the severity of the liver injury. Prominent among these were both type 1 and type III interferons and interferon-responsive genes associated previously with apoptosis, including multiple members of the ISG12 and 2’-5’ oligoadenylate synthetase families. Ifnl3 and Ifnl2 transcript abundance correlated strongly with disease severity, but mice with dual type 1 and type III interferon receptor deficiency remained fully susceptible to liver injury. Collectively, our data show that IRF3-mediated transcription is required for HAV-induced liver injury in mice and identify key IRF3-responsive genes associated with pathogenicity, providing a clear distinction from the transcription-independent role of IRF3 in liver injury following binge exposure to alcohol.

The infectivity and pathogenicity of hepatitis A virus live-attenuated vaccine strain H2 in type I interferon receptor-deficient mice

“…It seems that Ifnar −/− mice with 129Sv/Ev or C57BL/6 genetic backgrounds are different, which possibly shows different immunopathology following viral infection. In addition, liver injury is closely linked to the replicative capacity of the virus in the liver ( Sun et al., 2021 ). Moreover, it has been reported that the 3ABC protein encoded by HAV has host-specific cleavage activity for MAVS and cannot degrade the MAVS protein of mice, thus leading to liver injury.…”

GepLiver: an integrative liver expression atlas spanning developmental stages and liver disease phases

“… 78 PolyA Paired GepLiver-bulk-43 GSE166353 Sun, L. et al . 79 rRNA-d Paired GepLiver-bulk-44 GSE48052 Lee, S. M. et al . 80 PolyA Single GepLiver-bulk-45 GSE95424 Kan, F. et al .…”

Recent advances in hepatitis A virus research and clinical practice guidelines for hepatitis A virus infection in Japan

“…21,23,24,227 Interferon and cytokine signaling play a role in inhibition of HAV replication. 211,216,[228][229][230][231][232] Ultrastructural alterations were observed in HAV-infected cells, such as large polyribosomes, swelling of the perinuclear space and the endoplasmic reticulum, and dilatation of Golgi cisternae. 233 Glucose-regulated protein 78, which is a chaperone protein and orchestrates the unfolded protein response in the endoplasmic reticulum, is involved in regulation of HAV replication.…”

“…Cleavage of mitochondrial antiviral signaling by HAV 3ABC protease boosts viral replication and promotes disease pathogenesis, and HAV protease inhibitors suppress these reactions, as well as cleaving HAV polyproteins, resulting in inhibition of HAV replication 21,23,24,227 . Interferon and cytokine signaling play a role in inhibition of HAV replication 211,216,228–232 . Ultrastructural alterations were observed in HAV‐infected cells, such as large polyribosomes, swelling of the perinuclear space and the endoplasmic reticulum, and dilatation of Golgi cisternae 233 .…”