IRF3-mediated pathogenicity in a murine model of human hepatitis A.
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
25
07
2021
accepted:
17
09
2021
revised:
12
10
2021
pubmed:
1
10
2021
medline:
25
11
2021
entrez:
30
9
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34591933
doi: 10.1371/journal.ppat.1009960
pii: PPATHOGENS-D-21-01552
pmc: PMC8509855
doi:
Substances chimiques
Interferon Regulatory Factor-3
0
Irf3 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009960Subventions
Organisme : NIAID NIH HHS
ID : R01 AI143894
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI103083
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016086
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI138337
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI131685
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA027456
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI150095
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA068782
Pays : United States
Déclaration de conflit d'intérêts
The authors declare that no competing interests exist.
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