Abstract
Due to the scarcity of immunocompetent animal models for chronic viral hepatitis, little is known about the role of the innate intrahepatic immune system during viral replication in the liver. These insights are however fundamental for the understanding of the inappropriate adaptive immune responses during the chronic phase of the infection. We apply the Lymphocytic Choriomenigitis Virus (LCMV) clone 13 mouse model to examine chronic virus-host interactions of Kupffer cells (KC) and infiltrating monocytes (IM) in an infected liver. LCMV infection induced overt clinical hepatitis, with rise in ALT and serum cytokines, and increased intrahepatic F4/80 expression. Despite ongoing viral replication, whole liver transcriptome showed baseline expression levels of inflammatory cytokines, interferons, and interferon induced genes during the chronic infection phase. Transcriptome analyses of sorted KC and IMs using NanoString technology revealed two unique phenotypes with only minimal overlap. At the chronic viral infection phase, KC showed no increased transcription of activation markers Cd80 and Cd86, but an increased expression of genes related to antigen presentation, whereas monocytes were more activated and expressed higher levels of Tnf transcripts. Although both KCs and intrahepatic IM share the surface markers F4/80 and CD11b, their transcriptomes point towards distinctive roles during virus-induced chronic hepatitis.
Highlights
Detailed knowledge of intrahepatic immune responses is crucial for a better understanding of the processes underlying immunopathology
Lymphocytic Choriomenigitis Virus (LCMV) clone 13 infection induces evident hepatitis accompanied by changes in F4/80highCD11bint transcribed high amounts of Emr1 (F4/80) expressing cells
Peak of intrahepatic LCMV replication was associated with evident rise of serum ALT, preceded by peak in IFNγ and CXCL1, and coincided with tumor necrosis factor (TNF) and IL-10 levels (Fig 1D)
Summary
Detailed knowledge of intrahepatic immune responses is crucial for a better understanding of the processes underlying immunopathology. Chronic viral hepatitis induced by the Hepatitis B (HBV) and hepatitis C (HCV) virus affects almost 500 million people worldwide and leads to progressive liver fibrosis, decompensated cirrhosis, and hepatocellular carcinoma [1]. Studies of liver residing leukocytes are seldom performed in patients, PLOS ONE | DOI:10.1371/journal.pone.0166094. Role of Myeloid Cells in LCMV-Induced Hepatitis support in the form of salaries for authors FH and SdJ, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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