Cholestasis induced liver pathology results in dysfunctional immune responses after arenavirus infection

Elisabeth Lang,Jun Huang,Vitaly I Pozdeev,Haifeng C Xu,Dieter Häussinger,Yuan Zhuang,Balamurugan Sundaram,Gereon Poschmann,Aleksandra A Pandyra,Prashant V Shinde,Philipp A Lang,Karl S Lang,Kai Stühler,Verena Keitel

doi:10.1038/s41598-018-30627-y

Abstract

Immune responses are critical for defense against pathogens. However, prolonged viral infection can result in defective T cell immunity, leading to chronic viral infection. We studied immune activation in response to arenavirus infection during cholestasis using bile duct ligation (BDL). We monitored T cell responses, virus load and liver pathology markers after infection with lymphocytic choriomeningitis virus (LCMV). BDL mice failed to induce protective anti-viral immunity against LCMV and consequently exhibited chronic viral infection. BDL mice exhibited reduced anti-viral T cell immunity as well as reduced type 1 interferon production early after LCMV infection. Consistently, the presence of serum from BDL mice reduced the responsiveness of dendritic cell (DC) and T cell cultures when compared to Sham controls. Following fractionation and mass spectrometry analyses of sera, we identified several serum factors to be upregulated following BDL including bilirubin, bile acids, 78 kDa Glucose regulated protein (GRP78) and liver enzymes. Bilirubin and GRP78 were capable of inhibiting DC and T cell activation. In this work, we demonstrate that liver damage mediated by cholestasis results in defective immune induction following arenavirus infection.

Highlights

Failure to process bile acids from the liver by either intrahepatic or extrahepatic mechanisms can lead to acute cholestasis[1]
When mice were infected with the non-cytolytic lymphocytic choriomeningitis virus (LCMV) following bile duct ligation (BDL), increases in liver damage markers were only significant at day 8 post infection (p.i.) relative to the BDL controls (Fig. 1A,B)
Expression levels of collagens in liver tissue from BDL infected animals were similar to BDL controls 20 days after infection (Fig. 1C). α-smooth muscle actin (SMA) protein expression was comparable between BDL treated animals in the presence or absence of LCMV (Fig. 1D,E)

Summary

Introduction

Failure to process bile acids from the liver by either intrahepatic or extrahepatic mechanisms can lead to acute cholestasis[1]. There were higher levels of LCMV in the organs of BDL animals compared to Sham operated controls 8 days following infection (Fig. 1F). LCMV infected cells were found in liver tissue in BDL mice, while no virus replication was observed in liver tissue of control animals (Fig. 1H).

Results

Conclusion