Research Article: Interferon-beta expression and type I interferon receptor signaling of hepatocytes prevent hepatic necrosis and virus dissemination in Coxsackievirus B3-infected mice

Date Published: August 3, 2018

Publisher: Public Library of Science

Author(s): Wolfgang Koestner, Julia Spanier, Tanja Klause, Pia-K. Tegtmeyer, Jennifer Becker, Vanessa Herder, Katharina Borst, Daniel Todt, Stefan Lienenklaus, Ingo Gerhauser, Claudia N. Detje, Robert Geffers, Martijn A. Langereis, Florian W. R. Vondran, Qinggong Yuan, Frank J. M. van Kuppeveld, Michael Ott, Peter Staeheli, Eike Steinmann, Wolfgang Baumgärtner, Frank Wacker, Ulrich Kalinke, Stanley M. Lemon.


During Coxsackievirus B3 (CVB3) infection hepatitis is a potentially life threatening complication, particularly in newborns. Studies with type I interferon (IFN-I) receptor (IFNAR)-deficient mice revealed a key role of the IFN-I axis in the protection against CVB3 infection, whereas the source of IFN-I and cell types that have to be IFNAR triggered in order to promote survival are still unknown. We found that CVB3 infected IFN-β reporter mice showed effective reporter induction, especially in hepatocytes and only to a minor extent in liver-resident macrophages. Accordingly, upon in vitro CVB3 infection of primary hepatocytes from murine or human origin abundant IFN-β responses were induced. To identify sites of IFNAR-triggering we performed experiments with Mx reporter mice, which upon CVB3 infection showed massive luciferase induction in the liver. Immunohistological studies revealed that during CVB3 infection MX1 expression of hepatocytes was induced primarily by IFNAR-, and not by IFN-III receptor (IFNLR)-triggering. CVB3 infection studies with primary human hepatocytes, in which either the IFN-I or the IFN-III axis was inhibited, also indicated that primarily IFNAR-, and to a lesser extent IFNLR-triggering was needed for ISG induction. Interestingly, CVB3 infected mice with a hepatocyte-specific IFNAR ablation showed severe liver cell necrosis and ubiquitous viral dissemination that resulted in lethal disease, as similarly detected in classical IFNAR-/- mice. In conclusion, we found that during CVB3 infection hepatocytes are major IFN-I producers and that the liver is also the organ that shows strong IFNAR-triggering. Importantly, hepatocytes need to be IFNAR-triggered in order to prevent virus dissemination and to assure survival. These data are compatible with the hypothesis that during CVB3 infection hepatocytes serve as important IFN-I producers and sensors not only in the murine, but also in the human system.

Partial Text

Coxsackievirus B3 (CVB3) is a single-stranded RNA virus that belongs to the genus of human Enterovirus [1]. CVB3 infections are very common, especially in children and neonates, and mostly cause only mild disease. However, occasionally also severe disease with fatal outcome, such as myocarditis, meningoencephalitis, or hepatitis, can occur. In adults, only few cases of CVB3-induced hepatic necrosis have been reported [2, 3], whereas in neonates CVB3-induced hepatitis is more frequent [4]. Especially in Taiwan several outbreaks of CVB3 infections with predominant hepatitis and occasionally lethal outcome of up to 30% have been reported [5–7]. Recently, the analysis of murine neonates revealed that increased susceptibility to CVB3 correlated with high expression of the Coxsackievirus-adenovirus receptor in the liver, which decreased with age [8]. Moreover, lower expression of IFN-α during the first year of human life might contribute to increased infection susceptibility in infants [9].

Several studies demonstrated a predominant role of IFN-I and IFNAR signaling in the pathogenesis of CVB3-induced hepatitis [16]. However, the cellular subsets that contribute to these effects are not known. Therefore, in the current study we aimed at identifying cell subsets that mount protective IFN-I responses and show IFNAR triggering upon CVB3 infection. In CVB3-infected mice, we found abundant IFN-β, IFN-α, and IFN-λ responses in the liver, of which IFN-β was produced primarily by hepatocytes. Moreover, hepatocytes showed exclusively IFNAR- and not IFNLR-dependent ISG induction in mice. Interestingly, IFNAR triggering of hepatocytes prevented severe liver cell necrosis and dissemination of the virus to other organs. CVB3 infection of human hepatocytes induced IFN-β as well as IFN-λ responses, whereas ISG expression was mainly triggered by IFN-β. These results indicate that during CVB3 infection similar mechanisms apply in the murine and the human system.




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