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 PLOS Pathogens | https://doi.org/10.1371/journal.ppat.1007235 August 3, 2018 1 / 23 OPEN ACCESS Citation: Koestner W, Spanier J, Klause T, Tegtmeyer P-K, Becker J, Herder V, et al. (2018) Interferon-beta expression and type I interferon receptor signaling of hepatocytes prevent hepatic necrosis and virus dissemination in Coxsackievirus B3-infected mice. PLoS Pathog 14(8): e1007235. Inflammation" (to UK). The funders had no role in 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. Author summary CVB3 belongs to human enteroviruses and is transmitted through the fecal-oral route. Infections with CVB3 are mostly unnoticed or cause flu-like symptoms, however, they can also cause severe disease, such as myocarditis, pancreatitis, and hepatitis. Although CVB3 does not efficiently trigger plasmacytoid dendritic cells, which are the main IFN-I producers in many other virus infections, IFNAR signaling plays a crucial role in CVB3 control. Therefore, we investigated which cells are stimulated to produce IFN-I following CVB3 infection and which cell types have to be IFNAR-triggered in order to confer antiviral protection. We found that upon CVB3 infection IFN-β was mainly expressed within the liver, especially by hepatocytes and not by liver resident macrophages. This was corroborated by in vitro CVB3 infection experiments with primary murine and human hepatocytes. Interestingly, IFNAR signaling of hepatocytes was required to control the virus. Collectively, our data indicate that hepatocytes, and not immune cells, are the key innate effector cells that are relevant for the control of CVB3 infection. Hepatocytes are key effector cells in anti-Coxsackievirus immunity PLOS Pathogens | https://doi.org/10.
Output: Interferon-beta expression and type I interferon receptor signaling of hepatocytes prevent hepatic necrosis and virus dissemination in Coxsackievirus B3-infected mice