Hepatocytes engulf and rapidly silence coxsackievirus, protecting the host against systemic viral pathology

Abstract

Abstract Liver has many biological functions, including (but by no means limited to) the removal, from the blood, of various pathogenic organisms. This phenomenon has been best-studied for bacteria, and is thought to be mainly mediated by Kupffer cells and sinusoidal endothelial cells; these cells, too, have been implicated in clearance of some viruses. However, to date, hepatocytes - which constitute ~90% of the liver’s biomass - have been thought to be bystanders in this activity. Herein we show that hepatocytes directly protect the host against type B coxsackieviruses (CVBs) by engulfing, then rapidly silencing, these pathogens. Novel CARHEP KO mice, which carry a hepatocyte-specific deletion of the coxsackievirus-adenovirus receptor (CAR), are unable to capture circulating CVB3, leading to a dramatic early rise in blood-borne virus, followed by markedly-elevated morbidity, mortality, and increased viral load. The enhanced pathogenicity in CARHEP KO mice occurs despite the production of abundant type I interferon (T1IFN), which is derived from plasmacytoid dendritic cells (pDCs). In addition, we show that in genetically-intact (wild type; WT) mice, the rapid hepatocyte silencing of trapped virus is dependent on IRF1; in its absence, CVB3 undergoes efficient productive replication in hepatocytes and, as a result, virus titers in all tested extrahepatic tissues are several logs higher than in WT animals. In summary, hepatocytes act as a trap for CVBs, internalizing the viruses and reducing systemic viral burden, and thereby protecting the host from systemic disease.