Abstract
Previous research suggests that hepatocytes catabolize chemical toxins but do not remove microbial agents, which are filtered out by other liver cells (Kupffer cells and endothelial cells). Here we show that, contrary to current understanding, hepatocytes trap and rapidly silence type B coxsackieviruses (CVBs). In genetically wildtype mice, this activity causes hepatocyte damage, which is alleviated in mice carrying a hepatocyte-specific deletion of the coxsackievirus-adenovirus receptor. However, in these mutant mice, there is a dramatic early rise in blood-borne virus, followed by accelerated systemic disease and increased mortality. Thus, wild type hepatocytes act similarly to a sponge for CVBs, protecting against systemic illness at the expense of their own survival. We speculate that hepatocytes may play a similar role in other viral infections as well, thereby explaining why hepatocytes have evolved their remarkable regenerative capacity. Our data also suggest that, in addition to their many other functions, hepatocytes might be considered an integral part of the innate immune system.
Highlights
Previous research suggests that hepatocytes catabolize chemical toxins but do not remove microbial agents, which are filtered out by other liver cells (Kupffer cells and endothelial cells)
coxsackievirus-adenovirus receptor (CAR) protein was expressed at high levels in the hearts of both wildtype (WT) and CARHEPKO mice, and was abundant in the WT liver, but was barely detectable in the CARHEPKO liver (Fig. 1c)
Given the established importance of Kupffer cells in clearing certain microbes, we considered it important to confirm that these cells maintained their normal level of CAR expression in the CARHEPKO mice
Summary
Previous research suggests that hepatocytes catabolize chemical toxins but do not remove microbial agents, which are filtered out by other liver cells (Kupffer cells and endothelial cells). This activity causes hepatocyte damage, which is alleviated in mice carrying a hepatocyte-specific deletion of the coxsackievirus-adenovirus receptor. In these mutant mice, there is a dramatic early rise in blood-borne virus, followed by accelerated systemic disease and increased mortality. We have generated mice carrying a hepatocyte-specific deletion of the coxsackievirus-adenovirus receptor (CARHEPKO mice), and have used them to demonstrate that WT hepatocytes act as a virus trap, thereby regulating CVB3-related mortality, morbidity, and systemic pathology, but at the cost of their own wellbeing. We suggest that hepatocytes may internalize and silence a large variety of different viruses, diminishing pathogen burden and protecting against disease, and that this activity might be considered an integral component of the innate antiviral immune response
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