Bile Acids Act as Soluble Host Restriction Factors Limiting Cytomegalovirus Replication in Hepatocytes

Abstract

The liver constitutes a prime site of cytomegalovirus (CMV) replication and latency. Hepatocytes produce, secrete, and recycle a chemically diverse set of bile acids, with the result that interactions between bile acids and cytomegalovirus inevitably occur. Here we determined the impact of naturally occurring bile acids on mouse CMV (MCMV) replication. In primary mouse hepatocytes, physiological concentrations of taurochenodeoxycholic acid (TCDC), glycochenodeoxycholic acid, and to a lesser extent taurocholic acid significantly reduced MCMV-induced gene expression and diminished the generation of virus progeny, while several other bile acids did not exert antiviral effects. The anticytomegalovirus activity required active import of bile acids via the sodium-taurocholate-cotransporting polypeptide (NTCP) and was consistently observed in hepatocytes but not in fibroblasts. Under conditions in which alpha interferon (IFN-␣) lacks antiviral activity, physiological TCDC concentrations were similarly effective as IFN-␥. A detailed investigation of distinct steps of the viral life cycle revealed that TCDC deregulates viral transcription and diminishes global translation in infected cells. IMPORTANCECytomegaloviruses are members of the Betaherpesvirinae subfamily. Primary infection leads to latency, from which cytomegaloviruses can reactivate under immunocompromised conditions and cause severe disease manifestations, including hepatitis. The present study describes an unanticipated antiviral activity of conjugated bile acids on MCMV replication in hepatocytes. Bile acids negatively influence viral transcription and exhibit a global effect on translation. Our data identify bile acids as site-specific soluble host restriction factors against MCMV, which may allow rational design of anticytomegalovirus drugs using bile acids as lead compounds. C ytomegaloviruses (CMV) are members of the Betaherpesvirinae subfamily and persist for life in infected individuals during alternating phases of latency and productive reactivation. Seroprevalence studies indicate that the large majority of the global human population is currently infected with human cytomegalovirus (HCMV) (human herpesvirus 5 [HHV-5]; taxonomy ID 10359). Although HCMV-related fatalities in apparently healthy individuals sporadically occur (1, 2), HCMV replication usually remains subclinical. This drastically changes under immunocompromising conditions, where untreated CMV infections often cause overt disease, including hepatitis (3) and dysfunction, bleeding, ulceration, and perforation of organs of the upper as well as lower gastrointestinal tract (4). HCMV hepatitis is particularly common in liver transplant recipients and is associated with organ dysfunction and graft failure (5-9).The species specificity of CMV precludes meaningful in vivo experimentation with HCMV in small animal models. Therefore, the homologous mouse CMV (MCMV) (Murid herpesvirus 1, taxonomy ID 10366), which infects Mus musculus (taxonomy ID 10090) as its natural host, has been estab...

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“…Bile is a type of secretion produced naturally by mammals and other vertebrates ( Table 1 ) [ 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. This fluid is rich in bile acids, which are aliphatic molecules that are conjugated in the liver with taurine or glycine.…”

Taurocholic acid inhibits the response to interferon-α therapy in patients with HBeAg-positive chronic hepatitis B by impairing CD8+ T and NK cell function

“…BAs facilitate digestion and absorption of lipids, regulate the metabolism of cholesterol, and promote bile secretion. 12 BAs have been reported to regulate various cellular functions, such as the inhibition of NLRP3 inflammasome activation, 13 enhancement of antiviral innate immunity, 14 regulation of viral replication, 15,16 and immunomodulatory effects of immune cells. [17][18][19] Notably, BAs are signaling molecules that activate nuclear receptors to promote HBV gene expression, inhibit IFN-α activity in cell and animal models, [20][21][22] and suppress human peripheral blood mononuclear cell (PBMC) activity in vitro.…”

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“…We hypothesized that bacterially regulated bile acids (i.e. unconjugated 1° and 2° bile acids) could be key players since they interact with bile acid receptors on many cell types to regulate metabolic and immune functions (30,31) and they have established proviral and antiviral functions (32,33). In fact, they have been shown to regulate norovirus infections in vitro and in vivo (34,35).…”