Type-I But Not Type-II Interferon Receptor Knockout Mice Are Susceptible to Biliary Atresia

Abstract

ABSTRACT:The etiology of biliary atresia (BA) is not yet understood, but recent studies have shown inflammation with an upregulated interferon (IFN) activity in the intra-and extrahepatic bile ducts of patients with BA. These findings support an inflammatory/ infectious cause of BA as mimicked in our infective murine model. To study the role of the IFN receptors in our model, we used mice with inactivated INF-alpha/beta receptor A129, with inactivated IFNgamma receptor G129, or inactivation of both interferon receptors AG129 as well as the wild type controls W129. Mice were infected with rotavirus within 48h of birth and 7 d postpartum. The incidence of BA in each group was determined during a 3 wk period. In the second week the virus load was measured. BA incidence was 76% in A129 and 67% in AG129 animals, whereas in the G129 group only 33% of the pups developed BA. The wild type presented with a BA-incidence of 15%, while 7 d old mice failed to develop BA. There was no significant difference in the virus load of the livers between the groups independent of clinical symptoms. In conclusion, inactivation of type I INF-receptor significantly increases the incidence of BA following postpartal rotavirus infection. This effect is independent of the presence of type II-INF-receptors. Thus, in our model a type I IFN-linked deregulation of the innate immune system appears to be crucial for the induction of biliary atresia.

Role of Interferon in Homologous and Heterologous Rotavirus Infection in the Intestines and Extraintestinal Organs of Suckling Mice

“…These findings support the conclusion that the STAT1-dependent IFN signaling responses are critical for controlling systemic replication of the heterologous simian RRV strain. In addition, these findings confirmed previous reports that IFN-␣/␤ is more important than IFN-␥ in clearing RRV systemic infection (36). However, in the present study type I and II IFNs appeared to be functioning collaboratively in restricting systemic replication and disease, since knockout of either the IFN-␣/␤ or IFN-␥ receptor alone did not result in the full-blown lethal disease syndrome.…”

Aetiology of biliary atresia: what is actually known?

“…Interferons seem to play a crucial role in this model, as Mx protein (an IFN type I specific indicator) persists in hepatocytes, bile ducts and intrahepatic endothelial cells of cholestatic mice beyond the second week after RRV infection [107,108]. In other studies, for instance with IFN-receptor knock-out mice, it can be shown that IFN type II attenuates the tropism of lymphocytes to bile ducts and is somehow imperative to the development of BA [99,109].…”

A Non-Mouse-Adapted Enterovirus 71 (EV71) Strain Exhibits Neurotropism, Causing Neurological Manifestations in a Novel Mouse Model of EV71 Infection

“…Without a functional interferon system, AG129 mice support both the spread from the primary infection site and the persistence in vivo of a number of viruses, including dengue virus (29), Sindbis virus (24), and rhesus rotavirus (10). IFNs have also been shown to play an important role in the antiviral defense against EV71 infection.…”