Temporal and Spatial Resolution of Type I and III Interferon ResponsesIn Vivo

Abstract

Although the action of interferons (IFNs) has been extensively studied in vitro, limited information is available on the spatial and temporal activation pattern of IFN-induced genes in vivo. We created BAC transgenic mice expressing firefly luciferase under transcriptional control of the Mx2 gene promoter. Expression of the reporter with regard to onset and kinetics of induction parallels that of Mx2 and is thus a hallmark for the host response. Substantial constitutive expression of the reporter gene was observed in the liver and most other tissues of transgenic mice, whereas this expression was strongly reduced in animals lacking functional type I IFN receptors. As expected, the reporter gene was induced not only in response to type I (␣ and ␤) and type III () IFNs but also in response to a variety of IFN inducers such as double-stranded RNA, lipopolysaccharide (LPS), and viruses. In vivo IFN subtypes show clear differences with respect to their kinetics of action and to their spatial activation pattern: while the type I IFN response was strong in liver, spleen, and kidney, type III IFN reactivity was most prominent in organs with mucosal surfaces. Infection of reporter mice with virus strains that differ in their pathogenicity shows that the IFN response is significantly altered in the strength of IFN action at sites which are not primarily infected as well as by the onset and duration of gene induction.

Contrasted Innate Responses to Two Viruses in Zebrafish: Insights into the Ancestral Repertoire of Vertebrate IFN-Stimulated Genes

“…Interestingly, this pattern matches partially the one of IFN-w1 itself, with a strong expression in the liver (11). Such contrasted patterns were not expected, yet they are reminiscent of studies performed in mice with an MX/luciferase reporter gene (51), where liver was observed to respond much more strongly than other organs to injected IFN or to Thogoto virus infection. Thus, strongly organ-biased expression of ISGs may well be the norm among vertebrates.…”

Preclinical Characterization of GLPG0634, a Selective Inhibitor of JAK1, for the Treatment of Inflammatory Diseases

“…In WBCs, Mx2 mRNA levels are modulated by IFN-a-JAK1/TYK2 signaling (23,24). Rats were dosed orally with GLPG0634 and both basal and ex vivo IFN-a-induced Mx2 mRNA levels were measured.…”

Trace amounts of sporadically reappearing HCV RNA can cause infection

“…First, the fact that HCV persisted in the absence of systemic viremia in both the source patient (8) and the infused chimpanzee in this study suggests that the unusual course of infection is due to the specific viral isolate rather than to host factors. While we excluded IFN resistance as described in a Japanese population due to mutations in the N-terminal NS5A region (18), it is possible that HCV persists in hepatocytes that become refractory to IFN signaling (19,20). Notably, the source patient experienced a very slow second-phase virological response to IFN-based therapy (not shown).…”