A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses.

Abstract

To examine the in vivo role(s) of type I interferons (IFNs) and to determine the role of a component of the type I IFN receptor (IFNAR1) in mediating responses to these IFNs, we generated mice with a null mutation (-/-) in the IFNAR1 gene. Despite compelling evidence for modulation of cell proliferation and differentiation by type I IFNs, there were no gross signs of abnormal fetal development or morphological changes in adult IFNAR1 -/-mice. However, abnormalities of hemopoietic cells were detected in IFNAR1 -/-mice. Elevated levels of myeloid lineage cells were detected in peripheral blood and bone marrow by staining with Mac-i and Gr-1 antibodies. Furthermore, bone marrow macrophages from IFNAR1 -/-mice showed abnormal responses to colony-stimulating factor 1 and lipopolysaccharide. IFNAR1 -/-mice were highly susceptible to viral infection: viral titers were undetected 24 hr after infection of IFNAR1 +/+ mice but were extremely high in organs of IFNAR1-/-mice, demonstrating that the type I IFN system is a major acute antiviral defence. In cell lines derived from IFNAR1 -/-mice, there was no signaling in response to IFN-a or -,B as measured by induction of 2'-5' oligoadenylate synthetase, antiviral, or antiproliferative responses. Importantly, these studies demonstrate that type I IFNs function in the development and responses of myeloid lineage cells, particularly macrophages, and that the IFNAR1 receptor component is essential for antiproliferative and antiviral responses to IFN-a and -1.

Type I interferons suppress CD4+ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection

“…C57BL/6 IFN-aR1 À/À mice [50,51] and congenic (CD45.1 1 ) OTI mice [52] were maintained in-house. BM chimeric mice were prepared by lethally irradiating recipient mice with 11Gy ( 137 Cs source), intravenously (i.v.)…”

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“…The primary defect in Stat1-mutant mice is susceptibility to microbial infections, similar to the combined phenotypes of IFNAR17/7 or IFNAR27/7 and IFNGR17/7 or IFNGR27/7 mice (Huang et al, 1993;Hwang et al, 1995;MuÈ ller et al, 1994). For example, Stat17/7 mice were exquisitely susceptible to vesicular stomatitis virus infection which produced lethal disease with extensive virus replication in mutant animals at challenge doses 10 8 -fold lower than in their wild-type counterparts.…”

Ligand-independent pathway that controls stability of interferon alpha receptor

“…The receptor consists of two subunits IFNAR1 and IFNAR2 (reviewed in [1]). IFNAR1 plays a key role in all aspects of IFNα-mediated effects in vitro and in vivo [2][3][4], and anti-proliferative activity of Type I IFN variants directly correlates with affinity of their binding to IFNAR1 [5].…”