Wild-Type Measles Virus Infection in Human CD46/CD150-Transgenic Mice: CD11c-Positive Dendritic Cells Establish Systemic Viral Infection

Abstract

We generated transgenic (TG) mice that constitutively express human CD46 (huCD46) and/or TLR-inducible CD150 (huCD150), which serve as receptors for measles virus (MV). These mice were used to study the spreading and pathogenicity of GFP-expressing or intact laboratory-adapted Edmonston and wild-type Ichinose (IC) strains of MV. Irrespective of the route of administration, neither type of MV was pathogenic to these TG mice. However, in ex vivo, limited replication of IC was observed in the spleen lymphocytes from huCD46/huCD150 TG and huCD150 TG, but not in huCD46 TG and non-TG mice. In huCD150-positive TG mouse cells, CD11c-positive bone marrow-derived myeloid dendritic cells (mDC) participated in MV-mediated type I IFN induction. The level and induction profile of IFN-β was higher in mDC than the profile of IFN-α. Wild-type IC induced markedly high levels of IFN-β compared with Edmonston in mDC, as opposed to human dendritic cells. We then generated huCD46/huCD150 TG mice with type I IFN receptor (IFNAR1)−/− mice. MV-bearing mDCs spreading to draining lymph nodes were clearly observed in these triple mutant mice in vivo by i.p. MV injection. Infectious lymph nodes were also detected in the double TG mice into which MV-infected CD11c-positive mDCs were i.v. transferred. This finding suggests that in the double TG mouse model mDCs once infected facilitate systemic MV spreading and infection, which depend on mDC MV permissiveness determined by the level of type I IFN generated via IFNAR1. Although these results may not simply reflect human MV infection, the huCD150/huCD46 TG mice may serve as a useful model for the analysis of MV-dependent modulation of mDC response.

Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

“…Mice transgenic for the human CD150 with the expression pattern in tissues closely correlating with humans, were generated as described previously 31 , crossed into C57BL/6 background more than 10 generations and maintained in PBES (Plateau de Biologie Experimentale de la Souris) of ENSLyon. About 8-to 12-week-old CD150tg mice or C57Bl/6 mice (Charles River, France) were injected i.p.…”

“…We then analyzed the immunological consequence of MV-H-CD150 interaction in vivo, using mice expressing transgenic human CD150 (CD150tg) in the similar pattern as humans 31 . CD150 was engaged by injecting UV-inactivated vesicular stomatitis virus (UV-VSV), expressing or not MV-H 28 .…”

Expression of the Sendai (murine parainfluenza) virus C protein alleviates restriction of measles virus growth in mouse cells

“…Therefore, it is likely that the SeV C protein To what extent its IFN antagonists V, C, and P proteins can interact with their target protein counterparts in mouse cells remain to be defined. Thus, in addition to cellular receptors, the ability to counteract the host IFN response is an important determinant for the host range of MV (15,(18)(19)(20)23). …”

“…Several transgenic or knock-in mice expressing human SLAM or CD46 have been generated as small animal models for measles (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). To facilitate MV replication, these mice usually have to be made defective in IFN signaling (16,(18)(19)(20) or used when they are newly born (15,17). Similarly, when human SLAM or CD46 is expressed by transfection, rodent cells become susceptible to MV, but do not allow MV growth as efficiently as primate cells (14,26).…”

MAVS-dependent IRF3/7 bypass of interferon β-induction restricts the response to measles infection in CD150Tg mouse bone marrow-derived dendritic cells

“…The dsRNA-sensing system is believed to be essentially the same in the human and mouse, except that the type I IFN basal level is relatively high in the intact mouse (Shingai et al, 2005). We have made mouse models for analysis of immune aberration induced by various virus infections .…”