Measles virus replication in lymphatic cells and organs of CD150 (SLAM) transgenic mice

Abstract

A transgenic mouse containing the complete human SLAM (hSLAM͞CD150) gene, including its endogenous promoter for transcription, was generated by using human genomic DNA cloned into a bacterial artificial chromosome. hSLAM, the primary receptor for measles viruses (MV), was expressed on activated B, T, and dendritic cells with an expression profile equivalent to that of humans. We demonstrated that hSLAM ؉ cells obtained from the transgenic mouse, including activated B, T, and dendritic cells, were susceptible to MV infection in a receptor-dependent manner. Evidence was provided for transient infection in the nasal lymph nodes of hSLAM ؉ mice after intranasal inoculation. Virus was rapidly cleared without signs of secondary replication. To improve the efficiency of MV production, the hSLAM ؉ mice were bred with mice having a Stat1-deficient background. These mice were more susceptible to MV infection and produced more virus particles. After intranasal and intraperitoneal inoculation of these mice with MV, infections of the thymus, spleen, nasal, mesenteric, and leg lymph nodes were detected. Upon necropsy, enlarged lymph nodes and spleen were apparent. Flow cytometric analysis showed that abnormally large numbers of mature neutrophils and natural killer cells caused the splenomegaly. The hSLAM transgenic mouse constitutes an improved rodent model for studying the interaction of MV with immune cells that more accurately reflects the infection pattern found in humans.activated lymphocytes ͉ transgenic mouse ͉ dendritic cells M easles viruses (MV) is one of the most contagious diseases known to man and is a major killer of children in the developing countries of Africa and South America. The high mortality rate associated with MV infection results from increased susceptibility to opportunistic infections. Although MV has been studied extensively, the mechanism for the immunosuppressive effects observed during MV infection remains unclear (1).The development of a mouse model may lead to a better understanding of the immune suppression induced by MV. This was previously attempted by expressing CD46, one of the two receptors for MV, in mice (2-6). However, CD46 receptor, a ubiquitously expressed glycoprotein, is only used by vaccine or laboratory adapted strains of MV. Recently, a second receptor for MV was discovered: CD150 or signaling lymphocytic activation molecule (SLAM) (7-9). SLAM is a host cell receptor for both vaccine and WT MV strains of MV. It is a 70-kDa, type

Dendritic cell subsets involved in type I IFN induction in mouse measles virus infection models

“…Bone marrow-derived DCs (BMDCs) were used to study MV permissiveness of DCs, initially in CD150Tg mice (Ohno et al, 2007, Shingai et al, 2005, Welstead et al, 2005. Studies using BMDCs from CD150Tg mice in combination with Mavs -/-, Irf3 -/-/Irf7 -/-, Ticam1 -/-and Myd88 -/-mice showed that type I IFN expression in BMDCs completely relied on MAVS but not TICAM-1 and MyD88 (Takaki et al, 2014).…”

“…Both attachment and infection of immature DCs with MV are blocked by DC-SIGN inhibitors, suggesting that DC-SIGN is critical for enhancement of CD46/CD150-mediated infection of DCs (de Witte et al, 2006). Human CD150 transgenic (Tg) and CD150 knock-in mice were generated as MV infection models to study receptor tropism and the immune dynamics of MV (Hahm et al, 2003, Hahm et al, 2004, Ohno et al, 2007, Sellin et al, 2006, Shingai et al, 2005, Welstead et al, 2005 and these mice were somehow permissive to MV in vivo. Systemic infection by WT strains of MV in vivo was observed in CD150Tg/Ifnar -/-mice, generated by crossing CD150Tg mice with mice having the disrupted IFN receptor 1 (Ifnar) gene; the other is CD150Tg/Stat1 -/-mice, generated by crossing CD150Tg mice with mice knocked out for the signal transduction and activator of transcription 1 (Stat1) gene, which is a major signaling molecule for the IFN receptor (Shingai et al, 2005, Welstead et al, 2005.…”

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).…”

BAC talk about cell type-specific regulation of human IL-10

“…BAC DNA inserts, typically 100-300 kb, are more likely to contain the complete set of regulatory elements required for tissue-specific and position-independent transgene expression. Examples of transgenic mice with cell-specific expression from BAC transgenes include mice with expression of human coagulation factor V restricted to platelets and liver (12) and mice that have a human-like tissue expression profile of hSLAM, the primary receptor for measles viruses (13). In the article by Ranatunga et al, the hIL-10BAC was faithfully expressed in myeloid cells, rescuing IL-10-deficient mice from lethal endotoxin shock.…”