Roles of Macrophages in Measles Virus Infection of Genetically Modified Mice (original) (raw)
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Journal of Virology, 2000
The dissemination of the Edmonston measles virus (Ed-MV) vaccine strain was studied with genetically modified mice defective for the alpha/beta interferon receptor and expressing human CD46 with human-like tissue specificity and efficiency. A few days after intranasal infection, macrophages expressing Ed-MV RNA were detected in the lungs, in draining lymph nodes, and in the thymus. In lymph nodes, large syncytia which stained positive for viral RNA and for macrophage surface marker proteins were found and apoptotic cell death was monitored. In the thymus, smaller syncytia which stained positive for macrophage and dendritic cell markers were detected. Thus, macrophages appear to be the main vectors for dissemination of MV infection in these mice; human macrophages may have a similar function in the natural host. We then compared the pathogenicities of two recombinant viruses lacking the C or V nonstructural proteins to that of the parental strain, Ed-MV. These viruses were less effective in spreading through the lymphatic system and, unlike Ed-MV, were not detected in the liver. After intracerebral inoculation the recombinant viruses caused lethal disease less often than Ed-MV and induced distinctive patterns of gliosis and inflammation. Ed-MV was reisolated from brain tissue, but its derivatives were not. C-and V-defective viruses should be considered as more-attenuated MV vaccine candidates.
Measles virus replication in lymphatic cells and organs of CD150 (SLAM) transgenic mice
Proceedings of the National Academy of Sciences, 2005
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.
Measles virus spread and pathogenesis in genetically modified mice
Journal of virology, 1998
Attenuated Edmonston measles virus (MV-Edm) is not pathogenic in standard mice. We show here that MV-Edm inoculated via the natural respiratory route has a limited propagation in the lungs of mice with a targeted mutation inactivating the alpha/beta interferon receptor. A high dose of MV-Edm administered intracerebrally is lethal for about half of these mice. To study the consequences of the availability of a high-affinity receptor for MV propagation, we generated alpha/beta interferon-defective mice expressing human CD46 with human-like tissue specificity. Intranasal infection of these mice with MV-Edm resulted in enhanced spread to the lungs and more prominent inflammatory response. Virus replication was also detected in peripheral blood mononuclear cells, the spleen, and the liver. Moreover, intracerebral inoculation of adult animals with low MV-Edm doses caused encephalitis with almost inevitably lethal outcome. We conclude that in mice alpha/beta interferon controls MV infectio...
Differential permissivity to measles virus infection of human and CD46-transgenic murine lymphocytes
Journal of General Virology, 2001
Analysis of measles virus (MV) pathogenesis requires the development of an adequate small animal model of MV infection. In this study, permissivity to MV infection was compared in human and transgenic murine T lymphocytes, expressing different levels of the human MV receptor, CD46. Whereas MV binding and entry correlated with CD46 expression, higher levels of MV replication were always observed in human T lymphocytes. This suggests the existence of intracellular factors, acting posterior to virus entry, that could limit MV replication in murine lymphocytes and should be considered when creating new animal models of MV infection.
Biochemical and Biophysical Research Communications, 1998
pression of production of interleukein-12 (IL-12), a mo-Measles virus (MV) can infect mouse macrophages to nokine essential for activating T helper 1 and natural cause a prolonged non-cytopathic infection that prokiller cells (8, 18). Ligation of macrophage receptors duces low levels of infectious virus for days. We have including the receptor for MV reproduces the suppresgenerated RAW264.7 mouse macrophages expressing husion on IL-12 production (18, 33). These observations man CD46, a cell surface complement regulatory protein suggest that interactions between MV and cellular rethat serves as a receptor for laboratory-adapted strains ceptors play a role in MV-induced immunosuppression. of MV. Laboratory-adapted MV strains efficiently enter The human cell receptor for laboratory-adapted the CD46-positive mouse macrophages to cause a cytostrains of MV is membrane cofactor protein (CD46), a pathic infection with extensive multinucleated cells and transmembrane complement regulatory protein widely pseudopodia-like extensions. However, MV infection of expressed on nucleated human cells (5, 25). CD46 normouse macrophages through CD46 is self-limiting. Both mally protects autologous cells from complement lysis viral protein synthesis and infectious virus production by binding and promoting degradation of C3b and C4b are abruptly terminated after the second day of infecin the complement activation cascades (21, 32). The tion. This novel virus-cell interaction is seen only in extracellular portion of CD46 contains binding sites mouse macrophages but not in mouse or hamster fibroblasts expressing human CD46. The possible role of CD46 for C3b, C4b as well as MV (17, 22). The intracellular in macrophage antiviral response restricting MV repli-portion of CD46 consists of a common juxtamembrane cation is discussed. ᭧ 1998 Academic Press region followed by alternative distal cytoplasmic sequences called Cyt1 and Cyt2 that are generated by differential mRNA splicing (26, 27). We have previously shown that the CD46 cytoplasmic domains can Monocytes and macrophages are major targets for the interact with cellular kinases in mouse macrophage measles virus (MV) in measles patients (6). These cells lysates (37). Tyrosine-containing sequences in these cyserve important roles in innate immune responses. Along toplasmic domains apparently influence surface exwith dendritic cells, macrophages also process antigens pression of CD46 as well as interaction with macroand instruct lymphocytes to mount adaptive immune rephage kinases in vitro (37, 39). We have generated sponses (7, 23). Recent evidence indicates that MV intermouse macrophages (RAW264.7) expressing human feres with the communication of macrophages and den-CD46 with a Cyt1 or Cyt2 cytoplasmic domain. Here, dritic cells with lymphocytes, thus disrupting a critical we demonstrate that MV can infect mouse macrocross talk between the innate and adaptive arms of the phages through CD46-independent or CD46-dependent immune system (8, 11, 18, 31). Immune suppression leadpathways with different outcomes. MV infection of ing to secondary infections is believed to be a major cause mouse macrophages without CD46 causes a prolonged of death in measles patients (3, 10, 24). non-cytopathic infection. By contrast, MV infection of MV-infected cells can suppress proliferation of uninmouse macrophages through CD46 leads to a cytofected peripheral blood mononuclear cells (PBMC) pathic but self-limiting infection, due to drastic supthrough cell contact (28, 29). MV infection of monopression of viral protein synthesis and infectious virus cytes, macrophages, and dendritic cells leads to supproduction after the second day of infection. MATERIALS AND METHODS Cells and viruses. Mouse macrophages expressing human CD46
Journal of Virology, 2007
The human signaling lymphocyte activation molecule (SLAM, also called CD150), a regulator of antigendriven T-cell responses and macrophage functions, acts as a cellular receptor for measles virus (MV), and its V domain is necessary and sufficient for receptor function. We report here the generation of SLAM knockin mice in which the V domain of mouse SLAM was replaced by that of human SLAM. The chimeric SLAM had an expected distribution and normal function in the knockin mice. Splenocytes from the SLAM knockin mice permitted the in vitro growth of a virulent MV strain but not that of the Edmonston vaccine strain.
Journal of Experimental Medicine, 1997
Measles causes a profound immune suppression which is responsible for the high morbidity and mortality induced by secondary infections. Dendritic cells (DC) are professional antigen-presenting cells required for initiation of primary immune responses. To determine whether infection of DC by measles virus (MV) may play a role in virus-induced suppression of cell-mediated immunity, we examined the ability of CD1a ϩ DC derived from cord blood CD34 ϩ progenitors and Langerhans cells isolated from human epidermis to support MV replication.
Journal of …, 2011
Measles virus (MV) vaccine effectively protects seronegative individuals against infection. However, inhibition of vaccine-induced seroconversion by maternal antibodies after vaccination remains a problem, as it leaves infants susceptible to MV infection. In cotton rats, passive transfer of MV-specific IgG mimics maternal antibodies and inhibits vaccine-induced seroconversion. Here, we report that immunization in the presence of passively transferred IgG inhibits the secretion of neutralizing antibodies but not the generation of MV-specific B cells. This finding suggested that MV-specific B cells require an additional stimulus to mature into antibody-secreting plasma cells. In order to provide such a stimulus, we generated a recombinant Newcastle disease virus (NDV) expressing the MV hemagglutinin (NDV-H). In contrast to MV, NDV-H induced high levels of type I interferon in plasmacytoid dendritic cells and in lung tissue. In cotton rats immunized with NDV-H, neutralizing antibodies were also generated in the presence of passively transferred antibodies. In the latter case, however, the level and kinetics of antibody generation were reduced. In vitro, alpha interferon stimulated the activation of MV-specific B cells from MV-immune spleen cells. NDV infection (which induces alpha interferon) had the same effect, and stimulation could be abrogated by antibodies neutralizing alpha interferon, but not interleukin 6 (IL-6). In vivo, coapplication of UV-inactivated MV with NDV led to increased MV-specific antibody production in the presence and absence of passively transferred antibodies. These data indicate that MV-specific B cells are being generated after immunization in the presence of maternal antibodies and that the provision of alpha interferon as an additional signal leads to antibody secretion.
Human lymphocyte cytotoxicity against mumps virus-infected target cells. Requirement for non-T cells
The Journal of Immunology, 1975
Subpopulations of human lymphocytes were tested for their capacity to kill mumps virus-infected target cells in a 51chromium release assay. Using two different cell fractionation techniques, lymphocytes were fractionated into T cell-enriched (primarily T cells) and T cell-depleted (primarily B cells) subpopulations. Filtration of lymphocytes through columns coated with human immunoglobulin and rabbit anti-human-immunoglobulin (Ig-anti-Ig) rendered the resulting T-cell preparation reactive as effector cells against target cells carrying mumps virus antigens. In the second technique, lymphocytes were fractionated by centrifugation into two fractions according to their ability to form spontaneous ros~ettes with sheep erythrocytes (E). The E-rosette-forming population (primarily T cells) was shown to lack cytotoxic activity against mumps virus-infected target cells. This activity was present in the nonrosetting population. The results suggest that the effector cells involved in this cytotoxic system are of a non-T variety. Protection and recovery from viral infection is assumed to depend on several immunological mechanisms, involving a complex interplay between different cell types, antibodies, and complement components (1, 2). The relative importance of any single mechanism is difficult to assess and probably varies during different phases of the infection (1, 2). The necessity of an intact cellular response is, however, clearly demonstrated by the severe viral infections found in children with defective cell-mediated immunity (1). In vitro studies in mice have shown immune lymphocytes to be capable of lysing virus-infected target cells (3-5). Recently, more detailed characterizations of cytotoxic effector cells have been made in mice infected with lymphocytic choriomeningitis (LCM) 3 virus (5, 6), Sindbis virus (7), and ectromelia virus (8). In all instances it was shown that T cells were responsible for