Efficient MHC Class II‐restricted presentation of measles virus to T cells relies on its targeting to its cellular receptor human CD46 and involves an endosomal pathway

Gerlier, Denis

doi:10.1006/cbir.1994.1080

Cited by 12 publications

(7 citation statements)

References 6 publications

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“…In the murine system, chemokine activation requires both CD46 expression on the surface and signaling through TLR9, which suggests that CD46 mediates the capture and internalization of HHV-6A viral particles, allowing access of viral DNA to the endosomal compartment containing TLR9. Indeed, CD46 was shown to efficiently internalize opsonized bacteria (77) and to transport measles virus into the endosome/lysosome compartment for efficient major histocompatibility complex class II-restricted presentation in both human (78) and murine cells (79). Furthermore, our results demonstrate that in addition to the murine TLR9, HHV-6A could stimulate human TLR9, underlining the significance of the murine model for studying this aspect of HHV-6A pathogenesis.…”

Section: Discussionmentioning

confidence: 58%

Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9

Reynaud

Jégou

Welsch

et al. 2014

J Virol

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Human herpesvirus 6 (HHV-6) is widely spread in the human population and has been associated with several neuroinflammatory diseases, including multiple sclerosis. To develop a small-animal model of HHV-6 infection, we analyzed the susceptibility of several lines of transgenic mice expressing human CD46, identified as a receptor for HHV-6. We showed that HHV-6A (GS) infection results in the expression of viral transcripts in primary brain glial cultures from CD46-expressing mice, while HHV-6B (Z29) infection was inefficient. HHV-6A DNA persisted for up to 9 months in the brain of CD46-expressing mice but not in the nontransgenic littermates, whereas HHV-6B DNA levels decreased rapidly after infection in all mice. Persistence in the brain was observed with infectious but not heat-inactivated HHV-6A. Immunohistological studies revealed the presence of infiltrating lymphocytes in periventricular areas of the brain of HHV-6A-infected mice. Furthermore, HHV-6A stimulated the production of a panel of proinflammatory chemokines in primary brain glial cultures, including CCL2, CCL5, and CXCL10, and induced the expression of CCL5 in the brains of HHV-6A-infected mice. HHV-6A-induced production of chemokines in the primary glial cultures was dependent on the stimulation of toll-like receptor 9 (TLR9). Finally, HHV-6A induced signaling through human TLR9 as well, extending observations from the murine model to human infection. Altogether, this study presents a first murine model for HHV-6A-induced brain infection and suggests a role for TLR9 in the HHV-6A-initiated production of proinflammatory chemokines in the brain, opening novel perspectives for the study of virus-associated neuropathology. IMPORTANCEHHV-6 infection has been related to neuroinflammatory diseases; however, the lack of a suitable small-animal infection model has considerably hampered further studies of HHV-6-induced neuropathogenesis. In this study, we have characterized a new model for HHV-6 infection in mice expressing the human CD46 protein. Infection of CD46 transgenic mice with HHV-6A resulted in long-term persistence of viral DNA in the brains of infected animals and was followed by lymphocyte infiltration and upregulation of the CCL5 chemokine in the absence of clinical signs of disease. The secretion of a panel of chemokines was increased after infection in primary murine brain glial cultures, and the HHV-6-induced chemokine expression was inhibited when TLR9 signaling was blocked. These results describe the first murine model for HHV-6A-induced brain infection and suggest the importance of the TLR9 pathway in HHV-6A-initiated neuroinflammation.

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Section: Discussionmentioning

confidence: 58%

Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9

Reynaud

Jégou

Welsch

et al. 2014

J Virol

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“…Thus, at least for the N protein, the source of peptides presented by MHC class II molecules is most likely derived from endocytosed MV particles. Compared with the amount of MV which fuses with the plasma membrane, the amount of endocytosed MV is rather limited (2 to 3% of the total virus captured by the target cells) (11). The sensitivity of the GPI-anchored CD46 molecule to H-induced down-regulation and its ability to mediate MV endocytosis indicate that it is mainly if not solely the four SCR regions of CD46 that are involved in these two processes.…”

Section: Discussionmentioning

confidence: 99%

Glycosyl-phosphatidylinositol-anchored and transmembrane forms of CD46 display similar measles virus receptor properties: virus binding, fusion, and replication; down-regulation by hemagglutinin; and virus uptake and endocytosis for antigen presentation by major histocompatibility complex class II molecules

Varior-Krishnan¹,

Trescol-Biémont²,

Naniche³

et al. 1994

J Virol

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The CD46 molecule is a receptor for measles virus (MV), CD46, which protects autologous cells from complement-mediated damage, exists in several isoforms which are variably expressed in different human tissues. These isoforms differ in their cytoplasmic and transmembrane regions and in a small portion of their proximal extracytoplasmic regions. To examine the role of the cytoplasmic and transmembrane regions of CD46 in MV infection, mouse M12 B cells stably expressing a transmembrane or a chimeric glycosylphosphatidylinositol (GPI)-anchored form of CD46 (CD46-GPI) were used. Both the GPI-anchored and transmembrane CD46 forms were able to mediate MV binding. MV binding mediated by the GPI-anchored form but not that mediated by the transmembrane form was abolished after treatment with phosphatidylinositol phospholipase C. MV infection of both M12.CD46 and M12.CD46-GPI cells but not parental M12 cells resulted in MV replication. Expression of hemagglutinin induced cell surface down-regulation of both CD46 and CD46-GPI. Both M12.CD46 and M12.CD46-GPI cells were able to efficiently capture MV for presentation

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“…A major function of professional antigen presenting cells is the processing of exogenous antigens for presentation on major histocompatibilty complexes (MHCs), and this processing can be affected by complement (44). A large body of work has demonstrated that CD46, like other virus receptors, can quantitatively and qualitatively affect the presentation of antigen on both class I and II and can increase the MHC class II‐restricted presentation of measles hemagglutinin by up to 100 fold (15–17, 45). The role of CD46 in antigen presentation has been best demonstrated by a series of experiments in which the fusion and replication of the measles virus was inactivated, so that receptor binding provided the only remaining route into the cell (15–17, 45).…”

Section: Cd46 In the Regulation Of Cellular Immune Functionmentioning

confidence: 99%

CD46: A complement regulator and pathogen receptor that mediates links between innate and acquired immune function

Russell

2004

Tissue Antigens

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In the last 10 years, the human cell-surface molecule, CD46, has evolved from 'just another complement regulator' to a receptor for a striking array of pathogens. CD46 not only protects cells from complement-mediated attack and facilitates infection by a large number of pathogens, but also exerts complex effects on cellular immune function. It has been proposed that CD46 links innate and adaptive immunity by affecting cellular immune function in response to complement binding, and the role of CD46 in the pathogenesis of many infectious pathogens is now the subject of intense investigation. So far, the flood of information that implicates CD46 in modifying a host response to measles, Neisseria, human herpes virus 6, and pathogens that activate complement has not yet been matched with a comprehensive understanding of the molecular mechanisms by which CD46 affects immune function. This review summarizes the evidence that points to a significant role for CD46 in a range of pathological processes and describes how CD46 might exert its effects by altering signal transduction and antigen presentation pathways.

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Efficient MHC Class II‐restricted presentation of measles virus to T cells relies on its targeting to its cellular receptor human CD46 and involves an endosomal pathway

Cited by 12 publications

References 6 publications

Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9

Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9

CD46: A complement regulator and pathogen receptor that mediates links between innate and acquired immune function

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