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      Myeloid Infection Links Epithelial and B Cell Tropisms of Murid Herpesvirus-4

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      PLoS Pathogens

      Public Library of Science

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          Abstract

          Gamma-herpesviruses persist in lymphocytes and cause disease by driving their proliferation. Lymphocyte infection is therefore a key pathogenetic event. Murid Herpesvirus-4 (MuHV-4) is a rhadinovirus that like the related Kaposi's Sarcoma-associated Herpesvirus persists in B cells in vivo yet infects them poorly in vitro. Here we used MuHV-4 to understand how virion tropism sets the path to lymphocyte colonization. Virions that were highly infectious in vivo showed a severe post-binding block to B cell infection. Host entry was accordingly an epithelial infection and B cell infection a secondary event. Macrophage infection by cell-free virions was also poor, but improved markedly when virion binding improved or when macrophages were co-cultured with infected fibroblasts. Under the same conditions B cell infection remained poor; it improved only when virions came from macrophages. This reflected better cell penetration and correlated with antigenic changes in the virion fusion complex. Macrophages were seen to contact acutely infected epithelial cells, and cre/lox-based virus tagging showed that almost all the virus recovered from lymphoid tissue had passed through lysM + and CD11c + myeloid cells. Thus MuHV-4 reached B cells in 3 distinct stages: incoming virions infected epithelial cells; infection then passed to myeloid cells; glycoprotein changes then allowed B cell infection. These data identify new complexity in rhadinovirus infection and potentially also new vulnerability to intervention.

          Author Summary

          Rhadinoviruses cause lymphocytic cancers. Their infection of lymphocytes is therefore an important therapeutic target. How this occurs is unclear. One prevalent hypothesis has been that virions directly infect lymphocytes when they enter new hosts. Here we show that host entry by Murid Herpesvirus-4, a close relative of the Kaposi's Sarcoma-associated Herpesvirus, is an epithelial rather than a lymphocyte infection: the mucosal lymphoid colonization typical of acute infectious mononucleosis only occurred later. Macrophages were closely associated with the acutely infected epithelium, and most if not all of the virus reaching B cells showed evidence of previous myeloid cell infection. Macrophage-derived virions showed a greatly enhanced capacity for lymphocyte infection that was associated with antigenic changes in the viral fusion proteins. Thus host colonization required epithelial and myeloid infections before there was lymphocyte infection. The implication is that each of these infection events could be independently targeted to limit viral persistence.

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          Most cited references 68

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          Conditional gene targeting in macrophages and granulocytes using LysMcre mice.

          Conditional mutagenesis in mice has recently been made possible through the combination of gene targeting techniques and site-directed mutagenesis, using the bacteriophage P1-derived Cre/loxP recombination system. The versatility of this approach depends on the availability of mouse mutants in which the recombinase Cre is expressed in the appropriate cell lineages or tissues. Here we report the generation of mice that express Cre in myeloid cells due to targeted insertion of the cre cDNA into their endogenous M lysozyme locus. In double mutant mice harboring both the LysMcre allele and one of two different loxP-flanked target genes tested, a deletion efficiency of 83-98% was determined in mature macrophages and near 100% in granulocytes. Partial deletion (16%) could be detected in CD11c+ splenic dendritic cells which are closely related to the monocyte/macrophage lineage. In contrast, no significant deletion was observed in tail DNA or purified T and B cells. Taken together, LysMcre mice allow for both specific and highly efficient Cre-mediated deletion of loxP-flanked target genes in myeloid cells.
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            Functions of cell surface heparan sulfate proteoglycans.

            The heparan sulfate on the surface of all adherent cells modulates the actions of a large number of extracellular ligands. Members of both cell surface heparan sulfate proteoglycan families, the transmembrane syndecans and the glycosylphosphoinositide-linked glypicans, bind these ligands and enhance formation of their receptor-signaling complexes. These heparan sulfate proteoglycans also immobilize and regulate the turnover of ligands that act at the cell surface. The extracellular domains of these proteoglycans can be shed from the cell surface, generating soluble heparan sulfate proteoglycans that can inhibit interactions at the cell surface. Recent analyses of genetic defects in Drosophila melanogaster, mice, and humans confirm most of these activities in vivo and identify additional processes that involve cell surface heparan sulfate proteoglycans. This chapter focuses on the mechanisms underlying these activities and on the cellular functions that they regulate.
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              Notch–RBP-J signaling controls the homeostasis of CD8− dendritic cells in the spleen

              Signaling through Notch receptors and their transcriptional effector RBP-J is essential for lymphocyte development and function, whereas its role in other immune cell types is unclear. We tested the function of the canonical Notch–RBP-J pathway in dendritic cell (DC) development and maintenance in vivo. Genetic inactivation of RBP-J in the bone marrow did not preclude DC lineage commitment but caused the reduction of splenic DC fraction. The inactivation of RBP-J in DCs using a novel DC-specific deleter strain caused selective loss of the splenic CD8− DC subset and reduced the frequency of cytokine-secreting CD8− DCs after challenge with Toll-like receptor ligands. In contrast, other splenic DC subsets and DCs in the lymph nodes and tissues were unaffected. The RBP-J–deficient splenic CD8− DCs were depleted at the postprogenitor stage, exhibited increased apoptosis, and lost the expression of the Notch target gene Deltex1. In the spleen, CD8− DCs were found adjacent to cells expressing the Notch ligand Delta-like 1 in the marginal zone (MZ). Thus, canonical Notch–RBP-J signaling controls the maintenance of CD8− DCs in the splenic MZ, revealing an unexpected role of the Notch pathway in the innate immune system.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                September 2012
                September 2012
                20 September 2012
                : 8
                : 9
                Affiliations
                Division of Virology, Department of Pathology, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom
                University of California-Berkeley, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: PGS BF RM. Performed the experiments: PGS BF RM JSM LG. Analyzed the data: PGS BF RM JSM LG. Wrote the paper: PGS.

                [¤]

                Current address: Immunology-Vaccinology, Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.

                Article
                PPATHOGENS-D-12-01360
                10.1371/journal.ppat.1002935
                3447751
                23028329

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 14
                Funding
                PGS is a Wellcome Trust Senior Clinical Fellow (GR076956MA). This work was also supported by Wellcome Trust project grant WT089111MA, Medical Research Council grant G0701185, and BBSRC grant BB/J014419/1. BF and RM are supported by the Portuguese Foundation for Science and Technology. LG is supported by the Fonds National Belge de la Recherche Scientifique (FNRS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Microbiology
                Virology
                Viral Transmission and Infection
                Host Cells
                Viral Entry
                Animal Models of Infection
                Viral Persistence and Latency
                Host-Pathogen Interaction

                Infectious disease & Microbiology

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