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      Glucocortiocoid Treatment of MCMV Infected Newborn Mice Attenuates CNS Inflammation and Limits Deficits in Cerebellar Development

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          Abstract

          Infection of the developing fetus with human cytomegalovirus (HCMV) is a major cause of central nervous system disease in infants and children; however, mechanism(s) of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV) results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC) proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virus-infected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNF-α, IFN-β and IFNγ) in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV.

          Author Summary

          Intrauterine infection with human cytomegalovirus (HCMV) is a leading cause of developmental brain damage. In the U.S., an estimated 2,000 infants a year develop brain damage as a result of intrauterine infection with HCMV. In this study, we examined the contribution of host immune responses induced by CMV infection to abnormal development of the CNS by treating neonatal mice infected with MCMV with glucocorticoids. We found that glucocorticoid treatment of infected mice decreased the inflammatory response within the CNS without altering the level of virus replication. In addition, abnormalities in the structure of the cerebellum, as well as abnormalities in granule neuron precursor cell proliferation were normalized in MCMV infected mice following glucocorticoid treatment. These studies suggest that the host immune response to CMV infection is damaging to the developing CNS and that it may be possible to limit CNS disease by modulating inflammation. Moreover, understanding how inflammation and the immune response may alter the developmental program within the CNS could offer important insight into the mechanisms of disease leading to abnormal brain development following intrauterine infection.

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          Most cited references104

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          Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog.

          Cerebellar granule cells are the most abundant type of neuron in the brain, but the molecular mechanisms that control their generation are incompletely understood. We show that Sonic hedgehog (Shh), which is made by Purkinje cells, regulates the division of granule cell precursors (GCPs). Treatment of GCPs with Shh prevents differentiation and induces a potent, long-lasting proliferative response. This response can be inhibited by basic fibroblast growth factor or by activation of protein kinase A. Blocking Shh function in vivo dramatically reduces GCP proliferation. These findings provide insight into the mechanisms of normal growth and tumorigenesis in the cerebellum.
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            Sonic hedgehog regulates the growth and patterning of the cerebellum.

            The molecular bases of brain development and CNS malignancies remain poorly understood. Here we show that Sonic hedgehog (Shh) signaling controls the development of the cerebellum at multiple levels. SHH is produced by Purkinje neurons, it is required for the proliferation of granule neuron precursors and it induces the differentiation of Bergmann glia. Blocking SHH function in vivo results in deficient granule neuron and Bergmann glia differentiation as well as in abnormal Purkinje neuron development. Thus, our findings provide a molecular model for the growth and patterning of the cerebellum by SHH through the coordination of the development of cortical cerebellar cell types. In addition, they provide a cellular context for medulloblastomas, childhood cancers of the cerebellum.
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              N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation.

              To address the role of N-myc in neurogenesis and in nervous system tumors, it was conditionally disrupted in neuronal progenitor cells (NPCs) with a nestin-Cre transgene. Null mice display ataxia, behavioral abnormalities, and tremors that correlate with a twofold decrease in brain mass that disproportionately affects the cerebellum (sixfold reduced in mass) and the cerebral cortex, both of which show signs of disorganization. In control mice at E12.5, we observe a domain of high N-Myc protein expression in the rapidly proliferating cerebellar primordium. Targeted deletion of N-myc results in severely compromised proliferation as shown by a striking decrease in S phase and mitotic cells as well as in cells expressing the Myc target gene cyclin D2, whereas apoptosis is unaffected. Null progenitor cells also have comparatively high levels of the cdk inhibitors p27(Kip1) and p18(Ink4c), whereas p15(Ink4b), p21(Cip1), and p19(Ink4d) levels are unaffected. Many null progenitors also exhibit altered nuclear morphology and size. In addition, loss of N-myc disrupts neuronal differentiation as evidenced by ectopic staining of the neuron specific marker betaTUBIII in the cerebrum. Furthermore, in progenitor cell cultures derived from null embryonic brain, we observe a dramatic increase in neuronal differentiation compared with controls. Thus, N-myc is essential for normal neurogenesis, regulating NPC proliferation, differentiation, and nuclear size. Its effects on proliferation and differentiation appear due, at least in part, to down-regulation of a specific subset of cyclin-dependent kinase inhibitors.
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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
                March 2013
                March 2013
                7 March 2013
                : 9
                : 3
                : e1003200
                Affiliations
                [1 ]Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                [2 ]Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                [3 ]Department of Histology and Embryology, Faculty of Medicine University of Rijeka, Rijeka, Croatia
                [4 ]Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                University of California, San Diego, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SJ WJB. Performed the experiments: KK GRB EPP DC WJB. Analyzed the data: KK GRB EPP DC. Contributed reagents/materials/analysis tools: SJ WJB. Wrote the paper: KK WJB.

                [¤]

                Current address: Immunobiology, University Hospital Basel, Basel, Switzerland.

                Article
                PPATHOGENS-D-12-02090
                10.1371/journal.ppat.1003200
                3591306
                23505367
                4ab37979-0919-4d73-9d18-167524148a35
                Copyright @ 2013

                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.

                History
                : 26 August 2012
                : 8 January 2013
                Page count
                Pages: 18
                Funding
                This investigation received financial support from the NINDS (5R01NS065845-03; www.ninds.nih.gov), NIAID (1R01AI089956-01A1; www.niaid.nih.gov) and the NIAID Training grant in immunological disease and basic immunology (T32 AI 007051; www.niaid.nih.gov) from the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Developmental Biology
                Stem Cells
                Neural Stem Cells
                Cell Differentiation
                Morphogenesis
                Immunology
                Immunologic Subspecialties
                Neuroimmunology
                Immune Response
                Immunomodulation
                Immunopathology
                Microbiology
                Immunity
                Immune Defense
                Immunoregulation
                Immunotherapy
                Inflammation
                Virology
                Animal Models of Infection
                Emerging Infectious Diseases
                Host-Pathogen Interaction
                Neuroscience
                Developmental Neuroscience
                Neural Stem Cells
                Neurogenesis
                Medicine
                Clinical Immunology
                Infectious Diseases
                Viral Diseases
                Cytomegalovirus Infection
                Infectious Disease Control
                Infectious Diseases of the Nervous System

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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