Gene expression profiling of microglia infected by a highly neurovirulent murine leukemia virus: implications for neuropathogenesisReportar como inadecuado

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, 3:26

First Online: 12 May 2006Received: 11 November 2005Accepted: 12 May 2006


BackgroundCertain murine leukemia viruses MLVs are capable of inducing progressive spongiform motor neuron disease in susceptible mice upon infection of the central nervous system CNS. The major CNS parenchymal target of these neurovirulent retroviruses NVs are the microglia, whose infection is largely coincident with neuropathological changes. Despite this close association, the role of microglial infection in disease induction is still unknown. In this paper, we investigate the interaction of the highly virulent MLV, FrCasE, with microglia ex vivo to evaluate whether infection induces specific changes that could account for neurodegeneration. Specifically, we compared microglia infected with FrCasE, a related non-neurovirulent virus NN F43-Fr57E, or mock-infected, both at a basic virological level, and at the level of cellular gene expression using quantitative real time RT-PCR qRT-PCR and Afffymetrix 430A mouse gene chips.

ResultsBasic virological comparison of NN, NV, and mock-infected microglia in culture did not reveal differences in virus expression that provided insight into neuropathogenesis. Therefore, microglial analysis was extended to ER stress gene induction based on previous experiments demonstrating ER stress induction in NV-infected mouse brains and cultured fibroblasts. Analysis of message levels for the ER stress genes BiP grp78, CHOP Gadd153, calreticulin, and grp58 in cultured microglia, and BiP and CHOP in microglia enriched fractions from infected mouse brains, indicated that FrCasE infection did not induce these ER stress genes either in vitro or in vivo. To broadly identify physiological changes resulting from NV infection of microglia in vitro, we undertook a gene array screen of more than 14,000 well-characterized murine genes and expressed sequence tags ESTs. This analysis revealed only a small set of gene expression changes between infected and uninfected cells <18. Remarkably, gene array comparison of NN- and NV-infected microglia revealed only 3 apparent gene expression differences. Validation experiments for these genes by Taqman real-time RT-PCR indicated that only single Ig IL-1 receptor related protein SIGIRR transcript was consistently altered in culture; however, SIGIRR changes were not observed in enriched microglial fractions from infected brains.

ConclusionThe results from this study indicate that infection of microglia by the highly neurovirulent virus, FrCasE, does not induce overt physiological changes in this cell type when assessed ex vivo. In particular, NV does not induce microglial ER stress and thus, FrCasE-associated CNS ER stress likely results from NV interactions with another cell type or from neurodegeneration directly. The lack of NV-induced microglial gene expression changes suggests that FrCasE either affects properties unique to microglia in situ, alters the expression of microglial genes not represented in this survey, or affects microglial cellular processes at a post-transcriptional level. Alternatively, NV-infected microglia may simply serve as an unaffected conduit for persistent dissemination of virus to other neural cells where they produce acute neuropathogenic effects.

Electronic supplementary materialThe online version of this article doi:10.1186-1742-4690-3-26 contains supplementary material, which is available to authorized users.

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Autor: Derek E Dimcheff - L Gwenn Volkert - Ying Li - Angelo L DeLucia - William P Lynch


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