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STAT1 Signaling in Astrocytes Is Essential for Control of Infection in the Central Nervous System.

ABSTRACT: The local production of gamma interferon (IFN-?) is important to control Toxoplasma gondii in the brain, but the basis for these protective effects is not fully understood. The studies presented here reveal that the ability of IFN-? to inhibit parasite replication in astrocytes in vitro is dependent on signal transducer and activator of transcription 1 (STAT1) and that mice that specifically lack STAT1 in astrocytes are unable to limit parasite replication in the central nervous system (CNS). This susceptibility is associated with a loss of antimicrobial pathways and increased cyst formation in astrocytes. These results identify a critical role for astrocytes in limiting the replication of an important opportunistic pathogen. IMPORTANCE:Astrocytes are the most numerous cell type in the brain, and they are activated in response to many types of neuroinflammation, but their function in the control of CNS-specific infection is unclear. The parasite Toxoplasma gondii is one of the few clinically relevant microorganisms that naturally infects astrocytes, and the studies presented here establish that the ability of astrocytes to inhibit parasite replication is essential for the local control of this opportunistic pathogen. Together, these studies establish a key role for astrocytes as effector cells and in the coordination of many aspects of the protective immune response that operates in the brain.

SUBMITTER: Hidano S

PROVIDER: S-EPMC5101356 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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STAT1 Signaling in Astrocytes Is Essential for Control of Infection in the Central Nervous System.

Hidano Shinya S Randall Louise M LM Dawson Lucas L Dietrich Hans K HK Konradt Christoph C Klover Peter J PJ John Beena B Harris Tajie H TH Fang Qun Q Turek Bradley B Kobayashi Takashi T Hennighausen Lothar L Beiting Daniel P DP Koshy Anita A AA Hunter Christopher A CA

mBio 20161108 6

The local production of gamma interferon (IFN-γ) is important to control Toxoplasma gondii in the brain, but the basis for these protective effects is not fully understood. The studies presented here reveal that the ability of IFN-γ to inhibit parasite replication in astrocytes in vitro is dependent on signal transducer and activator of transcription 1 (STAT1) and that mice that specifically lack STAT1 in astrocytes are unable to limit parasite replication in the central nervous system (CNS). Th ...[more]

PMID: 27834206

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Project description:Prenatal Human Cytomegalovirus (HCMV) infection often causes CNS maldevelopment. In a murine model, we detect Murine Cytomegalovirus (MCMV) in brain following intra-peritoneal inoculation at birth. Infected mice show impaired cerebellar development and impaired neurologic function on a beam balance test as adults. Among developmental genes differentially regulated, hindbrain expression of the homeodomain transcription factor HOXa5 was reduced with infection, and fewer HOXa5 expressing neurons were found in vestibular nuclei. Based on the hypothesis that immune activation connects focal viral infection and global CNS maldevelopment, we defined the components of CNS immune response. Flow cytometry showed a large increase in both number and activation of CNS monocytes. Monocytes were found in close association with infected cells by immunohistochemistry (IHC). Oligonucleotide microarrays contained herein identified many differentially expressed genes related to innate immune response. Chemokines, cytokines, cell surface receptors, and proteases are some of the many immunological genes shown to be differentially regulated by MCMV infection. These results together show that MCMV infection induces a complex immune response associated with changes in developmental gene expression and lasting neurologic defecit. Keywords: disease state comparison (virus infection) and competetive hybridization for expression analysis Previous work empirically determined the kinetics of viral spread to and replication in the Balb-C murine CNS. Balb-C mice were inoculated intra-peritoneally at birth, and harvested at 5, 8, 12, and 21 days post inoculation for cerebellar experiments. Controls were mock infected with vehicle (DMEM cell growth media) and harvested at the same timepoints. Each microarray was a two channel MEEBO array, upon which labeled and reverse transcribed cDNA from 3 pooled infected cerebella and three pooled uninfected cerebella competetively hybridized. Three unique biological replicates were performed with day 5 cDNA, 5 unique biological replicates at day 8, 5 unique biological replicates at day 12, and 4 unique biological replicates at day 21. For the analysis, colors channels were seperated and treated as independent hybridizations. However, since the experiments were dual channel, the primary data may be employed to generate ratio based measurements, and each sample is provided a corresponding number that can be used to pair the processed data and derive ratios (mock 3, infected 3). Mice were similarly inoculated and harvested at 5, 15, and 21 days post natal for liver tissue analysis. Inoculation was performed by injection with a microsyringe of 50ul titered virus delivering 500-1000 PFU per animal.

Dataset Information

STAT1 Signaling in Astrocytes Is Essential for Control of Infection in the Central Nervous System.

Publications

STAT1 Signaling in Astrocytes Is Essential for Control of Infection in the Central Nervous System.

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