Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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MCMV Infection of Developing Central Nervous System, Developmental and Immunological Response

ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: William Britt

PROVIDER: E-GEOD-9945 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Altered development of the brain after focal herpesvirus infection of the central nervous system.

Koontz Thad T Bralic Marina M Tomac Jelena J Pernjak-Pugel Ester E Bantug Glen G Jonjic Stipan S Britt William J WJ

The Journal of experimental medicine 20080211 2

Human cytomegalovirus infection of the developing central nervous system (CNS) is a major cause of neurological damage in newborn infants and children. To investigate the pathogenesis of this human infection, we developed a mouse model of infection in the developing CNS. Intraperitoneal inoculation of newborn animals with murine cytomegalovirus resulted in virus replication in the liver followed by virus spread to the brain. Virus infection of the CNS was associated with the induction of inflamm ...[more]

PMID: 18268036

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Project description:Neurologic manifestations are among the most frequently reported complications of COVID-19. However, given the paucity of tissue samples and highly infectious nature of the etiologic agent of COVID-19, we have limited information to understand the neuropathogenesis of COVID-19. Therefore to better understand the impact of COVID-19 in brain, we employed mass-spectrometry-based proteomics using data-independent acquisition mode (DIA) to investigate cerebrospinal fluid (CSF) proteins collected from two different non-human primates, Rhesus Macaque and African Green Monkeys for the neurologic effects of the infection. These monkeys exhibited minimal to mild pulmonary pathology but moderate to severe CNS pathology. Our results indicate that CSF proteome changes after infection resolution correspond with bronchial virus abundance during early infection and revealed substantial differences between the infected NHPs and their age-matched uninfected controls, suggesting these differences could reflect altered secretion of CNS factors in response to SARS-CoV-2-induced neuropathology. We also observed the infected animals to exhibit much scattered data distributions as compared to the tightly clustered corresponding controls which suggest the heterogeneity of the CSF proteome change and the host response to the viral infection. In addition, dysregulated CSF proteins were preferentially enriched in functional pathways associated with progressive neurodegenerative disorders, hemostasis and innate immune responses that could influence neuroinflammatory responses following COVID-19. Mapping dysregulated proteins to the Human Brain Protein Atlas found that these proteins tended to be enriched in brain regions that exhibit more frequent injury following COVID-19. It therefore appears reasonable to speculate that such CSF protein changes could serve as signatures for neurologic injury, identify important regulatory pathways in this process, and potentially reveal therapeutic targets to prevent or attenuate the development of neurologic injuries following COVID-19.

Dataset Information

MCMV Infection of Developing Central Nervous System, Developmental and Immunological Response

Publications

Altered development of the brain after focal herpesvirus infection of the central nervous system.

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