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Understanding the Cellular and Molecular Mechanism of Mouse Hepatitis Virus Induced Neuroinflammation and Demyelination in an Experimental Mice Model

Chatterjee, Dhriti (2014) Understanding the Cellular and Molecular Mechanism of Mouse Hepatitis Virus Induced Neuroinflammation and Demyelination in an Experimental Mice Model. PhD thesis, Indian Institute of Science Education & Research Kolkata.

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    Abstract

    Neurotropic mouse hepatitis virus (MHV) is a member of the Coronavirus family induces hepatitis, meningitis, encephalitis, myelitis, neuritis, demyelination and axonal loss which mimics certain pathology of human neurological diseases multiple sclerosis (MS). Natural and genetically constructed recombinant MHV strains (generated by targeted RNA recombination) with differential pathological properties are used to understand the mechanisms of demyelination and concomitant axonal loss in a strain specific manner. These encompass both demyelinating (DM) and nondemyelinating (NDM) strains of MHVs, on which several comparative studies have been performed correlating the phenotypes, genomic sequences, and their pathogenicity. During acute infection, neurotropic DM strain infect a number of cell types in the CNS such as neurons, astrocytes, oligodendrocytes and microglia in the brain but in the spinal cord they preferentially infect neuron in the gray matter and oligodendrocytes and microglia in the white matter. Whereas, NDM strain infects more or less all the neural cell types in the brain but in the spinal cord due to their limited ability to spread through neuron they are unable to infect oligodendrocytes in the white matter. Despite the fact that both strains can infect neurons, there is impaired inter-neuronal spread of the NDM strain in vivo and in vitro as well as a lack of translocation from gray matter to white matter. Moreover, previous studies have demonstrated that MHV-A59 can induce demyelination in immunocompromised mice (RAG-/- mice) which lacks functional T and B cell. Direct viral induced neuronal and glial cell pathology could be responsible for CNS resident microglia mediated innate immune activation and demyelination without involving adaptive immune system. Microgliaare the major resident innate immune cells in the CNS, where they constantly assess the microenvironment and produce factors that influence surrounding astrocytes and neurons. Under physiological conditions, microglia exhibit a deactivated phenotype that is associated with the production of anti-inflammatory and neurotrophic factors. Microglia appear to be the major initial sensors of danger or stranger signals recognized pattern recognition receptors that bind to so-called pathogen associated molecular patterns, and they secrete inflammatory mediators that can act on astrocytes to induce secondary inflammatory responses. Microglia acquire activated phenotype in response to pathogen invasion or tissue damage and thereby promote an inflammatory response. In most cases, this response is self-limiting, resolving once infection has been eradicated or the tissue damage has been repaired. Sustained inflammation resulting in tissue pathology implies persistence of an inflammatory stimulus or a failure in normal resolution mechanisms. Multiple sclerosis has long been recognized as inflammatory diseases but recently the term neuroinflammation has come to denote chronic, CNS specific inflammationlike glial responses, (mediated by mainly microglia and astrocytes), chronic plaque formation and dystrophic neurite growth. Though this is well accepted that MS is a T cell mediated and antibody mediated autoimmune disease process of MS but with the impending contribution of the glial response specially microglia in the initiation and sustaining the inflammatory processes in the CNS remains unanswered and needs further investigation on neuroinflammation.

    Item Type: Thesis (PhD)
    Additional Information: Dr. Jayasri Das Sarma
    Uncontrolled Keywords: Acute Innate Immune Activation; Cellular Mechanism; Demyelinating Diseases; Demyelination; Experimental Mice Model; Hepatitis Virus; Inflammatory Cells; Microglia; Molecular Mechanism; Mouse; Myelin; Neuroinflammation; RSA59
    Subjects: Q Science > QH Natural history > QH301 Biology
    Divisions: Faculty of Medicine, Health and Life Sciences > School of Biological Sciences
    Depositing User: IISER Kolkata Librarian
    Date Deposited: 20 Nov 2014 17:08
    Last Modified: 20 Nov 2014 17:08
    URI: http://eprints.iiserkol.ac.in/id/eprint/132

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