Nexus between CD4+ T Cell-Microglia/Macrophages in Neurotropic Murine Coronavirus Mouse Hepatitis Virus-Induced Neuroinflammation

Chakravarty, Debanjana (2021) Nexus between CD4+ T Cell-Microglia/Macrophages in Neurotropic Murine Coronavirus Mouse Hepatitis Virus-Induced Neuroinflammation. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Debanjana Chakravarty (14IP035)) 14IP035_DBS.pdf - Submitted Version Restricted to Repository staff only Download (19MB)

Abstract

Chronic progressive neuroinflammatory disease multiple sclerosis (MS) is characterized by loss of neuronal cell functions resulting from axonal degeneration and demyelination. Infiltration of T lymphocytes and activation of microglia, along with their interplay are the major pathophysiological events leading to neurodegeneration in MS. While Experimental autoimmune encephalitis model depicts a pathogenic role of CD4+ T cells, our studies using a spike protein recombinant strain of Mouse Hepatitis Virus (MHV-RSA59), which mimics the pathological hallmarks of axonal loss and demyelination, exhibits a protective function of CD4+ T cells. Previous studies as well as our studies re-emphasized that RSA59 induced neuroinflammation can be initiated by brain resident microglia and peripheral monocyte derived macrophages, without help from CD4+ T cells. Our studies show that CD4+ T cells are less in number in the CNS at days 3 and 5p.i. The significant infiltration is observed at day 7p.i., after which all other peripheral immune cells decline in number, but CD4+ T cells remains significantly high even at day 16 p.i. Using CD4-/- mice, it was revealed that absence of CD4+ T leads to prolonged virus persistence, promotes augmented poliomyelitis, dorsal root ganglionic inflammation at the acute phase. Microglia/macrophage remains highly phagocytic at the chronic phase in the absence of CD4+T cells and leads to enhanced bulbous vacuolation of neuropil as well as demyelination. My further study exhibited that microglia/macrophage activation and CD4+ T, CD8+ and Treg cell subsets infiltration in the CNS at the acute phase enhances, as the mice transits from a young to adult phase of life, that leads to reduced demyelination at the chronic phase of RSA59 induced neuroinflammation. Furthermore, Treg expansion in the cervical lymph nodes is also enhanced in adult mice compared to young mice. In summary, our studies show a protective role of CD4+T cells as well as involvement of Treg cells upon RSA59 induced neuroinflammation, which is in contrast of EAE, where CD4+T cells are pathogenic in nature. Hence, our studies emphasise on designing robust therapeutics in MS, after understanding the etiology and the initiation of inflammation in the MS patients.

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