The regulatory role of CD40-CD40L axis in mounting host immunity against Murine-CoV-RSA59

Saadi, Fareeha (2021) The regulatory role of CD40-CD40L axis in mounting host immunity against Murine-CoV-RSA59. PhD thesis, Indian Institute of Science Education and Research Kolkata.

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The CNS neuroinflammatory demyelinating disease multiple sclerosis (MS) is characterized by loss of neuronal functions resulting from myelin loss with or without axonal degeneration mediated by myelinolytic CD4⁺ T cells. As the interaction between the T cell-expressed CD40L and the macrophage-expressed CD40 is indispensable for optimal T cell activation and differentiation, blockade of CD40-CD40L interaction is shown to be host-protective in experimental autoimmune encephalomyelitis, an autoimmune model for MS. By contrast, CNS-infiltrating CD4⁺ T cells protect the CNS from demyelination in the Mouse Hepatitis Virus (MHV-A59/RSA59)-induced demyelination model of MS. The absence of CD4⁺ T cells significantly affects the microglial activation; typically, M2 microglial activation fails to resolve during the chronic infection, rendering mice more susceptible to acute poliomyelitis, chronic demyelination, and axonal bulbar vacuolation. This study investigated the CD4-microglia nexus at the molecular level using CD40L⁻/⁻ mice. The results show that the expression of both CD40 and CD40L in the CNS is modulated upon RSA59 infection. CD40L-deficient mice are more susceptible to RSA59 infection, perhaps due to reduced microglia/macrophage activation and significantly dampened effector CD4⁺ T recruitment to the CNS during days 7- 10 p.i. CD40L⁻/⁻ mice exhibited severe demyelination mediated by phagocytic microglia/macrophages, axonal loss, and persistent poliomyelitis during chronic infection. Studies using CD40⁻/⁻ mice further showed a similar susceptibility of mice to RSA59 infection, which underscored the dysregulated inflammatory response in the brains mediated by neutrophils. Thus, indicating CD40-CD40L as host-protective against RSA59-induced demyelination. This suggests a novel target in designing prophylaxis for virus-induced demyelination and axonal degeneration, in contrast to immunosuppression which holds only for autoimmune mechanisms of inflammatory demyelination.

Item Type: Thesis (PhD)
Additional Information: Supervisor: Prof. Jayasri Das Sarma
Uncontrolled Keywords: CD40-CD40L Axis; CD40 Ligand; Host Immunity; Murine-CoV-RSA59; RSA59; RSA59 Induced Disease
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Department of Biological Sciences
Depositing User: IISER Kolkata Librarian
Date Deposited: 30 Mar 2022 07:59
Last Modified: 30 Mar 2022 07:59

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