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.

Text (PhD thesis of Fareeha Saadi (14IP005)) 14IP005_DBS.pdf - Submitted Version Restricted to Repository staff only Download (17MB)

Abstract

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.

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