Murine β-coronavirus MHV-RSA59 orchestrates the interplay of oxidative stress and inflammatory pathways in neuroinflammation.

Mouse Hepatitis Virus MHV-A59/RSA59 is hepato-neurotropic strain known to induce an array of stress pathways leading to severe neuroinflammation and demyelination. Previous studies have explored the ability of MHV-A59 or RSA59 to modulate host stress pathways to exert its pathogenic effects. Oxidative and inflammatory stress are critical in neuroinflammation and demyelination, leading to different virus-induced neurodegeneration and associated pathogenesis. Various studies have linked the role of iNOS in the crosstalk of oxidative-inflammatory stress. This study aims to investigate the crosstalk of oxidative stress and inflammatory pathways in M-CoV-MHV-RSA59 infection in a reductionist model in neuronal Neuro2A and astrocytoma DBT cells. Our findings demonstrate that while Neuro2A cells exhibited a persistent increase in ROS levels, leading to upregulation of Nrf2 and its downstream antioxidant enzymes HMOX1 and Catalase, astrocytoma DBT cells displayed a transient ROS peak with an initial downregulation of Nrf2 and impaired antioxidant response. Additionally, we observed differential regulation of key stress responders, such as XBP-1 and DJ-1, highlighting distinct cellular adaptations to viral infection. The inflammatory mediators NF-κB and iNOS activation patterns further underscored the differential inflammatory response, with sustained upregulation in Neuro2A cells, whereas DBT cells showed delayed activation. These findings suggest that neuronal cells engage an intrinsic antioxidant defense, while glial cells exhibit a compromised response. Our study provides mechanistic insights into oxidative and inflammatory crosstalk in the neuro-glial Neuro2A and DBT cells and in MHV-induced neuroinflammation, offering potential therapeutic targets for ameliorating neurodegenerative demyelinating disorders such as multiple sclerosis.