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DJ-1-Nrf2 axis is activated upon murine β-coronavirus infection in the CNS.

ABSTRACT: Coronaviruses have emerged as alarming pathogens owing to their inherent ability of genetic variation and cross-species transmission. Coronavirus infection burdens the endoplasmic reticulum (ER.), causes reactive oxygen species production and induces host stress responses, including unfolded protein response (UPR) and antioxidant system. In this study, we have employed a neurotropic murine β-coronavirus (M-CoV) infection in the Central Nervous System (CNS) of experimental mice model to study the role of host stress responses mediated by interplay of DJ-1 and XBP1. DJ-1 is an antioxidant molecule with established functions in neurodegeneration. However, its regulation in virus-induced cellular stress response is less explored. Our study showed that M-CoV infection activated the glial cells and induced antioxidant and UPR genes during the acute stage when the viral titer peaks. As the virus particles decreased and acute neuroinflammation diminished at day ten p.i., a significant up-regulation in UPR responsive XBP1, antioxidant DJ-1, and downstream signaling molecules, including Nrf2, was recorded in the brain tissues. Additionally, preliminary in silico analysis of the binding between the DJ-1 promoter and a positively charged groove of XBP1 is also investigated, thus hinting at a mechanism behind the upregulation of DJ-1 during MHV-infection. The current study thus attempts to elucidate a novel interplay between the antioxidant system and UPR in the outcome of coronavirus infection.

SUBMITTER: Kundu S

PROVIDER: S-EPMC8418700 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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DJ-1-Nrf2 axis is activated upon murine β-coronavirus infection in the CNS.

Kundu Soumya S Saadi Fareeha F Sengupta Sourodip S Antony Gisha Rose GR Raveendran Vineeth A VA Kumar Rahul R Kamble Mithila Ashok MA Sarkar Lucky L Burrows Amy A Pal Debnath D Sen Ganes C GC Sarma Jayasri Das JD

Brain disorders (Amsterdam, Netherlands) 20210905

Coronaviruses have emerged as alarming pathogens owing to their inherent ability of genetic variation and cross-species transmission. Coronavirus infection burdens the endoplasmic reticulum (ER.), causes reactive oxygen species production and induces host stress responses, including unfolded protein response (UPR) and antioxidant system. In this study, we have employed a neurotropic murine β-coronavirus (M-CoV) infection in the Central Nervous System (CNS) of experimental mice model to study the ...[more]

PMID: 34514445

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Project description:BackgroundThe etiology of Rasmussen's encephalitis (RE), a rare chronic neurological disorder characterized by CD8+ T cell infiltration and unihemispheric brain atrophy, is still unknown. Various human herpes viruses (HHVs) have been detected in RE brain, but their contribution to RE pathogenesis is unclear.MethodsHHVs infection and relevant immune response were compared among brain tissues from RE, temporal lobe epilepsy (TLE) and traumatic brain injury (TBI) patients. Viral antigen or genome, CD8+ T cells, microglia and innate immunity molecules were analyzed by immunohistochemical staining, DNA dot blot assay or immunofluorescence double staining. Cytokines were measured by multiplex flow cytometry. Cell apoptosis was visualized by TUNEL staining. Viral infection, immune response and the severity of unihemispheric atrophy were subjected to correlation analysis.ResultsAntigens of various HHVs were prevalent in RE and TLE brains, and the cumulative viral score of HHVs positively correlated with the unihemispheric atrophy in RE patients. CD8+ T cells infiltration were observed in both RE and TLE brains and showed co-localization with HHV antigens, but their activation, as revealed by Granzyme B (GZMB) release and apoptosis, was found only in RE. In comparison to TLE, RE brain tissues contained higher level of inflammatory cytokines, but the interferon-β level, which was negatively correlated with cumulative viral score, was relatively lower. In line with this, the DNA sensor STING and IFI16, rather than other innate immunity signaling molecules, were insufficiently activated in RE.ConclusionsCompared with TBI, both RE and TLE had prevalently HHV infection and immune response in brain tissues. However, in comparison to TLE, RE showed insufficient activation of antiviral innate immunity but overactivation of cytotoxic T cells. Our results show the relatively lower level of antiviral innate immunity and overactivation of cytotoxic T cells in RE cases upon HHV infection, the overactivated T cells might be a compensate to the innate immunity but the causative evidence is lack in our study and need more investigation in the future.

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DJ-1-Nrf2 axis is activated upon murine β-coronavirus infection in the CNS.

Publications

DJ-1-Nrf2 axis is activated upon murine β-coronavirus infection in the CNS.

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