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Brain Disord ; 4: 100021, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1426913


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 ß-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.

Ann Neurosci ; 28(3-4): 201-218, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1477158


Background: Coronaviruses (CoVs) are single-stranded, polyadenylated, enveloped RNA of positive polarity with a unique potential to alter host tropism. This has been exceptionally demonstrated by the emergence of deadly virus outbreaks of the past: Severe Acute Respiratory Syndrome (SARS-CoV) in 2003 and Middle East Respiratory Syndrome (MERS-CoV) in 2012. Summary: The 2019 outbreak by the new cross-species transmission of SARS-CoV-2 has put the world on alert. CoV infection is triggered by receptor recognition, membrane fusion, and successive viral entry mediated by the surface Spike (S) glycoprotein. S protein is one of the major antigenic determinants and the target for neutralizing antibodies. It is a valuable target in antiviral therapies because of its central role in cell-cell fusion, viral antigen spread, and host immune responses leading to immunopathogenesis. The receptor-binding domain of S protein has received greater attention as it initiates host attachment and contains major antigenic determinants. However, investigating the therapeutic potential of fusion peptide as a part of the fusion core complex assembled by the heptad repeats 1 and 2 (HR1 and HR2) is also warranted. Along with receptor attachment and entry, fusion mechanisms should also be explored for designing inhibitors as a therapeutic intervention. Key message: In this article, we review the S protein function and its role in mediating membrane fusion, spread, tropism, and its associated pathogenesis with notable therapeutic strategies focusing on results obtained from studies on a murine ß-Coronavirus (m-CoV) and its associated disease process.

J Virol ; 94(14)2020 07 01.
Article in English | MEDLINE | ID: covidwho-823496


Mouse hepatitis virus (MHV) is a murine betacoronavirus (m-CoV) that causes a wide range of diseases in mice and rats, including hepatitis, enteritis, respiratory diseases, and encephalomyelitis in the central nervous system (CNS). MHV infection in mice provides an efficient cause-effect experimental model to understand the mechanisms of direct virus-induced neural-cell damage leading to demyelination and axonal loss, which are pathological features of multiple sclerosis (MS), the most common disabling neurological disease in young adults. Infiltration of T lymphocytes, activation of microglia, and their interplay are the primary pathophysiological events leading to disruption of the myelin sheath in MS. However, there is emerging evidence supporting gray matter involvement and degeneration in MS. The investigation of T cell function in the pathogenesis of deep gray matter damage is necessary. Here, we employed RSA59 (an isogenic recombinant strain of MHV-A59)-induced experimental neuroinflammation model to compare the disease in CD4-/- mice with that in CD4+/+ mice at days 5, 10, 15, and 30 postinfection (p.i.). Viral titer estimation, nucleocapsid gene amplification, and viral antinucleocapsid staining confirmed enhanced replication of the virions in the absence of functional CD4+ T cells in the brain. Histopathological analyses showed elevated susceptibility of CD4-/- mice to axonal degeneration in the CNS, with augmented progression of acute poliomyelitis and dorsal root ganglionic inflammation rarely observed in CD4+/+ mice. Depletion of CD4+ T cells showed unique pathological bulbar vacuolation in the brain parenchyma of infected mice with persistent CD11b+ microglia/macrophages in the inflamed regions on day 30 p.i. In summary, the current study suggests that CD4+ T cells are critical for controlling acute-stage poliomyelitis (gray matter inflammation), chronic axonal degeneration, and inflammatory demyelination due to loss of protective antiviral host immunity.IMPORTANCE The current trend in CNS disease biology is to attempt to understand the neural-cell-immune interaction to investigate the underlying mechanism of neuroinflammation, rather than focusing on peripheral immune activation. Most studies in MS are targeted toward understanding the involvement of CNS white matter. However, the importance of gray matter damage has become critical in understanding the long-term progressive neurological disorder. Our study highlights the importance of CD4+ T cells in safeguarding neurons against axonal blebbing and poliomyelitis from murine betacoronavirus-induced neuroinflammation. Current knowledge of the mechanisms that lead to gray matter damage in MS is limited, because the most widely used animal model, experimental autoimmune encephalomyelitis (EAE), does not present this aspect of the disease. Our results, therefore, add to the existing limited knowledge in the field. We also show that the microglia, though important for the initiation of neuroinflammation, cannot establish a protective host immune response without the help of CD4+ T cells.

Axons/immunology , Axons/metabolism , CD4 Antigens/deficiency , Coronavirus Infections/immunology , Coronavirus Infections/virology , Murine hepatitis virus/physiology , Poliomyelitis/etiology , Animals , Axons/pathology , Brain/immunology , Brain/metabolism , Brain/pathology , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Coronavirus Infections/pathology , Cytokines/metabolism , Disease Models, Animal , Disease Susceptibility/immunology , Ganglia, Spinal/immunology , Ganglia, Spinal/metabolism , Ganglia, Spinal/pathology , Immunohistochemistry , Inflammation Mediators/metabolism , Mice