Biology subjects

Das Sarma, J.

Publications and source records attributed to Das Sarma, J..

2 recordsLinked to original sources

bioRxiv2022

Ifit2 regulates murine-coronavirus spread to the spinal cord white matter and its associated myelin pathology

Ifit2, an interferon-induced protein with tetratricopeptide repeats 2, plays a critical role in restricting neurotropic murine {beta}-coronavirus RSA59 infection. RSA59 intracranial injection of Ifit2 deficient (-/-) compared to wild type (WT) mice results in impaired acute microglial activation, associated with reduced CX3CR1 expression, which consecutively limits migration of peripheral lymphocytes into the brain, leading to impaired virus control followed by severe morbidity and mortality. While the protective role of Ifit2 is established for acute viral encephalitis, less is known about its influence on demyelination during the chronic phase of RSA59 infection. Our current study demonstrates that Ifit2 deficiency causes extensive RSA59 viral spread throughout both the spinal cord grey and white matter and is associated with impaired CD4+ T cell infiltration. Cervical lymph nodes of RSA59 infected Ifit2-/- mice showed reduced activation of CD4+ T cells and impaired IFN{gamma} expression during acute encephalomyelitis. Furthermore, blood-brain-barrier integrity was preserved in the absence of Ifit2 as evidenced by integral, tight junction protein ZO-1 expression surrounding the meninges and blood vessels and decreased Texas red dye uptake. In contrast to WT mice exhibiting only sparse myelin loss, the chronic disease phase in Ifit2-/- mice was associated with severe demyelination and persistent viral load, even at low infection doses. Overall, our study highlights that Ifit2 provides antiviral functions by promoting acute neuroinflammation and thereby aiding virus control and limiting severe demyelination. Author SummaryThe role of interferons in providing protective immunity against viral spread and pathogenesis is well known. Interferons execute their function by inducing certain genes collectively called as interferon stimulated genes (ISGs) among which Interferon-induced protein with tetratricopeptide repeats 2, Ifit2, is known for restricting neurotropic viral replication and spread in the brain. So far, not much has been investigated about its role in viral spread to the spinal cord and its associated myelin pathology. Towards this our study using neurotropic murine-{beta}-coronavirus and Ifit2 deficient mice demonstrate that Ifit2 deficiency causes extensive viral spread throughout grey and white matter of spinal cord accompanied by impaired microglial activation and CD4+ T cell infiltration. Furthermore, infected Ifit2 deficient mice showed impaired activation of T cells in cervical lymph node and Blood-Brain-Barrier was relatively intact. Ifit2 deficient mice developed viral induced severe chronic neuroinflammatory demyelination accompanied by the presence of ameboid shaped phagocytotic microglia/macrophages.

neuroscience↗

bioRxiv2022

Inducible Nitric Oxide Synthase deficiency leads to early demyelination by altering the balance between pro- and anti-inflammatory responses against Murine-β-Coronavirus

The neurological disease Multiple sclerosis (MS) is characterized by neuroinflammation and demyelination orchestrated by the activated glial cells, the CNS infiltrating leukocytes, and their reciprocal interaction through inflammatory signals. Inducible nitric oxide synthase (iNOS), an enzyme that catalyzes sustained nitric oxide production in response to an inflammatory stimulus, is a pro-inflammatory marker expressed particularly by the microglia/macrophages (MG/M{varphi}) during neuroinflammation. In MS, iNOS has been reportedly associated with the disease pathology; however, studies dissecting its role in the underlying mechanisms, specifically demyelination, are limited. Therefore, we studied the role of iNOS in a recombinant beta-coronavirus-MHV-RSA59-induced neuroinflammation, which is a prototypic animal model used to investigate the pathological hallmarks of MS, neuroinflammatory demyelination, and axonal degeneration. During the acute phase of infection with RSA59, wildtype C57BL/6 (WT) mice had significantly upregulated iNOS expression in macrophages, natural killer cells, and natural killer T cells suggesting a role for iNOS in RSA59-induced neuroinflammation. Studies comparing RSA59-infected WT and iNOS-deficient mice revealed that iNOS deficiency aggravated the disease with increased CNS infiltration of macrophages and neutrophils and enhanced mortality. As early as 9-10 days after the infection, the CNS of iNOS-deficient mice had substantially higher demyelination marked with morphologically defined MG/M{varphi} in the demyelinating regions. Transcript analysis confirmed the significant upregulation of type2 macrophage (M2) markers-Arginase 1, CD206, and TREM2-in the CNS of iNOS-deficient mice. Corroborating to the phenotype, the iNOS-deficient mice showed a significantly higher expression of TGF{beta}-an anti-inflammatory cytokine- and increased T regulatory (Treg) cell infiltration, indicating an anti-inflammatory milieu established early after the infection. These observations highlight a protective role of iNOS in virus-induced neuroinflammation whereas its absence leads to MG/M{varphi} polarization towards a phenotype that may be involved in the exacerbated demyelination pathology. Author summaryContrary to the reported pathogenic role of inducible nitric oxide synthase (iNOS) in multiple sclerosis and related autoimmune animal models, we show that the mice deficient in iNOS show an exacerbated disease with accelerated demyelination accompanied by heightened production of an anti-inflammatory and phagocytic markers and more numbers of Tregs in a mouse model of a recombinant mouse hepatitis virus RSA59 infection. Therefore, iNOS may play protective and regulatory roles in this beta-coronavirus infection.

neuroscience↗