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Neurotropic mouse hepatitis virus (MHV-A59/RSA59) infection in mice induces acute neuroinflammation due to direct neural cell dystrophy, which proceeds with demyelination with or without axonal loss, the pathological hallmarks of human neurological disease, Multiple sclerosis (MS). Recent studies in the RSA59-induced neuroinflammation model of MS showed a protective role of CNS-infiltrating CD4 + T cells compared to their pathogenic role in the autoimmune model. The current study further investigated the molecular nexus between CD4 + T cell-expressed CD40Ligand and microglia/macrophage-expressed CD40 using CD40L -/- mice. Results demonstrate CD40L expression in the CNS is modulated upon RSA59 infection. We show evidence that CD40L -/- mice are more susceptible to RSA59 induced disease due to reduced microglia/macrophage activation and significantly dampened effector CD4 + T recruitment to the CNS on day 10 p.i. Additionally, CD40L -/- mice exhibited severe demyelination mediated by phagocytic microglia/macrophages, axonal loss, and persistent poliomyelitis during chronic infection, 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.

Background Multiple sclerosis (MS) is characterized by neuroinflammation and demyelination orchestrated by activated neuroglial cells, CNS infiltrating leukocytes, and their reciprocal interactions through inflammatory signals. An inflammatory stimulus triggers inducible nitric oxide synthase (NOS2), a pro-inflammatory marker of microglia/macrophages (MG/Mφ) to catalyze sustained nitric oxide production. NOS2 during neuroinflammation, has been associated with MS disease pathology; however, studies dissecting its role in demyelination are limited. We studied the role of NOS2 in a recombinant β-coronavirus-MHV-RSA59 induced neuroinflammation, an experimental animal model mimicking the pathological hallmarks of MS: neuroinflammatory demyelination and axonal degeneration. Objective Understanding the role of NOS2 in murine-β-coronavirus-MHV-RSA59 demyelination. Methods Brain and spinal cords from mock and RSA59 infected 4–5-week-old MHV-free C57BL/6 mice (WT) and NOS2-/- mice were harvested at different disease phases post infection (p.i.) (day 5/6-acute, day 9/10-acute-adaptive and day 30-chronic phase) and compared for pathological outcomes. Results NOS2 was upregulated at the acute phase of RSA59-induced disease in WT mice and its deficiency resulted in severe disease and reduced survival at the acute-adaptive transition phase. Low survival in NOS2-/- mice was attributed to (i) high neuroinflammation resulting from increased accumulation of macrophages and neutrophils and (ii) Iba1 + phagocytic MG/Mφ mediated-early demyelination as observed at this phase. The phagocytic phenotype of CNS MG/Mφ was confirmed by significantly higher mRNA transcripts of phagocyte markers-CD206, TREM2, and Arg1 and double immunolabelling of Iba1 with MBP and PLP. Further, NOS2 deficiency led to exacerbated demyelination at the chronic phase as well. Conclusion Taken together the results imply that the immune system failed to control the disease progression in the absence of NOS2. Thus, our observations highlight a protective role of NOS2 in murine-β-coronavirus induced demyelination.

Multiple sclerosis (MS) is characterized by neuroinflammation and demyelination orchestrated by activated neuroglial cells, CNS infiltrating leukocytes, and their reciprocal interactions through inflammatory signals. An inflammatory stimulus triggers inducible nitric oxide synthase (NOS2), a pro-inflammatory marker of microglia/macrophages (MG/M[phi]) to catalyze sustained nitric oxide production. NOS2 during neuroinflammation, has been associated with MS disease pathology; however, studies dissecting its role in demyelination are limited. We studied the role of NOS2 in a recombinant [beta]-coronavirus-MHV-RSA59 induced neuroinflammation, an experimental animal model mimicking the pathological hallmarks of MS: neuroinflammatory demyelination and axonal degeneration. Understanding the role of NOS2 in murine-[beta]-coronavirus-MHV-RSA59 demyelination. Brain and spinal cords from mock and RSA59 infected 4-5-week-old MHV-free C57BL/6 mice (WT) and NOS2-/- mice were harvested at different disease phases post infection (p.i.) (day 5/6-acute, day 9/10-acute-adaptive and day 30-chronic phase) and compared for pathological outcomes. NOS2 was upregulated at the acute phase of RSA59-induced disease in WT mice and its deficiency resulted in severe disease and reduced survival at the acute-adaptive transition phase. Low survival in NOS2-/- mice was attributed to (i) high neuroinflammation resulting from increased accumulation of macrophages and neutrophils and (ii) Iba1 + phagocytic MG/M[phi] mediated-early demyelination as observed at this phase. The phagocytic phenotype of CNS MG/M[phi] was confirmed by significantly higher mRNA transcripts of phagocyte markers-CD206, TREM2, and Arg1 and double immunolabelling of Iba1 with MBP and PLP. Further, NOS2 deficiency led to exacerbated demyelination at the chronic phase as well. Taken together the results imply that the immune system failed to control the disease progression in the absence of NOS2. Thus, our observations highlight a protective role of NOS2 in murine-[beta]-coronavirus induced demyelination.

The recent surge in emerging viral infections warrants the need to design broad-spectrum antivirals. We aimed to develop a lead molecule that targets the membrane to block fusion, an obligate step of enveloped virus infection. The approach is based on the Coronin-1 protein of Mycobacterium, which presumably inhibits the phagosome-lysosome fusion, and a unique Trp-Asp (WD) sequence is placed at the distorted -meander motif. We have designed a WD-based branched lipopeptide that supports C=OHN hydrogen-bonding, the tryptophan-tryptophan - stacking, and the intermolecular H-bonding between COO and CO2H groups. These cooperative interactions are expected to create a -sheet-like supramolecular assembly at the membrane surface, which increases the interfacial order, and decreases the water penetration. Myr-D(WD)2 was shown to block artificial membrane fusion completely. We demonstrated that the Myr-D(WD)2 supramolecular organization can restrict the infection from H1N1, H9N2, murine coronavirus, and human coronavirus (HCoV-OC43). Together, the present study provided an evidence-based broad-spectrum antiviral potential of a designed small lipopeptide.

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/Mϕ) 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/Mϕ 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 TGFβ- 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/Mϕ polarization towards a phenotype that may be involved in the exacerbated demyelination pathology. Competing Interest Statement The authors have declared no competing interest.