Biology subjects

Das Sarma, S.

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

4 recordsLinked to original sources

bioRxiv2026

LIF-LIFR/gp130 Survival Signaling and Connexin 47 Dysregulation upon Murine-β-Coronavirus Infection: Discovery of a Novel ERK2 Phosphorylation Site at Cx47 C-Terminal Domain

Oligodendrocyte (OLG) injury and loss are increasingly recognized as major determinants of demyelination and remyelination failure in multiple sclerosis (MS), alongside conventional immune-mediated processes. However, the mechanism underlying OLG injury and remyelination failure remains incompletely understood. Astrocyte-oligodendrocyte interactions mediated by Connexin (Cx)-43-Cx47 gap junction (GJ) communication and leukemia inhibitory factor (LIF)-LIFR/gp130 signaling are critical for oligodendroglial survival, homeostasis, and myelination. Despite their established role, how these pathways are altered during neuroinflammatory diseases remains unclear. To address this, we integrated a murine {beta}-coronavirus (RSA59)-induced in vivo model with enriched primary oligodendrocyte precursor cell (OPC) and mature OLG cultures to investigate the effect of RSA59 infection on OLGs, Cx47-mediated GJ communication, and LIF-LIFR/gp130 Signaling. We observed that RSA59 directly targets oligodendroglial lineage cells, including OPCs and mature OLGs, and induces apoptosis in mature OLGs. Despite increased OPC abundance, RSA59 infection reduces the expression of mature and myelinating markers CNPase and MBP, raising the possibility of impaired oligodendrocyte maturation and myelination. RSA59 infection also differentially regulates Cx47-mediated GJ communication and LIF-LIFR/gp130 signaling, crucial for OLG survival and homeostasis. Furthermore, our studies demonstrate that extracellular signal-regulated kinase (ERK), a downstream effector of LIF signaling, phosphorylates the Cx47 C-terminal domain (Cx47CT) at Serine-372 residue, identifying a previously unreported mechanism. Collectively, these findings reveal that RSA59 infection disrupts interconnected oligodendroglial communication and survival pathways, providing mechanistic insights into virus-induced chronic demyelination pathology. The study further identifies Cx47-mediated GJ communication and LIF-LIFR/gp130 signaling as crucial therapeutic targets, and highlights ERK-dependent Cx47CT phosphorylation as a potential regulatory mechanism.

neuroscience↗

bioRxiv2026

CX3CR1+ microglia/macrophages, activated T cells, and IFN-γ-driven stimulation confer age-dependent protective immunity in young-adult mice following β-coronavirus infection.

Age-dependent variation in the immune response is a critical determinant of host susceptibility, disease severity, and long-term sequelae in coronavirus infections, a principle strikingly demonstrated by the COVID-19 pandemic caused by SARS-CoV-2. Although primarily pneumotropic, coronaviruses carry significant neurotropic potential, driving neurological complications whose severity is profoundly determined by host age. Elderly individuals and often children suffer disproportionately severe disease, whereas young adults relatively mount protective responses; yet the cellular and molecular determinants of this age-dependent neuroprotection remain poorly characterized. Using juvenile and young-adult C57BL/6 mice intracranially inoculated with {beta}-coronavirus MHV-RSA59, a murine equivalent of human coronaviruses, we examined immune dynamics at days 5 (innate-acute), 7 (innate-to-adaptive transition), and 30 (chronic) post-infection. Young-adult mice exhibited only occasional demyelination, in stark contrast to the extensive demyelination observed across all spinal cord levels in juveniles. This differential outcome was attributable to enhanced age-dependent immune maturation, characterized by efficient T cell-microglia/macrophage crosstalk enabling effective viral control by day 7 post-infection. Young adults displayed greater glial activation, heightened cytokine release, CX3CR1+ microglia activation, and augmented CNS trafficking of CX3CR1+ and MHC II+ monocytes/macrophages, IFN-{gamma}+ CD4+/CD8+ T cells, and CXCR3+ effector T cells relative to juveniles. Reduced naive T cell frequencies and elevated effector/central memory T cell populations in cervical lymph nodes further indicate a robust adaptive memory response conferring long-term protection. Additionally, greater regulatory T cell accumulation in young adults facilitates timely suppression of excessive neuroinflammation as viral burden subsides. Together, these findings define the age-dependent immune landscape that underpins neuroprotection in {beta}-coronavirus infection.

immunology↗

bioRxiv2026

CD40 Signaling Restricts Retrograde Viral Spread and Provides Neuroprotection to Retinal Ganglion Cells in a Murine β-Coronavirus Model of Optic Neuritis

CD40, a co-stimulatory receptor of the tumor necrosis factor receptor superfamily expressed on microglia and macrophages, is an upstream regulator of innate antiviral defense in coronavirus-induced neuroinflammation, but its specific role in the visual system remains undefined. Here, we demonstrate that CD40 signaling is essential for restricting retrograde axonal transport of the murine {beta}-coronavirus RSA59 from the brain to the retina and for preventing chronic neurodegeneration in a model of viral optic neuritis. Wild-type and CD40-/- mice were intracranially inoculated with RSA59, and viral burden, neuroinflammation, and neurodegeneration were assessed at acute (day 5), bridging (day 7), and chronic (day 30) stages. CD40-/- mice exhibited significantly increased clinical severity and [~]30% mortality by day 12 post-infection, compared to 100% survival in WT mice. CD40 deficiency resulted in elevated viral loads in the optic nerve and enhanced retrograde viral dissemination across all retinal layers, whereas in WT mice, the virus was largely confined to the ganglion cell layer. CD40-/- mice exhibited impaired early microglial activation and compensatory astrogliosis during the acute and bridging phases. By day 30 p.i., although viral-N protein was undetectable by immunohistochemistry in both genotypes, CD40-/- optic nerves retained significantly higher persistent viral RNA and exhibited extensive demyelination, oligodendrocyte loss, axonal depletion, and upregulation of phagocytic markers. Critically, CD40-/- retinas showed persistent astrogliosis, accumulation of phagocytic microglia/macrophages, and a significant loss of Brn3a+ retinal ganglion cells. These findings establish CD40 as a critical molecular node governing coronavirus optic neuritis, linking early innate immune regulation to long-term neuronal survival.

immunology↗

bioRxiv2024

4-Phenylbutyric acid modulates Connexin 43 expression restricting murine-β-coronavirus infectivity and virus-induced demyelination

Gap junction intercellular communication, particularly involving Connexin 43 and Connexin 47, plays a critical role in maintaining CNS homeostasis and has been implicated in Multiple Sclerosis (MS) pathology. Thus, warranting further studies in experimental animal models to understand how modulation of Cx43 expression can influence MS pathology. Intracranial infection with murine-{beta}-coronavirus Mouse Hepatitis Virus (MHV-A59) in mice results in acute pathology characterized by high viral titers, glial activation in the brain and chronic neuroinflammatory demyelination, effectively mimicking key pathological hallmarks of MS and serving as a robust model to investigate its viral etiology. MHV-A59 infection leads to a pronounced downregulation of Cx43 during the acute phase, emphasizing its critical role in virus-induced CNS pathology. In this study, we investigated the potential of in vivo 4-phenylbutyric acid (4-PBA) administration in modulating Cx43 expression in this MHV-induced model and its consequence on chronic virus-induced demyelination. Our results reveal that 4-PBA treatment reduced acute MHV-A59 infectivity and viral spread in the brain while modulating the glial cell response, mounting host immunity. Treatment with 4-PBA effectively preserved the expression of both Cx43 and Cx47 in infected CNS cells, counteracting their infection-induced downregulation. Furthermore, MHV-A59 infection downregulated the expression of ER-resident thioredoxin family protein (ERp29), a well-known molecular chaperone of Cx43, which was rescued by 4-PBA treatment. We further validated if such downregulation of ERp29 is also evident in MS demyelinating plaques. In human MS patient-derived brain tissue, reduced Cx43 and ERp29 staining was observed in demyelinating plaques. Our studies revealed that 4-PBA treatment not only limits viral replication and spread throughout the brain but also protects the mice against severe chronic neuroinflammatory demyelination. These findings suggest that targeting Cx43 with 4-PBA holds significant therapeutic potential for addressing virus-induced neuroinflammatory demyelination and MS by preserving gap junction intercellular communication.

neuroscience↗