Altered NAD metabolism during CNS viral infection and modest immunometabolic effects of NMN in different contexts

Abstract Viral infection of the central nervous system (CNS) is increasingly linked to neurodegenerative disease, yet the metabolic programs that shape antiviral immunity and neuroinflammation remain poorly defined. Nicotinamide adenine dinucleotide (NAD) regulates mitochondrial function and immune signaling, and supplementation with its precursor nicotinamide mononucleotide (NMN) has been proposed as a therapeutic strategy; its impact during active CNS viral infection remains unclear. Here, we performed an exploratory study to characterize NAD metabolism and immunometabolic responses across both acute and chronic CNS viral infection using Theiler’s murine encephalomyelitis virus (TMEV), a model of virus-induced neurodegeneration. Integrated transcriptomic, metabolomic, and histopathological analyses revealed stage-dependent remodeling of NAD-related pathways during TMEV infection. Chronic infection was characterized by marked induction of selected NAD-related genes, accompanied by accumulation of L-kynurenine and MNA. In vitro, NMN supplementation modestly increased NAD levels while downregulating a subset of inflammatory transcripts under basal conditions, suggesting subtle shifts in basal immunometabolic states. During infection, NMN produced context-dependent effects on inflammatory responses and viral replication, although these effects were generally modest. In vivo , NMN increased CNS and systemic MNA levels in selected infection contexts and was associated with an IgG1-skewed humoral immune response but did not substantially alter viral persistence or neuropathology. Collectively, these findings demonstrate that CNS viral infection is accompanied by dynamic remodeling of NAD-related pathways, particularly in chronic infection. NMN supplementation produces modest, context-dependent effects on metabolic and immune responses, with limited impact on overall disease outcomes.