GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE306nnn/GSE306508/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE306508GEOGSEfalseMultimodal induction of hyperinflammation by IL-18 includes virus-specific NK immunodeficiency [NKILC1_RNAseq]Hemophagocytic Lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with multiple contributors and often an infectious trigger. The Macrophage Activation Syndrome (MAS) subtype is linked to marked IL-18 excess, cytotoxic T-lymphocyte (CTL) activation, and natural killer (NK) cell abnormalities. We asked how excess IL-18 shapes NK and CTL responses to viral challenge. Mice with chronic IL-18 overproduction (Il18tg), showed NK-cytopenia and baseline CTL activation resembling MAS-susceptible patients. NK transcriptomes indicated transcription/division with few changes in canonical NK programs. Infection of Il18tg mice with lymphocytic-choriomeningitis virus resulted in HLH/MAS but intact viral control. Early after NK-dependent mousepox infection, Il18tg NKs failed to appropriately activate but their CTLs became hyperactivated, and mousepox control remained intact. However, mousepox-infected Il18tg mice then developed hepatosplenic necrosis and other signs of HLH/MAS; and their poor viral control paralleled their failed expansion of mousepox-specific CTLs. Il18bpKO mice, despite more normal resting lymphocytes, succumbed similarly to viremic HLH/MAS. Transfer of pre-activated NKs into Il18tg mice restored their virus-specific CTL response and rescued survival. Thus, excess IL-18 contributes to HLH/MAS via disparate effects on CTL and NK cells, demonstrating a novel, context-specific NK immunodeficiency and highlighting how subtle host-pathogen interactions can affect the mechanisms and treatment rationale of life-threatening HLH/MAS.2026/08/25GSE306508GSM9202369GSM9202367GSM9202378GSM9202368GSM9202379GSM9202372GSM9202373GSM9202362GSM9202370GSM9202381GSM9202371GSM9202376GSM9202365GSM9202377GSM9202366GSM9202374GSM9202363GSM9202364GSM9202375GSM920238019057306508Mus musculus