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Here, we reveal that virus-cell interactions and specific host signaling pathways in lymphoid tissues are determinants of systemic cytokine induction. Using Venezuelan equine encephalitis virus (VEEV) mutants with defined lymph node (LN) tropism in mice, we show that VEEV LN infection positively associates with systemic IFN-I and other proinflammatory cytokine induction. Maximal responses require coordinated activation of multiple IRF7-dependent Toll-like receptor and RIG-I-like receptor pathways. Combining targeted cell depletion and Visium HD spatial transcriptomics viral gene quantitation, we uncover a spatiotemporal, biphasic innate immune response to VEEV infection, with initial cytokine induction driven by VEEV replication in dendritic cell and monocyte\/macrophage subtypes within the LN subcapsular sinus. Surprisingly, active virus replication is curtailed in this LN compartment before 16hpi, when cytokine induction becomes dominated by non-VEEV-replicating bystander cells including plasmacytoid dendritic cells. These findings have direct implications for intervention against viral diseases characterized by lymphoid infection and subsequent spread to sites of terminal disease.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014509","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T17:43:33Z","timestamp":1786556613000},"page":"e1014509","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial dynamics of viral replication drive biphasic lymphoid activation and systemic alphavirus immune responses"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3372-4491","authenticated-orcid":true,"given":"Melaina 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