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Two waves of activation drive systemic innate immune responses to alphavirus infection

ABSTRACT: Venezuelan equine encephalitis virus (VEEV), like many mosquito-borne RNA viruses, causes severe prodromal illness characterized by robust systemic cytokine responses including type I interferon (IFN-I), yet the mechanisms initiating these systemic responses remain undefined. Using mutant viruses with altered lymph node (LN) tropism, we show that the extent of VEEV LN infection is positively associated with systemic induction of IFN-I and other proinflammatory cytokines. Further, robust IFN-I induction requires coordinated activation of multiple IRF-7-dependent pathways, with Toll-like receptor (TLR) and RIG-I-like receptor (RLR) pathways playing distinct, nonredundant roles. Combining targeted cell depletion and Visium HD spatial transcriptomics, we uncover a two-wave innate immune response to infection in vivo, with early cytokine induction driven by VEEV-infected myeloid cells at 8 hours post-infection (hpi), and a second wave dominated by uninfected bystander cells once active infection in the LN subsides by 16hpi. Together, these findings highlight the importance of early virus-host interactions in lymphoid tissues, revealing an opportunity for development of therapeutics against disseminated virus infection and immune-driven viral pathologies.

ORGANISM(S): Mus musculus

PROVIDER: GSE330974 | GEO | 2026/07/31

REPOSITORIES: GEO

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Project description:Highly pathogenic avian influenza viruses (HPAIV) induce severe inflammation in poultry and men. There is still an ongoing threat that these viruses may acquire the capability to freely spread as novel pandemic virus strains that may cause major morbidity and mortality. One characteristic of HPAIV infections is the induction of a cytokine burst that strongly contributes to viral pathogenicity. It has been suggested, that this cytokine overexpression is an intrinsic feature of infected cells and involves hyperinduction of p38 mitogen activated protein kinase (MAPK). Here we investigate the role of MAPK p38 signaling in the antiviral response against HPAIV in mice as well as in endothelial cells, the latter a primary source for cytokines during systemic infections. Global gene expression profiling of HPAIV infected endothelial cells in the presence of the MAP kinase p38-specific inhibitor SB202190 revealed, that inhibition of MAPK p38 leads to reduced expression of interferon (IFN) and other cytokines after A/Thailand/1(KAN-1)/2004 (H5N1) and A/FPV/Bratislava/79 (H7N7) infection. Furthermore, the expression of interferon stimulated genes (ISGs) after treatment with IFN or conditioned media from HPAIV infected cells was decreased when the target cells were preincubated with SB202190. Finally, promoter analysis confirmed a direct impact of p38 MAPK on the IFN-enhanceosome and ISG-promoter activity. In vivo inhibition of MAP kinase p38 greatly diminishes virus induced cytokine expression concomitant with reduced viral titers, thereby protecting mice from lethal infection. These observations show, that MAPK p38 acts on two levels of the antiviral IFN response: Initially the kinase regulates IFN induction and at a later stage MAPK p38 controls IFN signaling and thereby expression of IFN-stimulated genes. Thus, inhibition of MAP kinase p38 may be an antiviral strategy that significantly protects mice from lethal influenza via suppression of overshooting cytokine expression. HUVEC were infected with FPV in the presence or absence of a p38 MAP kinase inhibitor

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Two waves of activation drive systemic innate immune responses to alphavirus infection

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