Journal
VIROLOGY JOURNAL
Volume 10, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/1743-422X-10-34
Keywords
Modified vaccinia virus Ankara; Interleukin-1 beta induction; Viral interleukin-1 beta receptor; Inflammasome; Caspase-1; Human cells; Macrophages; Dendritic cells
Categories
Funding
- European Commission [FP6 MVACTOR LHSP-CT-2006-037536, FP6 BIOSAFE SSPE-CT-2006-022725]
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Background: Modified vaccinia virus Ankara (MVA) is a highly attenuated virus and a promising vaccine vector with potent immune stimulating properties. Deletion of the gene encoding the viral interleukin-1beta receptor (vIL-1 beta R) in MVA (MVA Delta IL-1 beta R) was previously shown to enhance memory T cell function. Here, we investigated the influence of vIL-1 beta R on blocking interleukin-1beta (IL-1 beta) upon MVA infection in various antigen presenting cells of murine and human origin, and analyzed whether inflammasome function contributes to IL-1 beta production in different cell types. Findings: Extending previous studies, immunizing mice with low doses of MVA Delta IL-1 beta R still showed enhanced memory CD8(+) T cell activation compared to MVA wild-type (MVAwt) immunization. In vitro, murine myeloid dendritic cells, and activated, but not naive primary macrophages were identified as potent producers of IL-1 beta upon infection with MVA. Importantly, free IL-1 beta was only detected in the absence of vIL-1 beta R. Moreover, MVA Delta IL-1 beta R increased amounts of bioactive IL-1 beta compared to MVAwt after infection of human THP-1 cells, as detected using a reporter system that only responds to active and free IL-1 beta. The MVA-mediated induction of IL-1 beta was confirmed to depend on inflammasome function in human and murine cells, however in murine cells this apparently involves caspase-1-independent pathways. Conclusions: MVA lacking IL-1 beta blocking activity leads to increased concentrations of free IL-1 beta upon infection of murine and human antigen presenting cells; this is likely responsible for enhanced memory T cell activation upon MVA Delta IL-1 beta R immunization of mice. Moreover, our results suggest that MVA-mediated IL-1 beta induction is a multifactorial process.
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