The NADL strain of bovine viral diarrhea virus induces the secretion of IL-1β through caspase 1 in bovine macrophages

Abstract

Bovine viral diarrhea virus (BVDV) infects different cell types including antigen-presenting cells such as macrophages. The infection induces pro-inflammatory cytokines like interleukin 1 beta (IL-1β), which is necessary to trigger a successful inflammatory response against infections. Several authors have reported differences between IL-1β gene expression and protein detection in BVDV-infected macrophages. These patterns may be related to inflammasome assembly, which promote the formation of active caspase 1 in order to produce mature IL-1β molecules. Our goal was to assess BVDV ability to induce the release of IL-β through a caspase 1 dependent pathway in bovine macrophages. We infected peripheral blood monocyte-derived macrophages using BVDV NADL strain at 0.001, 0.1, 2 and 10 multiplicities of infection (MOI) and we measured IL-1β at different times 2, 6, 12, 24, 48, 72 h. We found an increase of 1140-2154 pg for a MOI of 10:1 and 2:1 respectively. To inhibit caspase 1, we used either carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone (Z-VAD) or carbobenzoxy-tyr-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone (Y-VAD). We found decreased IL-1β secretion 2154 pg/ml to 854 pg/ml IL-1β secretion using Y-VAD and we observed decrease from 2154 pg/ml to 22.33 pg/ml with Z-VAD, and this inhibition was followed by diminished viral replication from 2.25 × 10⁷ to 2.1 × 10⁵ CCID₅₀, which suggests that caspase 1-dependent secretion of the IL-1β active molecule is important for viral replication. This is the first report showing that BVDV infected-bovine macrophages trigger the caspase 1 dependent pathway for IL-1β activation and that activation increases viral replication.

Keywords: BVDV-1; Flavivirus; Inflammasome; Innate immunity.