Search

Abstract Host immune control plays a pivotal role in resolving primary hepatitis-B-virus (HBV) infections. The complex interaction between HBV and host immune cells, however, remains unclear. In this study, the transcriptional profiling of specimens from animals infected with woodchuck hepatitis virus (WHV) indicated TLR2 mRNA accumulation as most strongly impacted during WHV infection resolution as compared to other mRNAs. Analysis of blood transcriptional modules demonstrated that monocytes and B-cells were the predominantly activated cell types in animals that showed resolution of infection, which was similar to the response of TLR2-stimulated PBMCs. Further investigation of TLR2-stimulated B-cells pointed at interactions between activated TLR signaling, Akt-mTOR, and glucose metabolic pathways. Moreover, analysis of B-cells from Tlr2−/−, Trif−/−, Myd88−/−, and Trif/Myd88−/− mice challenged with HBV particles indicated B-cell function and glucose metabolism alterations is TLR2-MyD88-mTOR axis dependent. Overall, our study implicates B-cell TLR2 activation in HBV infection resolution.

Beauvericin (BEA), a mycotoxin of the enniatin family produced by various toxigenic fungi, has been attributed multiple biological activities such as anti-cancer, anti-inflammatory, and anti-microbial functions. However, effects of BEA on dendritic cells remain unknown so far. Here, we identified effects of BEA on murine granulocyte–macrophage colony-stimulating factor (GM-CSF)-cultured bone marrow derived dendritic cells (BMDCs) and the underlying molecular mechanisms. BEA potently activates BMDCs as signified by elevated IL-12 and CD86 expression. Multiplex immunoassays performed on myeloid differentiation primary response 88 (MyD88) and toll/interleukin-1 receptor (TIR) domain containing adaptor inducing interferon beta (TRIF) single or double deficient BMDCs indicate that BEA induces inflammatory cytokine and chemokine production in a MyD88/TRIF dependent manner. Furthermore, we found that BEA was not able to induce IL-12 or IFNβ production in Toll-like receptor 4 (Tlr4)-deficient BMDCs, whereas induction of these cytokines was not compromised in Tlr3/7/9 deficient BMDCs. This suggests that TLR4 might be the functional target of BEA on BMDCs. Consistently, in luciferase reporter assays BEA stimulation significantly promotes NF-κB activation in mTLR4/CD14/MD2 overexpressing but not control HEK-293 cells. RNA-sequencing analyses further confirmed that BEA induces transcriptional changes associated with the TLR4 signaling pathway. Together, these results identify TLR4 as a cellular BEA sensor and define BEA as a potent activator of BMDCs, implying that this compound can be exploited as a promising candidate structure for vaccine adjuvants or cancer immunotherapies.