A surface antigen of Orientia tsutsugamushi activates human monocyte-derived dendritic cells via nuclear factor-kB & p38 mitogen-activated protein kinase pathways

BACKGROUND & OBJECTIVES: Scrub typhus is a chigger-borne disease caused by Orientia tsutsugamushi. The immunological reactions to O. tsutsugamushi infection are not completely understood. In this study, we investigated the response of dendritic cells (DCs) to a major 56-kDa scrub typhus antigen Sta56. METHODS: Monocyte-derived human DCs were incubated with different concentrations of recombinant Sta56 and analyzed for maturation based on phagocytic capacity, the ability to induce T-cell proliferation, expression of surface markers, cytokine secretion and activation of toll-like receptor (TLR)-dependent signalling pathways. RESULTS: Treatment of DCs with Sta56 induced cell surface expression of CD80, CD83, CD86 and MHC Class II increased the production of interleukin-12 (IL-12) p40, IL-12 p70 and IL-10 and decreased DC phagocytic capacity. Furthermore, Sta56 increased the ability of DCs to activate T-cell proliferation and interferon-γ secretion. TLR4-specific antibodies neutralized Sta56-elicited effects on DC maturation, suggesting direct interaction between Sta56 and TLR4. Moreover, Sta56 activated nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK) signalling as evidenced by decrease in Sta56-induced cytokine production and surface marker expression by specific inhibitors helenalin and SB203580, respectively, and increase in IκBα and p38 phosphorylation and NF-κB-DNA binding. INTERPRETATION & CONCLUSIONS: Our results showed that the surface antigen of O. tsutsugamushi activated DCs through interaction with TLR4 and activation of MAPK and NF-κB signalling, suggesting Sta56 as a potential candidate molecule for the development of vaccine against scrub typhus.