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

Abstract

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.

Genome-Wide Association Study Identifies Eight Novel Loci for Susceptibility of Scrub Typhus and Highlights Immune-Related Signaling Pathways in Its Pathogenesis

“…Further research on the CCKR signaling map, EGF receptor signaling pathway, FGF signaling pathway, PDGF signaling pathway, Wnt signaling pathway, and p53 pathway is needed in the future. Previous studies reported that the surface antigen of O. tsutsugamushi activates the nuclear factor-kB and p38 mitogen-activated protein kinase pathway and that intracellular invasion of O. tsutsugamushi is mediated by integrin signaling [ 26 ]. These signaling pathways were also identified in the present study ( Supplementary Table S4 ).…”