Ji-Hye Choi1, Taek-Chin Cheong1, Na-Young Ha1, Youngho Ko1, Chung-Hyun Cho2, Ju-Hong Jeon3, Insuk So3, In-Kyu Kim4, Myung-Sik Choi1, Ik-Sang Kim1, Nam-Hyuk Cho1,5*
1 Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea, 2 Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea, 3 Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea, 4 Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea, 5 Institute of Endemic Disease, Seoul National University Medical Research Center and Bundang Hospital, Jongno-Gu, Seoul, Republic of Korea
Dendritic cells (DCs) are the most potent antigen-presenting cells that link innate and adaptive immune responses, playing a pivotal role in triggering antigen-specific immunity. Antigen uptake by DCs induces maturational changes that include increased surface expression of major histocompatibility complex (MHC) and costimulatory molecules. In addition, DCs actively migrate to regional lymph nodes and activate antigen-specific naive T cells after capturing antigens. We characterize the functional changes of DCs infected with Orientia tsutsugamushi, the causative agent of scrub typhus, since there is limited knowledge of the role played by DCs in O. tsutsugamushi infection.
O. tsutsugamushi efficiently infected bone marrow-derived DCs and induced surface expression of MHC II and costimulatory molecules. In addition, O. tsutsugamushi induced autophagy activation, but actively escaped from this innate defense system. Infected DCs also secreted cytokines and chemokines such as IL-6, IL-12, MCP5, MIP-1α, and RANTES. Furthermore, in vitro migration of DCs in the presence of a CCL19 gradient within a 3D collagen matrix was drastically impaired when infected with O. tsutsugamushi. The infected cells migrated much less efficiently into lymphatic vessels of ear dermis ex vivo when compared to LPS-stimulated DCs. In vivo migration of O. tsutsugamushi-infected DCs to regional lymph nodes was significantly impaired and similar to that of immature DCs. Finally, we found that MAP kinases involved in chemotactic signaling were differentially activated in O. tsutsugamushi-infected DCs.
These results suggest that O. tsutsugamushi can target DCs to exploit these sentinel cells as replication reservoirs and delay or impair the functional maturation of DCs during the bacterial infection in mammals.