Orientia tsutsugamushi Subverts Dendritic Cell Functions by Escaping from Autophagy and Impairing Their Migration

Abstract

BackgroundDendritic 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.Methodology/Principal Finding 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.Conclusion/SignificanceThese 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.

Orientia tsutsugamushi Modulates Endoplasmic Reticulum-Associated Degradation To Benefit Its Growth

“…O. tsutsugamushi elicits but is not cleared by autophagy (56,57), autophagy is induced by and decreases ER stress (58), and amino acids resulting from autophagy benefit the intracellular growth of Anaplasma phagocytophilum and Ehrlichia chaffeensis (59,60), which are obligate intracellular bacteria that are in the order Rickettsiales with O. tsutsugamushi. Amino acids resulting from the autophagy response to O. tsutsugamushi-induced ER stress might a The predicted biological score (PBS) was calculated for each candidate protein to assess the reliability of each interaction, ranging from the highest probability of specificity (score of A) to the lowest probability of specificity (score of E) between two proteins.…”

Bacterial Pathogens versus Autophagy: Implications for Therapeutic Interventions

“…O. tsutsugamushi infection induces autophagy, however, most of the bacteria do not colocalize with autophagosomes, even when further stimulated with rapamycin . Therefore, O. tsutsugamushi must block autophagic recognition[36,37]. Another pathogen, Burkholderia pseudomallei promotes its replication in the cytosol of murine macrophages by evading LC3 targeting through an undefined process involving the type III secretion system ATPase BpscN[38].…”

Host‐microbe interaction in the gastrointestinal tract

“…). In addition, intracellular autophagic pathways, which can also regulate cell death and proliferation to restrict bacterial invasion (Benjamin et al ., ) can be targeted by species including Orientia tsutsugamushi and Mycobacterium tuberculosis (Shin et al ., ; Choi et al ., ) to facilitate epithelial penetrance.…”

“…Host-microbe interaction in the GI tract 5 (Shin et al, 2010;Choi et al, 2013) to facilitate epithelial penetrance.…”