Abstract
Dendritic cells (DCs) orchestrate host defenses against microorganisms. In infectious diseases due to intracellular bacteria, the inefficiency of the immune system to eradicate microorganisms has been attributed to the hijacking of DC functions. In this study, we selected intracellular bacterial pathogens with distinct lifestyles and explored the responses of monocyte-derived DCs (moDCs). Using lipopolysaccharide as a control, we found that Orientia tsutsugamushi, the causative agent of scrub typhus that survives in the cytosol of target cells, induced moDC maturation, as assessed by decreased endocytosis activity, the ability to induce lymphocyte proliferation and the membrane expression of phenotypic markers. In contrast, Coxiella burnetii, the agent of Q fever, and Brucella abortus, the agent of brucellosis, both of which reside in vacuolar compartments, only partly induced the maturation of moDCs, as demonstrated by a phenotypic analysis. To analyze the mechanisms used by C. burnetii and B. abortus to alter moDC activation, we performed microarray and found that C. burnetii and B. abortus induced a specific signature consisting of TLR4, TLR3, STAT1 and interferon response genes. These genes were down-modulated in response to C. burnetii and B. abortus but up-modulated in moDCs activated by lipopolysaccharide and O. tsutsugamushi. This transcriptional alteration was associated with the defective interferon-β production. This study demonstrates that intracellular bacteria specifically affect moDC responses and emphasizes how C. burnetii and B. abortus interfere with moDC activation and the antimicrobial immune response. We believe that comparing infection by several bacterial species may be useful for defining new pathways and biomarkers and for developing new treatment strategies.
Highlights
Dendritic cells (DCs) are specialized antigen-processing and presenting cells that act as sentinels at the interface between innate and adaptive immunity [1]
C. burnetii and B. abortus partly induce monocytederived DCs (moDCs) maturation We investigated the maturation of moDCs in response to the cytoplasmic bacterial pathogen O. tsutsugamushi and three vacuolar bacteria, C. burnetii, B. abortus and T. whipplei, using three criteria: the loss of endocytosis, the ability to induce lymphocyte proliferation and the expression of CD83
The endocytosis activity of the moDCs stimulated with B. abortus C. burnetii and O. tsutsugamushi was dramatically reduced compared to the control moDCs (21% 6 3%, 18% 6 2% and 17% 6 5%, respectively, Figure 1A, b–d and f)
Summary
Dendritic cells (DCs) are specialized antigen-processing and presenting cells that act as sentinels at the interface between innate and adaptive immunity [1]. Encounters with microorganisms or bacterial ligands, such as lipopolysaccharide (LPS), triggers the maturation of immature DCs [4], a process that is associated in vivo with their migration to secondary lymphoid organs where they interact with T-cells to orchestrate adaptive immune responses [1,4]. The prevention of DC maturation and/or migration may be a relevant strategy for intracellular bacteria to avoid efficient immune responses, as illustrated by some examples of bacterial infections. Salmonella enterica serovar Typhimurium interferes with the migration of intestinal DCs and hinders antigen presentation via the ubiquitination and degradation of MHC class II molecules, which prevents bacterial killing [5,6]. Chlamydia trachomatis and C. psittaci release molecules that delay antigen presentation by MHC class II molecules [11]
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