Intracellular Bacteria Interfere with Dendritic Cell Functions: Role of the Type I Interferon Pathway

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.

From Q Fever to Coxiella burnetii Infection: a Paradigm Change

“…Recently, we compared the responses of myeloid DCs (mDCs) to a panel of intracellular pathogens and demonstrated that the blockade of mDC maturation was partial, since they were still able to induce T-cell proliferation. The transcriptomic analysis of C. burnetii-stimulated mDCs revealed subtle alterations in type I IFN signaling (259). We also showed that C. burnetii is able to activate plasmacytoid DCs (pDCs), inducing their maturation and the release of type I IFN, a property of the host response to virus.…”

Coxiella burnetii epitope-specific T-cell responses in chronic Q fever patients

“…If this strong IFNγ response is insufficient to promote clearance of infection foci by activating C. burnetii -infected monocytes/macrophages then the defect could be downstream of IFNγ signaling as proposed previously (14). In particular, antigen-presenting cell maturation, function and interaction with T-cells as mediated via the IFN-IL-12p40 feedback loop (14, 17–19) in foci of infection could be compromised in persistent infection. Therefore, further research is required to clarify whether chronic Q fever patients can benefit from a therapeutic vaccine, or whether a completely different approach is needed to achieve clearance in this population.…”

Single-step genome-wide association study for resistance toPiscirickettsia salmonisin rainbow trout (Oncorhynchus mykiss)

“…Within the region associated with TD on Omy3 we identified a gene coding for the receptor DC-SIGN related with the immune response and expressed on macrophage and dendritic-cell surfaces (Ahmed et al 2015). It has been previously described that Mycobacterium tuberculosis , interferes with the Toll-like receptor signaling by DC-SIGN, inhibiting interleukin-12 production (Gorvel et al 2014), a proinflammatory cytokine, which plays a key role in the performance of phagocytes in teleost fish (Alvarez et al 2016).…”