Mito-xenophagic killing of bacteria is coordinated by a metabolic switch in dendritic cells

Radomski, Nadine; Kägebein, Danny; Liebler-Tenorio, Elisabeth M.; Karger, Axel; Rufer, Elke; Tews, Birke Andrea; Nagel, Stefanie; Einenkel, Rebekka; Müller, Anne; Rebbig, Annica; Knittler, Michael R.

doi:10.1038/s41598-017-04142-5

Cited by 12 publications

(15 citation statements)

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“…DCs and NK cells are among the first immune cells involved in counteracting a Chlamydia infection and spreading. Both cell types are known to be less permissive to the developmental cycle of Chlamydia than other cell types, resulting in impaired bacterial growth and reduced production of infectious elementary bodies (EBs) (90,91). During the course of DC infection, increased biogenesis of MVBs is directly coupled to increased formation and release of exosomal vesicles (dexosomes).…”

Section: Discussionmentioning

confidence: 99%

Chlamydia psittaci -Infected Dendritic Cells Communicate with NK Cells via Exosomes To Activate Antibacterial Immunity

et al. 2019

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Dendritic cells (DCs) and natural killer (NK) cells are critically involved in the early response against various bacterial microbes. Functional activation of infected DCs and NK cell-mediated gamma interferon (IFN-γ) secretion essentially contribute to the protective immunity against Chlamydia. How DCs and NK cells cooperate during the antichlamydial response is not fully understood. Therefore, in the present study, we investigated the functional interplay between Chlamydia-infected DCs and NK cells. Our biochemical and cell biological experiments show that Chlamydia psittaci-infected DCs display enhanced exosome release. We find that such extracellular vesicles (referred to as dexosomes) do not contain infectious bacterial material but strongly induce IFN-γ production by NK cells. This directly affects C. psittaci growth in infected target cells. Furthermore, NK cell-released IFN-γ in cooperation with tumor necrosis factor alpha (TNF-α) and/or dexosomes augments apoptosis of both noninfected and infected epithelial cells. Thus, the combined effect of dexosomes and proinflammatory cytokines restricts C. psittaci growth and attenuates bacterial subversion of apoptotic host cell death. In conclusion, this provides new insights into the functional cooperation between DCs, dexosomes, and NK cells in the early steps of antichlamydial defense.

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Section: Discussionmentioning

confidence: 99%

Chlamydia psittaci -Infected Dendritic Cells Communicate with NK Cells via Exosomes To Activate Antibacterial Immunity

et al. 2019

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“…1d,e ). In contrast to infected epithelial cells 30 , multiple peripheral small bacteria-positive vacuoles with diameters of 1–3 μm were observed (Fig. 1d,e ).…”

Section: Resultsmentioning

confidence: 91%

“…Therefore, the cells were incubated with chlamydia (MOI 40) for 24 h in the presence of inhibitors blocking different cellular uptake mechanisms (see methods). Lysates of infected and non-infected cells were analysed by Western blot probed for chlamydial (chl)HSP60 as a proxy for bacterial growth 30 (Fig. 1a ).…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we had demonstrated that C. psittaci -infected DCs harbour cell-autonomous self-protection mechanisms that disintegrate chlamydial inclusions and routes them for xenophagic degradation, leading to the generation of MHC I presented antigens 30 . Since both DCs and NK cells serve as essential part of a crucial “first line of defence” and are among the initial immune cells encountered by chlamydia during infection 1 , we asked whether NK cells are also capable of being infected by the bacteria and whether they mount self-defence strategies against such infections.…”

Section: Introductionmentioning

confidence: 99%

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NK Cell-Mediated Processing Of Chlamydia psittaci Drives Potent Anti-Bacterial Th1 Immunity

Radomski

Franzke

Matthiesen

et al. 2019

Sci Rep

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Natural killer (NK) cells are innate immune cells critically involved in the early immune response against various pathogens including chlamydia. Here, we demonstrate that chlamydia-infected NK cells prevent the intracellular establishment and growth of the bacteria. Upon infection, they display functional maturation characterized by enhanced IFN-γ secretion, CD146 induction, PKCϴ activation, and granule secretion. Eventually, chlamydia are released in a non-infectious, highly immunogenic form driving a potent Th1 immune response. Further, anti-chlamydial antibodies generated during immunization neutralize the infection of epithelial cells. The release of chlamydia from NK cells requires pKCϴ function and active degranulation, while granule-associated granzyme B drives the loss of chlamydial infectivity. Cellular infection and bacterial release can be undergone repeatedly and do not affect NK cell function. Strikingly, NK cells passing through such an infection cycle significantly improve their cytotoxicity. Thus, NK cells not only protect themselves against productive chlamydial infections but also actively trigger potent anti-bacterial responses. NK cells play an important role in the immune response against various pathogens including chlamydia 1. Through their interactions with other immune cells, they are important mediators between innate and adaptive immunity 2. NK cells express a set of activating/inhibiting receptors 3 , which generate signals whose balance determines which cellular program is chosen 4. They are activated by various cytokines 5 resulting in the activation of phospholipase C (PLC). PLC generates two messengers, 1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), which activate protein kinases C (PKCs) and mobilize Ca 2+ from intracellular stores. DAG promotes PKCϴ translocation to membranes and phospho-activation, regulating NK-mediated effector functions 6. To detect and lyse target cells, NK cells use distinct mechanisms: Antibody-dependent cell-mediated cytotoxicity (ADCC) and natural cytotoxic activity 7. In ADCC, the Fc part of target cell-bound IgG is recognized by the FcγRΙΙΙ receptor (CD16) on NK cells, upon which cytotoxic proteins are released in addition to IFN-γ. This leads to the cytotoxic killing of target cells 8. No prior sensitization is needed for natural cytotoxicity, allowing for rapid detection/killing by this mechanism 8. After direct contact with the target cell, secretory granules (containing granzymes and perforin) are released into the immunological gap 8. Moreover, NK cells can kill via TNF family ligands 9 as well as via the secretion of cytokines and chemokines 10. DAG-mediated activation of PKCs is sufficient to induce degranulation of NK cells, leading to the release of granzyme B 11. Granzyme B is initially synthesized as an inactive precursor whose propeptide is removed by cathepsin C 12 , generating the enzymatically active protease. Perforin mediates the entry of activated granzyme B into the cytoplasm of target cells, where a large number o...

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“…Parkin is essential for colocalization of ubiquitin along phagosomes markers within M. tuberculosis ; murine bone-marrow-derived-macrophages bearing double knockouts for PARK2 are more susceptible to M. tuberculosis or S. enterica growth and present a decrease in survival rate after infection ( 69 ). Parkin role in the clearance of intracellular bacteria is corroborated by functional assays performed using dendritic cells infected by Chlamydia: autophagosome degradation of chlamydial infections and MHC-I antigen presentation are increased in presence of Parkin ( 70 ).…”

Section: The Park2/parkin Casementioning

confidence: 95%

Genetic Susceptibility to Leprosy—From Classic Immune-Related Candidate Genes to Hypothesis-Free, Whole Genome Approaches

Cambri

Mira

2018

Front. Immunol.

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Genetics plays a crucial role in controlling susceptibility to infectious diseases by modulating the interplay between humans and pathogens. This is particularly evident in leprosy, since the etiological agent, Mycobacterium leprae, displays semiclonal characteristics not compatible with the wide spectrum of disease phenotypes. Over the past decades, genetic studies have unraveled several gene variants as risk factors for leprosy per se, disease clinical forms and the occurrence of leprosy reactions. As expected, several of these genes are immune-related; yet, hypothesis-free approaches have led to genes not classically linked to immune response. The PARK2, originally described as a Parkinson’s disease gene, illustrates the case: Parkin—the protein coded by PARK2—was defined as an important player regulating innate and adaptive immune responses only years after its description as a leprosy susceptibility gene. Interestingly, even with the use of powerful hypothesis-free study designs such as genome-wide association studies, most of the major gene effect controlling leprosy susceptibility remains elusive. One hypothesis to explain this “hidden heritability” is that rare variants not captured by classic association studies are of critical importance. To address this question, massively parallel sequencing of large segments of the human genome—even whole exomes/genomes—is an alternative to properly identify rare, disease-causing mutations. These mutations may then be investigated through sophisticated approaches such as cell reprogramming and genome editing applied to create in vitro models for functional leprosy studies.

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Mito-xenophagic killing of bacteria is coordinated by a metabolic switch in dendritic cells

Cited by 12 publications

References 74 publications

Chlamydia psittaci -Infected Dendritic Cells Communicate with NK Cells via Exosomes To Activate Antibacterial Immunity

Chlamydia psittaci -Infected Dendritic Cells Communicate with NK Cells via Exosomes To Activate Antibacterial Immunity

NK Cell-Mediated Processing Of Chlamydia psittaci Drives Potent Anti-Bacterial Th1 Immunity

Genetic Susceptibility to Leprosy—From Classic Immune-Related Candidate Genes to Hypothesis-Free, Whole Genome Approaches

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