Interferon-γ interferes with host cell metabolism during intracellular Chlamydia trachomatis infection

Shima, Kensuke; Kaeding, Nadja; Ogunsulire, Iretiolu M.; Kaufhold, Inga; Klinger, Matthias; Rupp, Jan

doi:10.1016/j.cyto.2018.05.039

Cited by 18 publications

(21 citation statements)

References 47 publications

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“…More interestingly, the observation, in our study, that the treatment of synovial cells with IFNγ was highly effective in inhibiting C. trachomatis infection and growth as well as inducing TLR2 and ISG56-related gene expression, suggests the importance of IFNγ-mediated immune response in the clearance of C. trachomatis infection. To date, IFNγ activity as an anti-chlamydial agent is believed to be mostly mediated by its ability to reduce tryptophan availability via the upregulation of the enzyme indoleamine 2,3-dioxygenase (IDO)-1, which metabolizes tryptophan into kynurenine, inhibiting chlamydial replication [40]. Nevertheless, in our study, the anti-chlamydial effect of IFNγ were present even after replenishing the intracellular and extracellular tryptophan pool by adding fresh culture media after the C. trachomatis infection.…”

Section: Discussionmentioning

confidence: 58%

Interferon-γ Possesses Anti-Microbial and Immunomodulatory Activity on a Chlamydia trachomatis Infection Model of Primary Human Synovial Fibroblasts

Pietro¹,

Filardo²,

Frasca

et al. 2020

Microorganisms

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Chlamydia trachomatis, an obligate intracellular pathogen, is the most common cause of bacterial sexually transmitted diseases, and it is potentially responsible for severe chronic sequelae, such as reactive arthritis. To date, details of the mechanisms by which Chlamydiae induce innate antimicrobial pathways in synovial fibroblasts, are not well characterized; therefore, herein, we investigated the effects of interferon (IFN)α, IFNβ, and IFNγ on the infection, and replication phases of the C. trachomatis developmental cycle, as well as on the induction of pattern recognition receptors (PRRs) and IFN-related pathways. To do so, we set up an in vitro chlamydial-infection model of primary human synovial cells treated with IFNs before or after the infection. We then determined the number of chlamydial inclusion forming units and inclusion size, as well as the expression of toll like receptor (TLR)2, TLR3, TLR4, cyclic GMP-AMP synthase (cGAS), stimulator of IFN gene (STING), IRF9, ISG56, and GBP1. The main result of our study is the significant inhibition of C. trachomatis infection and replication in human synovial cells following the treatment with IFNγ, whereas IFN-I proved to be ineffective. Furthermore, IFNγ greatly upregulated all the PRRs and ISGs examined. In conclusion, IFNγ exhibited a potent anti-Chlamydia activity in human synovial cells as well as the ability to induce a strong increase of innate immune pathways.

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Section: Discussionmentioning

confidence: 58%

Interferon-γ Possesses Anti-Microbial and Immunomodulatory Activity on a Chlamydia trachomatis Infection Model of Primary Human Synovial Fibroblasts

Pietro¹,

Filardo²,

Frasca

et al. 2020

Microorganisms

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“…In our previous study, we showed that IFN-g significantly reduced C. trachomatis-induced upregulation of mitochondrial respiration. Thus, this cytokine influences mitochondrial respiration differently than that observed with penicillin-induced persistence (10). Since chlamydial metabolism is strongly influenced by host metabolic activity, we investigated whether the expression pattern of chlamydial metabolic genes also differs in IFN-g-induced chlamydial persistence.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, we next investigated the chlamydial metabolism that could be linked to mitochondrial activity in productive and persistent infection. Fluorescence lifetime imaging microscopy (FLIM) of NAD(P)H has been demonstrated as a suitable tool for real-time analysis of chlamydial metabolism in living cells (10,40). Chlamydial metabolism was comparable between productive and penicillin-induced persistent infection at 24 hpi (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of Chlamydia trachomatis during Treatment with β-Lactam Antimicrobials

Shima

Kaufhold

Eder

et al. 2021

mBio

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Infection with the obligate intracellular bacterium Chlamydia trachomatis is the most common bacterial sexually transmitted disease worldwide. Since no vaccine is available to date, antimicrobial therapy is the only alternative in C. trachomatis infection. However, changes in chlamydial replicative activity and the occurrence of chlamydial persistence caused by diverse stimuli have been proven to impair treatment effectiveness. Here, we report the mechanism for C. trachomatis regulating host signaling processes and mitochondrial function, which can be used for chlamydial metabolic reprogramming during treatment with β-lactam antimicrobials. Activation of signal transducer and activator of transcription 3 (STAT3) is a well-known host response in various bacterial and viral infections. In C. trachomatis infection, inactivation of STAT3 by host protein tyrosine phosphatases increased mitochondrial respiration in both the absence and presence of β-lactam antimicrobials. However, during treatment with β-lactam antimicrobials, C. trachomatis increased the production of citrate as well as the activity of host ATP-citrate lyase involved in fatty acid synthesis. Concomitantly, chlamydial metabolism switched from the tricarboxylic acid cycle to fatty acid synthesis. This metabolic switch was a unique response in treatment with β-lactam antimicrobials and was not observed in gamma interferon (IFN-γ)-induced persistent infection. Inhibition of fatty acid synthesis was able to attenuate β-lactam-induced chlamydial persistence. Our findings highlight the importance of the mitochondrion-fatty acid interplay for the metabolic reprogramming of C. trachomatis during treatment with β-lactam antimicrobials. IMPORTANCE The mitochondrion generates most of the ATP in eukaryotic cells, and its activity is used for controlling the intracellular growth of Chlamydia trachomatis. Furthermore, mitochondrial activity is tightly connected to host fatty acid synthesis that is indispensable for chlamydial membrane biogenesis. Phospholipids, which are composed of fatty acids, are the central components of the bacterial membrane and play a crucial role in the protection against antimicrobials. Chlamydial persistence that is induced by various stimuli is clinically relevant. While one of the well-recognized inducers, β-lactam antimicrobials, has been used to characterize chlamydial persistence, little is known about the role of mitochondria in persistent infection. Here, we demonstrate how C. trachomatis undergoes metabolic reprogramming to switch from the tricarboxylic acid cycle to fatty acid synthesis with promoted host mitochondrial activity in response to treatment with β-lactam antimicrobials.

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“…photosynthetic carbon, tryptophan) in the proposed inclusion. Finally, these ideas are also strengthened by our current knowledge of chlamydial biology concerning, for instance, the recognized central importance of tryptophan metabolism and hypoxia in the chlamydial replication cycle 96 …”

Section: Resultsmentioning

confidence: 99%

Analysis of an improved Cyanophora paradoxa genome assembly

et al. 2019

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Glaucophyta are members of the Archaeplastida, the founding group of photosynthetic eukaryotes that also includes red algae (Rhodophyta), green algae, and plants (Viridiplantae). Here we present a high-quality assembly, built using long-read sequences, of the ca. 100 Mb nuclear genome of the model glaucophyte Cyanophora paradoxa. We also conducted a quick-freeze deep-etch electron microscopy (QFDEEM) analysis of C. paradoxa cells to investigate glaucophyte morphology in comparison to other organisms. Using the genome data, we generated a resolved 115-taxon eukaryotic tree of life that includes a well-supported, monophyletic Archaeplastida. Analysis of muroplast peptidoglycan (PG) ultrastructure using QFDEEM shows that PG is most dense at the cleavage-furrow. Analysis of the chlamydial contribution to glaucophytes and other Archaeplastida shows that these foreign sequences likely played a key role in anaerobic glycolysis in primordial algae to alleviate ATP starvation under night-time hypoxia. The robust genome assembly of C. paradoxa significantly advances knowledge about this model species and provides a reference for exploring the panoply of traits associated with the anciently diverged glaucophyte lineage.

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Interferon-γ interferes with host cell metabolism during intracellular Chlamydia trachomatis infection

Cited by 18 publications

References 47 publications

Interferon-γ Possesses Anti-Microbial and Immunomodulatory Activity on a Chlamydia trachomatis Infection Model of Primary Human Synovial Fibroblasts

Interferon-γ Possesses Anti-Microbial and Immunomodulatory Activity on a Chlamydia trachomatis Infection Model of Primary Human Synovial Fibroblasts

Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of Chlamydia trachomatis during Treatment with β-Lactam Antimicrobials

Analysis of an improved Cyanophora paradoxa genome assembly

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