Comprehensive Flux Modeling of Chlamydia trachomatis Proteome and qRT-PCR Data Indicate Biphasic Metabolic Differences Between Elementary Bodies and Reticulate Bodies During Infection

Yang, Meifang; Rajeeve, Karthika; Rudel, Thomas; Dandekar, Thomas

doi:10.3389/fmicb.2019.02350

Cited by 20 publications

(17 citation statements)

References 48 publications

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“…6), when RBs are known to asynchronously transition into EBs (56,57). The overall decrease in expression of bacterial glycolytic enzymes at mid-developmental cycle is consistent with previous RT-and quantitative RT-PCR data (19,58). However, we do note that our data differ from previous publications in that we saw the highest level of enzyme expression at 8 h postinfection rather than at 24 h postinfection.…”

Section: Discussionsupporting

confidence: 88%

Host and Bacterial Glycolysis during Chlamydia trachomatis Infection

Ende

Derré

2020

Infect Immun

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The obligate intracellular pathogen Chlamydia trachomatis is the leading cause of non-congenital blindness and causative agent of the most common sexually transmitted infection of bacterial origin. With a reduced genome, C. trachomatis is dependent on its host for survival, in part due to a need for the host cell to compensate for incomplete bacterial metabolic pathways. However, relatively little is known regarding how C. trachomatis is able to hijack host cell metabolism. In this study, we show that two host glycolytic enzymes, Aldolase A and Pyruvate Kinase, as well as Lactate Dehydrogenase, are enriched at the C. trachomatis inclusion membrane during infection. Inclusion localization was not species specific, as a similar phenotype was observed with C. muridarum. Time course experiments showed that the number of positive inclusions increased throughout the developmental cycle. Additionally, these host enzymes co-localized to the same inclusion and their localization did not appear dependent on sustained bacterial protein synthesis, or intact host actin, vesicular trafficking, or microtubules. Depletion of the host glycolytic enzyme Aldolase A resulted in decreased inclusion size and infectious progeny production, indicating a role for host glycolysis in bacterial growth. Finally, quantitative PCR analysis showed that expression of C. trachomatis glycolytic enzymes inversely correlated with host enzymes localization at the inclusion. We discuss potential mechanisms leading to inclusion localization of host glycolytic enzymes and how it could benefit the bacteria. Altogether, our findings provide further insight into the intricate relationship between host and bacterial metabolism during Chlamydia infection.

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Section: Discussionsupporting

confidence: 88%

Host and Bacterial Glycolysis during Chlamydia trachomatis Infection

Ende

Derré

2020

Infect Immun

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“…In C. trachomatis infection, glutamine is rapidly utilized via glutaminolysis and the TCA cycle in order to generate glutamate and other metabolites such as 2-oxoglutarate ( 24 ). Since citrate synthase, aconitate hydratase, and isocitrate dehydrogenase are lacking in the chlamydial TCA cycle ( 22 , 23 ), C. trachomatis has to acquire host cell-derived 2-oxoglutarate using the porin PorB or glutamine/glutamate that can be catabolized to 2-oxoglutarate to fuel its own TCA cycle ( 23 , 24 , 56 ). Therefore, we suggest that mitochondrial activation via PTPs-STAT3 plays a key role in the generation of ATP as well as the enhancement of glutamine metabolism to compensate for the truncated chlamydial TCA cycle in productive C. trachomatis infection.…”

Section: Discussionmentioning

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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“…Under special conditions, such as treatment with interferon-gamma (IFN-γ) or penicillin, nutrient deprivation, or co-infection with Herpes viruses ( Deka et al., 2006 ), RBs convert into persistent, nonreplicative particles, termed aberrant reticulate bodies (ARBs), which may re-convert into RBs and infectious EBs when the unfavorable conditions subside ( Elwell et al., 2016 ; Witkin et al., 2017 ; Xue et al., 2017 ; Panzetta et al., 2018 ). Both the Chlamydia cells and the host cells undergo massive metabolic changes during the different conversions ( Käding et al., 2014 ; Shima et al., 2018 ; Yang et al., 2019 ). In the persistent ARB state, Chlamydia trachomatis ceases to produce its major structural and membrane components ( Witkin et al., 2017 ), but the still ongoing basic metabolic reactions in the ARBs remain largely unknown.…”

Section: Metabolism and Persistencementioning

confidence: 99%

Persistence of Intracellular Bacterial Pathogens—With a Focus on the Metabolic Perspective

Eisenreich

Rudel

Heesemann

et al. 2021

Front. Cell. Infect. Microbiol.

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Persistence has evolved as a potent survival strategy to overcome adverse environmental conditions. This capability is common to almost all bacteria, including all human bacterial pathogens and likely connected to chronic infections caused by some of these pathogens. Although the majority of a bacterial cell population will be killed by the particular stressors, like antibiotics, oxygen and nitrogen radicals, nutrient starvation and others, a varying subpopulation (termed persisters) will withstand the stress situation and will be able to revive once the stress is removed. Several factors and pathways have been identified in the past that apparently favor the formation of persistence, such as various toxin/antitoxin modules or stringent response together with the alarmone (p)ppGpp. However, persistence can occur stochastically in few cells even of stress-free bacterial populations. Growth of these cells could then be induced by the stress conditions. In this review, we focus on the persister formation of human intracellular bacterial pathogens, some of which belong to the most successful persister producers but lack some or even all of the assumed persistence-triggering factors and pathways. We propose a mechanism for the persister formation of these bacterial pathogens which is based on their specific intracellular bipartite metabolism. We postulate that this mode of metabolism ultimately leads, under certain starvation conditions, to the stalling of DNA replication initiation which may be causative for the persister state.

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Comprehensive Flux Modeling of Chlamydia trachomatis Proteome and qRT-PCR Data Indicate Biphasic Metabolic Differences Between Elementary Bodies and Reticulate Bodies During Infection

Cited by 20 publications

References 48 publications

Host and Bacterial Glycolysis during Chlamydia trachomatis Infection

Host and Bacterial Glycolysis during Chlamydia trachomatis Infection

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

Persistence of Intracellular Bacterial Pathogens—With a Focus on the Metabolic Perspective

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