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

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...

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Vydáno v:	mBio Ročník 12; číslo 2
Hlavní autoři:	Shima, Kensuke, Kaufhold, Inga, Eder, Thomas, Käding, Nadja, Schmidt, Nis, Ogunsulire, Iretiolu M., Deenen, René, Köhrer, Karl, Friedrich, Dirk, Isay, Sophie E., Grebien, Florian, Klinger, Matthias, Richer, Barbara C., Günther, Ulrich L., Deepe, George S., Rattei, Thomas, Rupp, Jan
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States American Society for Microbiology 30.03.2021
Témata:	Anti-Bacterial Agents - pharmacology Antimicrobial agents Bacterial infections beta-lactams beta-Lactams - pharmacology Chlamydia Chlamydia Infections - drug therapy Chlamydia Infections - microbiology Chlamydia trachomatis Chlamydia trachomatis - drug effects Chlamydia trachomatis - genetics Chlamydia trachomatis - metabolism citrate Cytokines Electron transport Fatty acids Fatty Acids - metabolism HeLa Cells Humans Intracellular Lipids Metabolism Metabolites Mitochondria Mitochondria - drug effects Mitochondria - metabolism Penicillin Persistent infection Phospholipids Phosphorylation Proteins Research Article Respiration Sexually transmitted diseases STAT3 Stat3 protein STAT3 Transcription Factor - genetics STAT3 Transcription Factor - metabolism STD Tricarboxylic acid cycle β-Lactam antibiotics γ-Interferon penicillin beta-lactams citrate fatty acids mitochondria protein tyrosine phosphatase STAT3 persistence Chlamydia trachomatis metabolism
ISSN:	2150-7511, 2161-2129, 2150-7511
On-line přístup:	Získat plný text
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Shrnutí:	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. 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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2150-7511 2161-2129 2150-7511
DOI:	10.1128/mBio.00023-21