Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> during Treatment with β-Lactam Antimicrobials

ABSTRACT 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 rep...

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Autores principales:	Kensuke Shima, Inga Kaufhold, Thomas Eder, Nadja Käding, Nis Schmidt, Iretiolu M. Ogunsulire, René Deenen, Karl Köhrer, Dirk Friedrich, Sophie E. Isay, Florian Grebien, Matthias Klinger, Barbara C. Richer, Ulrich L. Günther, George S. Deepe, Thomas Rattei, Jan Rupp
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	Chlamydia trachomatis citrate STAT3 beta-lactams fatty acids metabolism Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1f21d46625f04f0eb17183c2f20ab571
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spelling	oai:doaj.org-article:1f21d46625f04f0eb17183c2f20ab5712021-11-10T18:37:48ZRegulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> during Treatment with β-Lactam Antimicrobials10.1128/mBio.00023-212150-7511https://doaj.org/article/1f21d46625f04f0eb17183c2f20ab5712021-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00023-21https://doaj.org/toc/2150-7511ABSTRACT 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.Kensuke ShimaInga KaufholdThomas EderNadja KädingNis SchmidtIretiolu M. OgunsulireRené DeenenKarl KöhrerDirk FriedrichSophie E. IsayFlorian GrebienMatthias KlingerBarbara C. RicherUlrich L. GüntherGeorge S. DeepeThomas RatteiJan RuppAmerican Society for MicrobiologyarticleChlamydia trachomatiscitrateSTAT3beta-lactamsfatty acidsmetabolismMicrobiologyQR1-502ENmBio, Vol 12, Iss 2 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Chlamydia trachomatis citrate STAT3 beta-lactams fatty acids metabolism Microbiology QR1-502
spellingShingle	Chlamydia trachomatis citrate STAT3 beta-lactams fatty acids metabolism Microbiology QR1-502 Kensuke Shima Inga Kaufhold Thomas Eder Nadja Käding Nis Schmidt Iretiolu M. Ogunsulire René Deenen Karl Köhrer Dirk Friedrich Sophie E. Isay Florian Grebien Matthias Klinger Barbara C. Richer Ulrich L. Günther George S. Deepe Thomas Rattei Jan Rupp Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> during Treatment with β-Lactam Antimicrobials
description	ABSTRACT 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.
format	article
author	Kensuke Shima Inga Kaufhold Thomas Eder Nadja Käding Nis Schmidt Iretiolu M. Ogunsulire René Deenen Karl Köhrer Dirk Friedrich Sophie E. Isay Florian Grebien Matthias Klinger Barbara C. Richer Ulrich L. Günther George S. Deepe Thomas Rattei Jan Rupp
author_facet	Kensuke Shima Inga Kaufhold Thomas Eder Nadja Käding Nis Schmidt Iretiolu M. Ogunsulire René Deenen Karl Köhrer Dirk Friedrich Sophie E. Isay Florian Grebien Matthias Klinger Barbara C. Richer Ulrich L. Günther George S. Deepe Thomas Rattei Jan Rupp
author_sort	Kensuke Shima
title	Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> during Treatment with β-Lactam Antimicrobials
title_short	Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> during Treatment with β-Lactam Antimicrobials
title_full	Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> during Treatment with β-Lactam Antimicrobials
title_fullStr	Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> during Treatment with β-Lactam Antimicrobials
title_full_unstemmed	Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> during Treatment with β-Lactam Antimicrobials
title_sort	regulation of the mitochondrion-fatty acid axis for the metabolic reprogramming of <named-content content-type="genus-species">chlamydia trachomatis</named-content> during treatment with β-lactam antimicrobials
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/1f21d46625f04f0eb17183c2f20ab571
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Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of <named-content content-type="genus-species">Chlamydia trachomatis</named-content> during Treatment with β-Lactam Antimicrobials

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