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Cell Rep. 2019 Mar 26;26(13):3502-3510.e6. doi: 10.1016/j.celrep.2019.02.103.

Limitation of TCA Cycle Intermediates Represents an Oxygen-Independent Nutritional Antibacterial Effector Mechanism of Macrophages.

Author information

1
Mikrobiologisches Institut, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
2
Mikrobiologisches Institut, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany; Klinik für Innere Medizin I, Universitätsklinikum Regensburg, 93053 Regensburg, Germany.
3
Institut für Funktionelle Genomik, Universität Regensburg, 93053 Regensburg, Germany.
4
Institut für Medizinischen Mikrobiologie, Universitätsklinikum Jena, 07743 Jena, Germany.
5
Institut für Klinische Mikrobiologie und Hygiene, Universitätsklinikum Regensburg, Universität Regensburg, 93053 Regensburg, Germany.
6
Medizinische Klinik 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91052 Erlangen, Germany.
7
Institut für Klinische Mikrobiologie und Hygiene, Universitätsklinikum Regensburg, Universität Regensburg, 93053 Regensburg, Germany. Electronic address: jonathan.jantsch@ukr.de.
8
Mikrobiologisches Institut, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: anja.luehrmann@uk-erlangen.de.

Abstract

In hypoxic and inflamed tissues, oxygen (O2)-dependent antimicrobial defenses are impaired due to a shortage of O2. To gain insight into the mechanisms that control bacterial infection under hypoxic conditions, we infected macrophages with the obligate intracellular pathogen Coxiella burnetii, the causative agent of Q fever. Our experiments revealed that hypoxia impeded C. burnetii replication in a hypoxia-inducible factor (HIF) 1α-dependent manner. Mechanistically, under hypoxia, HIF1α impaired the activity of STAT3, which in turn reduced the intracellular level of TCA cycle intermediates, including citrate, and impeded C. burnetii replication in macrophages. However, bacterial viability was maintained, allowing the persistence of C. burnetii, which is a prerequisite for the development of chronic Q fever. This knowledge will open future research avenues on the pathogenesis of chronic Q fever. In addition, the regulation of TCA cycle metabolites by HIF1α represents a previously unappreciated mechanism of host defense against intracellular pathogens.

KEYWORDS:

Coxiella burnetii; HIF1α; STAT3; citrate; macrophage

PMID:
30917307
DOI:
10.1016/j.celrep.2019.02.103
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