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Chlamydia pneumoniae infection results in generalized bone loss in mice
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Wolf-Watz)
Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). (Bergström)
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2008 (English)In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 10, no 10-11, 1175-1181 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2008. Vol. 10, no 10-11, 1175-1181 p.
Keyword [en]
Chlamydia pneumoniae; Bone; Osteoblasts; Bone loss
National Category
Infectious Medicine Microbiology in the medical area Immunology in the medical area
URN: urn:nbn:se:umu:diva-11207DOI: 10.1016/j.micinf.2008.06.010PubMedID: 18640288OAI: diva2:150878
Available from: 2008-11-27 Created: 2008-11-27 Last updated: 2013-05-13Bibliographically approved
In thesis
1. Infection biology of Chlamydia pneumoniae
Open this publication in new window or tab >>Infection biology of Chlamydia pneumoniae
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There are two main human pathogens in the family of Chlamydiaceae. Different serovars of Chlamydia trachomatis cause sexually-transmitted disease and eye infections whereas C. pneumoniae (TWAR) is a common cause of community-acquired respiratory infection. Chlamydia species are obligate, intracellular bacteria sharing a unique developmental cycle that occurs within a protected vacuole termed an inclusion. These microorganisms can be distinguished by two different forms: the infectious, metabolically inert elementary body (EB) and the reproducing non-infectious form, termed the reticulate body (RB). The cycle is terminated when re-differentiation of RBs back to infectious EBs occurs. Chlamydia possesses a type III secretion system (T3SS) essential for delivery of effector proteins into the host for host-cell interactions. This virulence system has been systematically characterized in several mammalian pathogens. Due to lack of a tractable genetic system for Chlamydia species, we have employed chemical genetics as a strategy to investigate molecular aspects of the T3SS. We have identified that the T3S-inhibitors INP0010 and INP0400 block the developmental cycle and interfere with secretion of T3S effector proteins in C. pneumoniae and C. trachomatis, without any cytotoxic effect. We have further shown that INP0010 decreases initiation of transcription in C. pneumoniae during the early mid-developmental cycle as demonstrated by a novel calculation, useful for measurement of transcription initiation in any intracellular pathogen. The mechanism regulating the signal(s) for primary as well as terminal differentiation of RBs has not been defined in Chlamydia. We show using T3S-inhibitors that INP0010 targets the T3SS and thereby arrests RB proliferation as well as RB to EB re-differentiation of C. pneumoniae as where INP0400 targets the T3SS and provokes a bacterial dissociation from the inclusion membrane presumed to mimic the natural occurrence of terminal differentiation. The effect of INP0010 on iron-responsive genes indicates a role for T3S in iron acquisition. Accordingly, our results suggest the possibility that C. pneumoniae acquires iron via the intracellular trafficking pathway of endocytosed transferrin. Moreover, we have for the first time presented data showing generalized bone loss from C. pneumoniae infection in mice. The infection was associated with increased levels of the bone resorptive cytokines IL-6 and IL-1beta. In addition, an increased sub-population of T-cells expressed RANKL during infection. Additionally, C. pneumoniae established an infection in a human osteoblast cell line in vitro with a similar cytokine profile as seen in vivo, supporting a causal linkage. Collectively, these data may indicate a previously unknown pathological role of C. pneumoniae in generalized bone loss.

Place, publisher, year, edition, pages
Umeå: Molekylärbiologi (Medicinska fakulteten), 2008. 70 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1164
Chlamydia pneumoniae, Type three secretion system, Bone
National Category
Clinical Science
urn:nbn:se:umu:diva-1582 (URN)978-91-7264-532-5 (ISBN)
Public defence
2008-04-04, Major Groove, 6L, Molekylärbiologen, UMEÅ, 13:00 (English)
Available from: 2008-03-17 Created: 2008-03-17 Last updated: 2010-01-18Bibliographically approved
2. Chemical genetics discloses the importance of heme and glucose metabolism in Chlamydia trachomatis pathogenesis
Open this publication in new window or tab >>Chemical genetics discloses the importance of heme and glucose metabolism in Chlamydia trachomatis pathogenesis
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chlamydiae are important human bacterial pathogens with an intracellular life cycle that consists of two distinct bacterial forms, an infectious form (EB) that infects the eukaryotic host cell, and a non-infectious form (RB) that allows intracellular proliferation. To be successful, chlamydiae need to alternate between EB and RB to generate infectious EB’s which are competent to infect new host cells.

Chemical genetics is an attractive approach to study bacterial pathogenesis; in principal this approach relies on an inhibitory compound that specifically inhibits a protein of interest. An obstacle in using this approach is target identification, however whole genome sequencing (WGS) of spontaneous mutants resistant to novel inhibitory compounds has significantly extended the utility of chemical genetic approaches by allowing the identification of their target proteins and/or biological pathways.

In this thesis, a chemical genetics approach is used, I have found that heme and glucose metabolism of C. trachomatis is specifically important for the transition from the RB form to the infectious EB form. Heme and glucose metabolism are both coupled to energy metabolism, which suggests a common link between the RB-to-EB transitions. In connection with the above findings I have developed strategies that enable the isolation of isogenic C. trachomatis mutant strains. These strategies are based on WGS of spontaneous mutant populations and subsequent genotyping of clonal strains isolated from these mutant populations. Experiments with the mutant strains suggest that the uptake of glucose-6-phosphate (G-6-P) regulates the RB-to-EB transition, representing one of the first examples where genetics has been used to study C. trachomatis pathogenesis. Additional experiments with the mutant strains indicate that G-6-P promotes bacterial growth during metabolic stress.

In concert with other findings presented in this thesis, I have fine-tuned methods that could be employed to reveal how novel inhibitory chemical compounds affect chlamydiae. In a broader context, I suggest that C. trachomatis could be used as a model organism to understand how new inhibitory drugs affect other bacterial pathogens.

In addition, I observed that C. pneumoniae infections resulted in generalized bone loss in mice and that these mice display a cytokine profile similar to infected bone cells in vitro. Thus, this study indicates that C. pneumoniae potentially can infect bone cells in vivo, resulting in bone loss, alternatively, the inflammatory responses seen in vivo could be the causative factor of the bone loss observed.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2013. 50 p.
Chlamydiae, heme metabolism, glucose metabolism, glucose-6-phosphate, RB-to-EB transition
National Category
Natural Sciences
Research subject
Molecular Biology
urn:nbn:se:umu:diva-70304 (URN)978-91-7459-673-1 (printed) (ISBN)978-91-7459-674-8 (digital) (ISBN)
Public defence
2013-06-04, Biomedicinhuset, Byggnad 6A, NUS, sal A5, Plan 0, Umeå universitet, Umeå, 13:00 (English)
Available from: 2013-05-14 Created: 2013-05-13 Last updated: 2013-05-14Bibliographically approved

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