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Chlamydia pneumoniae infection results in generalized bone loss in mice
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). (Wolf-Watz)
Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Rehabiliteringsmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). (Bergström)
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2008 (Engelska)Ingår i: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 10, nr 10-11, s. 1175-1181Artikel i tidskrift (Refereegranskat) Published
Ort, förlag, år, upplaga, sidor
2008. Vol. 10, nr 10-11, s. 1175-1181
Nyckelord [en]
Chlamydia pneumoniae; Bone; Osteoblasts; Bone loss
Nationell ämneskategori
Infektionsmedicin Mikrobiologi inom det medicinska området Immunologi inom det medicinska området
Identifikatorer
URN: urn:nbn:se:umu:diva-11207DOI: 10.1016/j.micinf.2008.06.010PubMedID: 18640288OAI: oai:DiVA.org:umu-11207DiVA, id: diva2:150878
Tillgänglig från: 2008-11-27 Skapad: 2008-11-27 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. Infection biology of Chlamydia pneumoniae
Öppna denna publikation i ny flik eller fönster >>Infection biology of Chlamydia pneumoniae
2008 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Molekylärbiologi (Medicinska fakulteten), 2008. s. 70
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1164
Nyckelord
Chlamydia pneumoniae, Type three secretion system, Bone
Nationell ämneskategori
Klinisk vetenskap
Identifikatorer
urn:nbn:se:umu:diva-1582 (URN)978-91-7264-532-5 (ISBN)
Disputation
2008-04-04, Major Groove, 6L, Molekylärbiologen, UMEÅ, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2008-03-17 Skapad: 2008-03-17 Senast uppdaterad: 2010-01-18Bibliografiskt granskad
2. Chemical genetics discloses the importance of heme and glucose metabolism in Chlamydia trachomatis pathogenesis
Öppna denna publikation i ny flik eller fönster >>Chemical genetics discloses the importance of heme and glucose metabolism in Chlamydia trachomatis pathogenesis
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå Universitet, 2013. s. 50
Nyckelord
Chlamydiae, heme metabolism, glucose metabolism, glucose-6-phosphate, RB-to-EB transition
Nationell ämneskategori
Naturvetenskap
Forskningsämne
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-70304 (URN)978-91-7459-673-1 (ISBN)978-91-7459-674-8 (ISBN)
Disputation
2013-06-04, Biomedicinhuset, Byggnad 6A, NUS, sal A5, Plan 0, Umeå universitet, Umeå, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2013-05-14 Skapad: 2013-05-13 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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