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Infection biology of Chlamydia pneumoniae
Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1164
Keyword [en]
Chlamydia pneumoniae, Type three secretion system, Bone
National Category
Clinical Science
Identifiers
URN: urn:nbn:se:umu:diva-1582ISBN: 978-91-7264-532-5 (print)OAI: oai:DiVA.org:umu-1582DiVA: diva2:141442
Public defence
2008-04-04, Major Groove, 6L, Molekylärbiologen, UMEÅ, 13:00 (English)
Opponent
Supervisors
Available from: 2008-03-17 Created: 2008-03-17 Last updated: 2010-01-18Bibliographically approved
List of papers
1. Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle
Open this publication in new window or tab >>Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle
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2007 (English)In: FEBS Lett, ISSN 0014-5793, Vol. 581, no 4, 587-595 p.Article in journal (Refereed) Published
Abstract [en]

Intracellular parasitism by Chlamydiales is a complex process involving transmission of metabolically inactive particles that differentiate, replicate, and re-differentiate within the host cell. A type three secretion system (T3SS) has been implicated in this process. We have here identified small molecules of a chemical class of acylated hydrazones of salicylaldehydes that specifically blocks the T3SS of Chlamydia. These compounds also affect the developmental cycle showing that the T3SS has a pivotal role in the pathogenesis of Chlamydia. Our results suggest a previously unexplored avenue for development of novel anti-chlamydial drugs.

Keyword
Animals, Anti-Bacterial Agents/chemistry/*pharmacology, Bacterial Proteins/*antagonists & inhibitors/genetics/*secretion, Cell Proliferation/drug effects, Chlamydia Infections/*microbiology, Chlamydia trachomatis/cytology/drug effects, Chlamydophila pneumoniae/cytology/*drug effects, Dose-Response Relationship; Drug, Down-Regulation/drug effects, Epithelial Cells/cytology/drug effects/microbiology, Gene Expression Regulation; Bacterial/drug effects, Genes; Bacterial, Hela Cells, Humans, Mice, Transcription; Genetic/drug effects, Yersinia Infections, Yersinia pseudotuberculosis/*drug effects
Identifiers
urn:nbn:se:umu:diva-12890 (URN)doi:10.1016/j.febslet.2007.01.013 (DOI)17257594 (PubMedID)
Available from: 2008-01-21 Created: 2008-01-21 Last updated: 2017-05-24Bibliographically approved
2. A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis
Open this publication in new window or tab >>A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis
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2006 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 39, 14566-14571 p.Article in journal (Refereed) Published
Abstract [en]

The intracellular pathogen Chlamydia trachomatis possesses a type III secretion (TTS) system believed to deliver a series of effector proteins into the inclusion membrane (Inc-proteins) as well as into the host cytosol with perceived consequences for the pathogenicity of this common venereal pathogen. Recently, small molecules were shown to block the TTS system of Yersinia pseudotuberculosis. Here, we show that one of these compounds, INP0400, inhibits intracellular replication and infectivity of C. trachomatis at micromolar concentrations resulting in small inclusion bodies frequently containing only one or a few reticulate bodies (RBs). INP0400, at high concentration, given at the time of infection, partially blocked entry of elementary bodies into host cells. Early treatment inhibited the localization of the mammalian protein 14-3-3beta to the inclusions, indicative of absence of the early induced TTS effector IncG from the inclusion membrane. Treatment with INP0400 during chlamydial mid-cycle prevented secretion of the TTS effector IncA and homotypic vesicular fusions mediated by this protein. INP0400 given during the late phase resulted in the detachment of RBs from the inclusion membrane concomitant with an inhibition of RB to elementary body conversion causing a marked decrease in infectivity.

Place, publisher, year, edition, pages
Washington: The Acad., 2006
Keyword
14-3-3 Proteins/metabolism, Anti-Bacterial Agents/chemistry/*pharmacology, Bacterial Proteins/*antagonists & inhibitors/metabolism, Cell Differentiation, Cell Membrane/metabolism, Chlamydia Infections/*drug therapy, Chlamydia trachomatis/cytology/*drug effects/*physiology/ultrastructure, Dose-Response Relationship; Drug, Inclusion Bodies/ultrastructure, Membrane Fusion, Phosphoproteins/metabolism, Protein Binding, Protein Transport
Identifiers
urn:nbn:se:umu:diva-16691 (URN)10.1073/pnas.0606412103 (DOI)16973741 (PubMedID)
Available from: 2007-10-09 Created: 2007-10-09 Last updated: 2017-12-14Bibliographically approved
3. The T3SS-inhibitor INP0010 decreases transcription initiation and modulates mRNA stability during early development in Chlamydia pneumoniae
Open this publication in new window or tab >>The T3SS-inhibitor INP0010 decreases transcription initiation and modulates mRNA stability during early development in Chlamydia pneumoniae
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:umu:diva-3013 (URN)
Available from: 2008-03-17 Created: 2008-03-17 Last updated: 2012-05-04Bibliographically approved
4. Small molecule inhibitors reveal a role for the Chlamydia type III secretion system in iron acquisition
Open this publication in new window or tab >>Small molecule inhibitors reveal a role for the Chlamydia type III secretion system in iron acquisition
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3014 (URN)
Available from: 2008-03-17 Created: 2008-03-17 Last updated: 2011-03-31Bibliographically approved
5. Chlamydia pneumoniae infection results in generalized bone loss in mice
Open this publication in new window or tab >>Chlamydia pneumoniae infection results in generalized bone loss in mice
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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
Keyword
Chlamydia pneumoniae; Bone; Osteoblasts; Bone loss
National Category
Infectious Medicine Microbiology in the medical area Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-11207 (URN)10.1016/j.micinf.2008.06.010 (DOI)18640288 (PubMedID)
Available from: 2008-11-27 Created: 2008-11-27 Last updated: 2017-12-14Bibliographically approved

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