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A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis
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).
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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. Vol. 103, no 39, 14566-14571 p.
Keyword [en]
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
URN: urn:nbn:se:umu:diva-16691DOI: 10.1073/pnas.0606412103PubMedID: 16973741OAI: diva2:156364
Available from: 2007-10-09 Created: 2007-10-09 Last updated: 2011-03-30Bibliographically 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

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Bailey, LeslieBergström, SvenElofsson, MikaelWolf-Watz, Hans
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