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Identifying, characterizing, and targeting chlamydial virulence factors to unleash the power of host cell-autonomous immunity
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
2024 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Identifiera, karaktärisera och påverka klamydias virulensfaktorer för att väcka värdcellens autonoma immunitet (Swedish)
Abstract [en]

Chlamydia trachomatis is the most common infectious cause of blindness and a prevalent bacterial agent of sexually transmitted infections, with an annual incidence exceeding 130 million cases. The current therapeutic approach to Chlamydia infections relies on broad-spectrum antibiotics. However, while generally effective, these antibiotics carry the risk of substantial collateral damage, for instance by promoting resistance in bystander pathogens and by adversely affecting commensal microbes. Hence, the development of a more sustainable, narrow-spectrum treatment would be advantageous. In this context, the bacterium’s highly specialized obligate intracellular lifestyle could offer a wealth of unique targets for intervention. This thesis specifically investigates the potential of harnessing the protective power of cell-autonomous immunity in our battle against Chlamydia.

It is envisaged that the therapeutic exploitation of cell-autonomous immunity will initially necessitate three pivotal steps. Firstly, it will require identifying protective host cellular defense programs and counteracting virulence factors, which could serve as potential molecular targets. Secondly, it will be crucial to determine the molecular mechanisms by which the pathogen’s virulence factors suppress the host cellular defenses. Thirdly, pharmacological means to target the identified virulence factors or host cellular defense programs will need to be identified. This thesis outlines three independent projects, executed concurrently, to advance our knowledge at these three steps.

The first project involved the implementation of an innovative molecular genetic screening approach, which was devised to reveal host cellular defense mechanisms that could effectively restrict the growth of C. trachomatis provided they were not actively suppressed by the pathogen. This investigation culminated in the discovery of a mutant C. trachomatis strain that lacks the ability to effectively evade xenophagy. Overall, this finding highlighted Chlamydia’s ability to evade this defense mechanism as a potential novel target for therapeutic intervention.

The second project encompassed the molecular characterization of CpoS, a C. trachomatis virulence factor previously identified to counteract cell-autonomous immunity by inhibiting induction of type-I interferon responses and premature host cell death. The analyses revealed that CpoS manipulates host cellular membrane trafficking and suppresses host cellular type-Iinterferon responses through its interactions with the host factor Rab35.

The third project involved a compound screening campaign that identified several novel selective anti-chlamydial compounds. Interestingly, one molecule exhibited reduced activity in xenophagy-deficient cells, implying a potential involvement of xenophagy in its mechanism of action.

In summary, this research pinpointed xenophagy as a potential defensive mechanism against C. trachomatis, offered in-depth understanding of the operational mode of the virulence factor CpoS, and discovered new selective therapeutic alternatives, which in part utilize xenophagyin their mechanism of action. Consequently, this thesis provides a comprehensive overview of the transition from fundamental research to the more application-oriented domain of drug discovery and may inspire the development of more sustainable therapeutic strategies for the clinical handling of Chlamydia infections.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. , p. 46
Series
Doctoral thesis / Umeå University, Department of Molecular Biology
Series
Umeå University Medical Dissertations, ISSN 0346-6612 ; 2308
Keywords [en]
Chlamydia trachomatis, cell-autonomous immunity, xenophagy, virulence factors, novel antimicrobials
National Category
Microbiology in the medical area
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-223912ISBN: 9789180703987 (electronic)ISBN: 9789180703970 (print)OAI: oai:DiVA.org:umu-223912DiVA, id: diva2:1855519
Public defence
2024-05-28, Major Groove, Norrlands universitetssjukhus, Försörjningsvägen 2A, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2024-05-07 Created: 2024-05-02 Last updated: 2024-05-07Bibliographically approved
List of papers
1. A forward genetic screen discovered a Chlamydia trachomatis mutant impaired in its ability to evade xenophagy
Open this publication in new window or tab >>A forward genetic screen discovered a Chlamydia trachomatis mutant impaired in its ability to evade xenophagy
(English)Manuscript (preprint) (Other academic)
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-223909 (URN)
Available from: 2024-05-01 Created: 2024-05-01 Last updated: 2024-05-03
2. The Chlamydia effector CpoS modulates the inclusion microenvironment and restricts the interferon response by acting on Rab35
Open this publication in new window or tab >>The Chlamydia effector CpoS modulates the inclusion microenvironment and restricts the interferon response by acting on Rab35
Show others...
2023 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 14, no 4, article id e0319022Article in journal (Refereed) Published
Abstract [en]

The obligate intracellular bacterium Chlamydia trachomatis inserts a family of inclusion membrane (Inc) proteins into the membrane of its vacuole (the inclusion). The Inc CpoS is a critical suppressor of host cellular immune surveillance, but the underlying mechanism remained elusive. By complementing a cpoS mutant with various natural orthologs and variants of CpoS, we linked distinct molecular interactions of CpoS to distinct functions. Unexpectedly, we found CpoS to be essential for the formation of inclusion membrane microdomains that control the spatial organization of multiple Incs involved in signaling and modulation of the host cellular cytoskeleton. While the function of CpoS in microdomains was uncoupled from its role in the suppression of host cellular defenses, we found the ability of CpoS to interact with Rab GTPases to be required not only for the manipulation of membrane trafficking, such as to mediate transport of ceramide-derived lipids (sphingolipids) to the inclusion, but also for the inhibition of Stimulator of interferon genes (STING)-dependent type I interferon responses. Indeed, depletion of Rab35 phenocopied the exacerbated interferon responses observed during infection with CpoS-deficient mutants. Overall, our findings highlight the role of Inc-Inc interactions in shaping the inclusion microenvironment and the modulation of membrane trafficking as a pathogenic immune evasion strategy.

IMPORTANCE: Chlamydia trachomatis is a prevalent bacterial pathogen that causes blinding ocular scarring and urogenital infections that can lead to infertility and pregnancy complications. Because Chlamydia can only grow within its host cell, boosting the intrinsic defenses of human cells may represent a novel strategy to fight pathogen replication and survival. Hence, CpoS, a Chlamydia protein known to block host cellular defenses, or processes regulated by CpoS, could provide new opportunities for therapeutic intervention. By revealing CpoS as a multifunctional virulence factor and by linking its ability to block host cellular immune signaling to the modulation of membrane trafficking, the present work may provide a foundation for such rationale targeting and advances our understanding of how intracellular bacteria can shape and protect their growth niche.

Place, publisher, year, edition, pages
American Society for Microbiology, 2023
Keywords
cell-autonomous immunity, interferon responses, intracellular bacteria, membrane microdomains, membrane trafficking, Rab GTPases
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-214251 (URN)10.1128/mbio.03190-22 (DOI)001041120000001 ()37530528 (PubMedID)2-s2.0-85169501656 (Scopus ID)
Funder
European Commission, PIOF-GA-2013-626116Swedish Research Council, 2016-06598Swedish Research Council, 2018-02286Swedish Research Council, 2021-06602Swedish Research Council, 2022-00852NIH (National Institutes of Health), AI100759; AI134891
Available from: 2023-09-18 Created: 2023-09-18 Last updated: 2024-05-02Bibliographically approved
3. A multi-strategy antimicrobial discovery approach reveals new ways to combat Chlamydia
Open this publication in new window or tab >>A multi-strategy antimicrobial discovery approach reveals new ways to combat Chlamydia
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-223910 (URN)10.1101/2023.11.30.569351 (DOI)
Available from: 2024-05-01 Created: 2024-05-01 Last updated: 2024-05-20Bibliographically approved

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Meier, Karsten

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34567896 of 18
CiteExportLink to record
Permanent link

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Citation style
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