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A multi-strategy antimicrobial discovery approach reveals new ways to combat Chlamydia
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).ORCID-id: 0009-0009-6904-1031
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
URN: urn:nbn:se:umu:diva-223910DOI: 10.1101/2023.11.30.569351OAI: oai:DiVA.org:umu-223910DiVA, id: diva2:1855471
Tillgänglig från: 2024-05-01 Skapad: 2024-05-01 Senast uppdaterad: 2024-11-26Bibliografiskt granskad
Ingår i avhandling
1. Identifying, characterizing, and targeting chlamydial virulence factors to unleash the power of host cell-autonomous immunity
Öppna denna publikation i ny flik eller fönster >>Identifying, characterizing, and targeting chlamydial virulence factors to unleash the power of host cell-autonomous immunity
2024 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[sv]
Identifiera, karaktärisera och påverka klamydias virulensfaktorer för att väcka värdcellens autonoma immunitet
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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2024. s. 46
Serie
Doctoral thesis / Umeå University, Department of Molecular Biology
Serie
Umeå University Medical Dissertations, ISSN 0346-6612 ; 2308
Nyckelord
Chlamydia trachomatis, cell-autonomous immunity, xenophagy, virulence factors, novel antimicrobials
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Forskningsämne
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-223912 (URN)9789180703987 (ISBN)9789180703970 (ISBN)
Disputation
2024-05-28, Major Groove, Norrlands universitetssjukhus, Försörjningsvägen 2A, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2024-05-07 Skapad: 2024-05-02 Senast uppdaterad: 2024-05-07Bibliografiskt granskad

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Ölander, MagnusRea Vázquez, DanielMeier, KarstenPuértolas-Balint, FabiolaRayón Díaz, MaríaSchröder, Björn O.Sixt, Barbara Susanne

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Ölander, MagnusRea Vázquez, DanielMeier, KarstenPuértolas-Balint, FabiolaRayón Díaz, MaríaSchröder, Björn O.Sixt, Barbara Susanne
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Institutionen för molekylärbiologi (Medicinska fakulteten)Molekylär Infektionsmedicin, Sverige (MIMS)Umeå Centre for Microbial Research (UCMR)
Mikrobiologi inom det medicinska området

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