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The Chlamydia effector CpoS modulates the inclusion microenvironment and restricts the interferon response by acting on Rab35
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). 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). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
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2023 (Engelska)Ingår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 14, nr 4, artikel-id e0319022Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
American Society for Microbiology, 2023. Vol. 14, nr 4, artikel-id e0319022
Nyckelord [en]
cell-autonomous immunity, interferon responses, intracellular bacteria, membrane microdomains, membrane trafficking, Rab GTPases
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-214251DOI: 10.1128/mbio.03190-22ISI: 001041120000001PubMedID: 37530528Scopus ID: 2-s2.0-85169501656OAI: oai:DiVA.org:umu-214251DiVA, id: diva2:1797924
Forskningsfinansiär
Europeiska kommissionen, PIOF-GA-2013-626116Vetenskapsrådet, 2016-06598Vetenskapsrådet, 2018-02286Vetenskapsrådet, 2021-06602Vetenskapsrådet, 2022-00852NIH (National Institutes of Health), AI100759; AI134891Tillgänglig från: 2023-09-18 Skapad: 2023-09-18 Senast uppdaterad: 2023-09-18Bibliografiskt granskad

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Meier, KarstenJachmann, Lana H.Türköz, GözdeBabu Sait, Mohammed RizwanPérez, LucíaSixt, Barbara Susanne

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Meier, KarstenJachmann, Lana H.Türköz, GözdeBabu Sait, Mohammed RizwanPérez, LucíaSixt, Barbara Susanne
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Molekylär Infektionsmedicin, Sverige (MIMS)Umeå Centre for Microbial Research (UCMR)Institutionen för molekylärbiologi (Medicinska fakulteten)
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