The Chlamydia effector CpoS modulates the inclusion microenvironment and restricts the interferon response by acting on Rab35

Author:

Meier Karsten123,Jachmann Lana H.123,Türköz Gözde123,Babu Sait Mohammed Rizwan123,Pérez Lucía123,Kepp Oliver45,Valdivia Raphael H.6,Kroemer Guido457,Sixt Barbara S.123ORCID

Affiliation:

1. Department of Molecular Biology, Umeå University , Umeå, Sweden

2. The Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University , Umeå, Sweden

3. Umeå Centre for Microbial Research (UCMR), Umeå University , Umeå, Sweden

4. Metabolomics and Cell Biology Platforms, Institut Gustave Roussy , Villejuif, France

5. Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France , Paris, France

6. Department of Molecular Genetics and Microbiology, Duke University School of Medicine , Durham, North Carolina, USA

7. Department of Biology, Institut du Cancer Paris CARPEM, Hôpital Européen Georges-Pompidou, AP-HP , Paris, France

Abstract

ABSTRACT 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.

Funder

European Commission

Vetenskapsrådet

HHS | National Institutes of Health

Agence Nationale de la Recherche

Institute Nationale du Cancer

DIM ELICIT

Publisher

American Society for Microbiology

Subject

Virology,Microbiology

Reference62 articles.

1. Animal Chlamydioses and Zoonotic Implications

2. Kuo CC , Stephens RS , Bavoil PM , Kaltenboeck B . 2011. The genus Chlamydia, p 846–865. In Krieg NR , JT Staley , DR Brown , BP Hedlund , BJ Paster , NL Ward , W Ludwig , WB Whitman (ed), Bergey’s Manual of systematic Bacteriology - The Bacteroidetes, Spirochaetes, Tenericutes (Mollicutes), Acidobacteria, Fibrobacteres, Fusobacteria, Dictyoglomi, Gemmatimonadetes, Lentisphaerae, Verrucomicrobia, Chlamydiae, and Planctomycetes. Springer, New York.

3. Trachoma

4. Female genital Chlamydia trachomatis infection: where are we heading?

5. Lymphogranuloma venereum: diagnostic and treatment challenges

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