Integrated Phosphoproteome and Transcriptome Analysis Reveals Chlamydia-Induced Epithelial-to-Mesenchymal Transition in Host Cells

Zadora, Piotr K.; Chumduri, Cindrilla; Imami, Koshi; Berger, Hilmar; Mi, Yang; Selbach, Matthias; Meyer, Thomas F.; Gurumurthy, Rajendra Kumar

doi:10.1016/j.celrep.2019.01.006

Cited by 54 publications

(47 citation statements)

References 68 publications

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“…Meyer and colleagues pioneered the use of ex vivo organotypic cultures and a novel fallopian tube organoid (FTO) model to investigate C. trachomatis infection in primary human epithelia 42, 43 . Partially dissected tissue from the ectocervix and fallopian tube—representing the lower and upper genital tracts, respectively—has been cultured ex vivo and infected with Chlamydia 42, 43 . These models were recently simplified by culturing isolated tubal epithelial cells in a three-dimensional matrix, generating self-renewing FTOs ( Figure 1C) 44 .…”

Section: Recent Advances In Cell Culture Infection Modelsmentioning

confidence: 99%

“…More recently, a global phosphoproteomic and transcriptomic analysis in ectocervical epithelial explants infected with C. trachomatis serovar L2 indicated that infection activates cell signaling pathways to promote an EMT-like signature 43 . The infection initiates at the top of the stratified epithelia and progresses toward the basal layer, suggesting that altering cell–cell junctions during EMT may provide access for subsequent rounds of infection.…”

Section: Chlamydia Activates Epithelial-to-mesenchymal Transitionsmentioning

confidence: 99%

“…The infection initiates at the top of the stratified epithelia and progresses toward the basal layer, suggesting that altering cell–cell junctions during EMT may provide access for subsequent rounds of infection. Indeed, downstream of the MAPK pathway, the transcriptional factors ETS1 and ERF promote EMT in infected cells, leading to the downregulation of E-cadherin and increased cell motility and invasion 43 . Collectively, these observations suggest that Chlamydia can promote the transformation of epithelial cells, which may contribute to cancers of the cervix and uterus.…”

Section: Chlamydia Activates Epithelial-to-mesenchymal Transitionsmentioning

confidence: 99%

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A renewed tool kit to explore Chlamydia pathogenesis: from molecular genetics to new infection models

Dolat

Valdivia

2019

F1000Res

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Chlamydia trachomatis is the most prevalent sexually transmitted bacterial pathogen and the leading cause of preventable blindness in the developing world. C. trachomatis invades the epithelium of the conjunctiva and genital tract and replicates within an intracellular membrane-bound compartment termed the inclusion. To invade and replicate in mammalian cells, Chlamydia remodels epithelial surfaces by reorganizing the cytoskeleton and cell–cell adhesions, reprograms membrane trafficking, and modulates cell signaling to dampen innate immune responses. If the infection ascends to the upper female genital tract, it can result in pelvic inflammatory disease and tissue scarring. C. trachomatis infections are associated with infertility, ectopic pregnancies, the fibrotic disorder endometriosis, and potentially cancers of the cervix and uterus. Unfortunately, the molecular mechanisms by which this clinically important human pathogen subverts host cellular functions and causes disease have remained relatively poorly understood because of the dearth of molecular genetic tools to study Chlamydiae and limitations of both in vivo and in vitro infection models. In this review, we discuss recent advances in the experimental molecular tool kit available to dissect C. trachomatis infections with a special focus on Chlamydia-induced epithelial barrier disruption by regulating the structure, function, and dynamics of epithelial cell–cell junctions.

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Section: Recent Advances In Cell Culture Infection Modelsmentioning

confidence: 99%

Section: Chlamydia Activates Epithelial-to-mesenchymal Transitionsmentioning

confidence: 99%

Section: Chlamydia Activates Epithelial-to-mesenchymal Transitionsmentioning

confidence: 99%

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A renewed tool kit to explore Chlamydia pathogenesis: from molecular genetics to new infection models

Dolat

Valdivia

2019

F1000Res

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“…Dysregulation of SRF activity has been associated with induction of the epithelial-to-mesenchymal transition (EMT)-a process through which epithelial cells transdifferentiate into scar-forming fibroblasts [133,134]. Intriguingly, Chlamydia infection has recently been shown to induce EMT, which likely promotes the scar-forming pathology observed in chronic C. trachomatis infections [79,[135][136][137]. Could chlamydial restructuring of actin contribute to this effect?…”

Section: Conclusion and Summarymentioning

confidence: 99%

Pathogenic Puppetry: Manipulation of the Host Actin Cytoskeleton by Chlamydia trachomatis

Caven

Carabeo

2019

IJMS

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The actin cytoskeleton is crucially important to maintenance of the cellular structure, cell motility, and endocytosis. Accordingly, bacterial pathogens often co-opt the actin-restructuring machinery of host cells to access or create a favorable environment for their own replication. The obligate intracellular organism Chlamydia trachomatis and related species exemplify this dynamic: by inducing actin polymerization at the site of pathogen-host attachment, Chlamydiae induce their own uptake by the typically non-phagocytic epithelium they infect. The interaction of chlamydial adhesins with host surface receptors has been implicated in this effect, as has the activity of the chlamydial effector TarP (translocated actin recruitment protein). Following invasion, C. trachomatis dynamically assembles and maintains an actin-rich cage around the pathogen's membrane-bound replicative niche, known as the chlamydial inclusion. Through further induction of actin polymerization and modulation of the actin-crosslinking protein myosin II, C. trachomatis promotes egress from the host via extrusion of the inclusion. In this review, we present the experimental findings that can inform our understanding of actin-dependent chlamydial pathogenesis, discuss lingering questions, and identify potential avenues of future study.Int. J. Mol. Sci. 2020, 21, 90 2 of 21 regulated by the Rho family GTPases RhoA-C, Rac1, and Cdc42-all of which are targets for modulation by pathogens seeking to restructure actin and thereby facilitate pathogenesis [6,7].The manipulation of host actin can promote a wide variety of beneficial outcomes for the pathogen. Salmonella spp. translocate the effectors SopE and SopE2 into host cells-these guanine exchange factor (GEF) mimics enhance the activity of Rac1 and Cdc42, creating localized concentrations of F-actin at the apical surface of mucosal epithelia [8][9][10][11]. The result is extensive ruffling of the plasma membrane at the site of Salmonella attachment, leading to internalization of the pathogen via micropinocytosis [8,[12][13][14]. Upon internalization and escape into the host cytosol, the Gram-positive intracellular pathogen Listeria monocytogenes induces the polymerization of actin on the bacterial surface through the activity of ActA, a surface protein functionally analogous to the nucleation promotion factor WASP [15]. ActA recruits an Arp2/3 complex to the bacterial pole, resulting in branched actin polymerization producing a comet-shaped structure that propels Listeria across the cytosol and into adjacent uninfected cells [16][17][18][19][20].Indeed, this dynamic can be observed even in non-invasive bacterial pathogens. Enteropathogenic and enterohemorrhagic E. coli (EPEC/EHEC) induce the formation of distinctive, actin-rich pedestals that facilitate their attachment to gastric epithelia. The virulence factor Tir is responsible for this effect: upon delivery into host cells by the E. coli type III secretion system (T3SS), Tir is incorporated into the plasma membrane, promoting EPEC/EHEC attachm...

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“…Much of what is known regarding Chlamydia 's mechanisms to manipulate host cells comes from in vitro studies using cancer-derived cell lines, such as HeLa cells, which provide ease of maintenance and genetic manipulation, but lack much of the relevance of an in vivo environment (Dolat and Valdivia, 2019 ). Beyond cancer-derived cell lines, immortalized and polarized cell lines of reproductive tissues have broadened the relevance of in vitro systems (Igietseme et al, 1994 ; Guseva et al, 2005 , 2007 ; Moore et al, 2008 ; King et al, 2009 ), and primary cells have provided systems with minimal artificial manipulation of cells (Prozialeck et al, 2002 ; Roth et al, 2010 ; Zadora et al, 2019 ; Maffei et al, 2020 ). Further, the use of three-dimensional (3D) and multi-cell type models have allowed for incorporating aspects of cell-cell interactions and tissue architecture (Nogueira et al, 2017 ; Edwards et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Murine Endometrial Organoids to Model Chlamydia Infection

Bishop

Boretto

Rutkowski

et al. 2020

Front. Cell. Infect. Microbiol.

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The obligate intracellular bacterium Chlamydia trachomatis is the leading cause of bacterial sexually transmitted infections. Once internalized in host cells, C. trachomatis undergoes a biphasic developmental cycle within a membrane-bound compartment, known as the inclusion. Successful establishment of the intracellular niche relies on bacterial Type III effector proteins, such as Inc proteins. In vitro and in vivo systems have contributed to elucidating the intracellular lifestyle of C. trachomatis, but additional models combining the archetypal environment of infection with the advantages of in vitro systems are needed. Organoids are three-dimensional structures that recapitulate the microanatomy of an organ's epithelial layer, bridging the gap between in vitro and in vivo systems. Organoids are emerging as relevant model systems to study interactions between bacterial pathogens and their hosts. Here, we took advantage of recently developed murine endometrial organoids (EMOs) and present a C. trachomatis-murine EMO infection model system. Confocal microscopy of EMOs infected with fluorescent protein-expressing bacteria revealed that inclusions are formed within the cytosol of epithelial cells. Moreover, infection with a C. trachomatis strain that allows for the tracking of RB to EB transition indicated that the bacteria undergo a full developmental cycle, which was confirmed by harvesting infectious bacteria from infected EMOs. Finally, the inducible gene expression and cellular localization of a Chlamydia Inc protein within infected EMOs further demonstrated that this model is compatible with the study of Type III secreted effectors. Altogether, we describe a novel and relevant system for the study of Chlamydia-host interactions.

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Integrated Phosphoproteome and Transcriptome Analysis Reveals Chlamydia-Induced Epithelial-to-Mesenchymal Transition in Host Cells

Cited by 54 publications

References 68 publications

A renewed tool kit to explore Chlamydia pathogenesis: from molecular genetics to new infection models

A renewed tool kit to explore Chlamydia pathogenesis: from molecular genetics to new infection models

Pathogenic Puppetry: Manipulation of the Host Actin Cytoskeleton by Chlamydia trachomatis

Murine Endometrial Organoids to Model Chlamydia Infection

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