Chlamydia trachomatis CT229 Subverts Rab GTPase-Dependent CCV Trafficking Pathways to Promote Chlamydial Infection

Faris, Robert; Merling, Marlena R; Andersen, Shelby E.; Dooley, Cheryl A.; Hackstadt, Ted; Weber, Mary M.

doi:10.1016/j.celrep.2019.02.079

Cited by 38 publications

(43 citation statements)

References 58 publications

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“…Genes with an average differential expression ratio 2 standard deviations away from the mean differential expression ratio for the entire genome were considered to be significantly upregulated and were included as part of the σ 54 regulon and listed in Table 1 or Table 2 , depending on the presence or absence of a predicted σ 54 promoter region upstream of the open reading frame. The protein roles listed in Table 1 and Table 2 were verified with data from previous studies ( 37 , 39 – 41 , 44 , 54 – 57 , 64 , 67 , 68 , 71 , 74 , 81 – 104 ).…”

Section: Methodssupporting

confidence: 78%

“…CopB and CopD have been shown to make up the translocator of the T3SS apparatus and are thus essential for attachment of the chlamydial cell to the host membrane ( 37 , 66 ). CT229 has been shown to be an inclusion membrane protein that is critical for the subverting of the host cell defenses that would otherwise lead to destruction and therefore is necessary for the establishment of the infection from the initial point of entry ( 67 , 68 ). These are just a few examples of T3SS-associated genes that were found to be regulated by σ 54 .…”

Section: Discussionmentioning

confidence: 99%

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Sigma 54-Regulated Transcription Is Associated with Membrane Reorganization and Type III Secretion Effectors during Conversion to Infectious Forms of Chlamydia trachomatis

Soules

LaBrie

May

et al. 2020

mBio

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Chlamydia bacteria are obligate intracellular organisms with a phylum-defining biphasic developmental cycle that is intrinsically linked to its ability to cause disease. The progression of the chlamydial developmental cycle is regulated by the temporal expression of genes predominantly controlled by RNA polymerase sigma (σ) factors. Sigma 54 (σ54) is one of three sigma factors encoded by Chlamydia for which the role and regulon are unknown. CtcC is part of a two-component signal transduction system that is requisite for σ54 transcriptional activation. CtcC activation of σ54 requires phosphorylation, which relieves inhibition by the CtcC regulatory domain and enables ATP hydrolysis by the ATPase domain. Prior studies with CtcC homologs in other organisms have shown that expression of the ATPase domain alone can activate σ54 transcription. Biochemical analysis of CtcC ATPase domain supported the idea of ATP hydrolysis occurring in the absence of the regulatory domain, as well as the presence of an active-site residue essential for ATPase activity (E242). Using recently developed genetic approaches in Chlamydia to induce expression of the CtcC ATPase domain, a transcriptional profile was determined that is expected to reflect the σ54 regulon. Computational evaluation revealed that the majority of the differentially expressed genes were preceded by highly conserved σ54 promoter elements. Reporter gene analyses using these putative σ54 promoters reinforced the accuracy of the model of the proposed regulon. Investigation of the gene products included in this regulon supports the idea that σ54 controls expression of genes that are critical for conversion of Chlamydia from replicative reticulate bodies into infectious elementary bodies. IMPORTANCE The factors that control the growth and infectious processes for Chlamydia are still poorly understood. This study used recently developed genetic tools to determine the regulon for one of the key transcription factors encoded by Chlamydia, sigma 54. Surrogate and computational analyses provide additional support for the hypothesis that sigma 54 plays a key role in controlling the expression of many components critical to converting and enabling the infectious capability of Chlamydia. These components include those that remodel the membrane for the extracellular environment and incorporation of an arsenal of type III secretion effectors in preparation for infecting new cells.

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Section: Methodssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Sigma 54-Regulated Transcription Is Associated with Membrane Reorganization and Type III Secretion Effectors during Conversion to Infectious Forms of Chlamydia trachomatis

Soules

LaBrie

May

et al. 2020

mBio

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“…RAB GTPases are master regulators of eukaryotic vesicular trafficking [91], and several of them (RABs 1, 4, 6, 8, 10, 11, 14, 34, 35, 39a, 39b) have been reported to localize at, or in close proximity of, the C. trachomatis inclusion membrane [92–96]. Despite this, until now, only one C. trachomatis protein, Inc CpoS (Table 1) , has been shown to bind and modulate the function of RABs (Figure 3A) .…”

Section: The Functions Of C Trachomatis Inc Proteinsmentioning

confidence: 99%

The multiple functions of the numerous Chlamydia trachomatis secreted proteins: the tip of the iceberg

Bugalhão¹,

Mota²

2019

Microb Cell

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Chlamydia trachomatis serovars are obligate intracellular bacterial pathogens mainly causing ocular and urogenital infections that affect millions of people worldwide and which can lead to blindness or sterility. They reside and multiply intracellularly within a membrane-bound vacuolar compartment, known as inclusion, and are characterized by a developmental cycle involving two morphologically and physiologically distinct chlamydial forms. Completion of the developmental cycle involves the secretion of > 70 C. trachomatis proteins that function in the host cell cytoplasm and nucleus, in the inclusion membrane and lumen, and in the extracellular milieu. These proteins can, for example, interfere with the host cell cytoskeleton, vesicular and non-vesicular transport, metabolism, and immune signalling. Generally, this promotes C. trachomatis invasion into, and escape from, host cells, the acquisition of nutrients by the chlamydiae, and evasion of cell-autonomous, humoral and cellular innate immunity. Here, we present an in-depth review on the current knowledge and outstanding questions about these C. trachomatis secreted proteins.

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“…Chlamydia Inc proteins counteract host defenses by deubiquitinating proteins at the inclusion, inhibiting the lytic activity of interferon induced factors (e.g. guanylate binding proteins) and suppressing cell death by subverting membrane trafficking to inhibit host surveillance programs and apoptosis (Coers et al, 2008;Faris et al, 2019;Fischer et al, 2017;Sixt et al, 2017). Despite these activities, Chlamydia is still recognized by the host cell which can lead to a pro-inflammatory response (Rasmussen et al, 1997), including the expression and secretion of chemokines, such as the neutrophil attractants interleukin-6 (IL-6) and interleukin-8 (IL-8) (Buchholz and Stephens, 2008;Rasmussen et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

An endometrial organoid model ofChlamydia-epithelial and immune cell interactions

Dolat

Valdivia

2020

Preprint

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Our understanding of how the obligate intracellular bacterium Chlamydia trachomatis reprograms the cell biology of host cells in the upper genital tract is largely based on observations made in cell culture with transformed epithelial cell lines. Here we describe a primary spherical organoid system derived from endometrial tissue to recapitulate epithelial cell diversity, polarity, and ensuing responses to Chlamydia infection. Using high-resolution and time-lapse microscopy, we catalogue the infection process in organoids from invasion to egress, including the reorganization of the cytoskeleton and positioning of intracellular organelles. We show this model is amenable to screening C. trachomatis mutants for defects in the fusion of pathogenic vacuoles, the recruitment of intracellular organelles, and inhibition of cell death. Moreover, we reconstructed a primary immune cell response by co-culturing infected organoids with neutrophils, and determined that the effector TepP limits the recruitment of neutrophils to infected organoids. Collectively, our model details a system to study the cell biology of Chlamydia infections in three dimensional structures that better reflect the diversity of cell types and polarity encountered by Chlamydia upon infection of their animal hosts.Summary statement3D endometrial organoids to model Chlamydia infection and the role of secreted virulence factors in reprogramming host epithelial cells and immune cell recruitment

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Chlamydia trachomatis CT229 Subverts Rab GTPase-Dependent CCV Trafficking Pathways to Promote Chlamydial Infection

Cited by 38 publications

References 58 publications

Sigma 54-Regulated Transcription Is Associated with Membrane Reorganization and Type III Secretion Effectors during Conversion to Infectious Forms of Chlamydia trachomatis

Sigma 54-Regulated Transcription Is Associated with Membrane Reorganization and Type III Secretion Effectors during Conversion to Infectious Forms of Chlamydia trachomatis

The multiple functions of the numerous Chlamydia trachomatis secreted proteins: the tip of the iceberg

An endometrial organoid model ofChlamydia-epithelial and immune cell interactions

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