Expansion of the Chlamydia trachomatis inclusion does not require bacterial replication

Engström, Patrik; Bergström, Malin; Alfaro, Astrid Carolina; Krishnan, Karthik; Bahnan, Wael; Almqvist, Fredrik; Bergström, Sven

doi:10.1016/j.ijmm.2015.02.007

Cited by 15 publications

(36 citation statements)

References 25 publications

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“…This counterintuitive finding is supported by a recent report that showed that C. trachomatis replication does not necessarily correlate with inclusion size, even in immortalized cells (50).…”

Section: Discussionmentioning

confidence: 64%

Stromal Fibroblasts Drive Host Inflammatory Responses That Are Dependent on Chlamydia trachomatis Strain Type and Likely Influence Disease Outcomes

Jolly

Rau

Chadha

et al. 2019

mBio

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Chlamydia trachomatisocular strains cause a blinding disease known as trachoma. These strains rarely cause urogenital infections and are not found in the upper genital tract or rectum. Urogenital strains are responsible for a self-limited conjunctivitis and the sequelae of infertility, ectopic pregnancy, and hemorrhagic proctitis. However, the differential cellular responses that drive these clinically observed disease outcomes are not completely understood. Primary conjunctival, endocervical, and endometrial epithelial and stromal fibroblast cells, HeLa229 cells, and immortalized conjunctival epithelial (HCjE) cells were infected with the ocular A/Har-13 (A) and Ba/Apache-2 (Ba) strains and urogenital D/UW-3 (D) and E/Bour (E) strains. Infection rates, progeny production, and cytokine/chemokine secretion levels were evaluated in comparison with those in uninfected cells. All strain types infected all cell types with similar levels of efficacy and development. However, progeny production levels differed among primary cells: Ba produced significantly more progeny than E in endocervical and endometrial fibroblasts, while A progeny were less abundant than E progeny.C.trachomatisinfection of primary epithelial cells elicited an increase in pro- and anti-inflammatory mediators compared to levels in uninfected cells, but there were no significant differences by strain type. In contrast, for primary fibroblasts, ocular strains elicited significant increases in the pro- and anti-inflammatory mediators macrophage inflammatory protein (MIP)-1β, thymus- and activation-regulated chemokine (TARC), interleukin (IL)-2, IL-12p70, and interferon gamma-induced protein 10 (IP-10) compared to levels in urogenital strains, while urogenital strains elicited a distinct and significant increase in the proinflammatory mediators IL-1α, IL-1β, IL-8, gamma interferon (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Our data indicate that primary fibroblasts, not epithelial cells, drive host inflammatory responses that are dependent on strain type and likely influence disease outcomes, establishing their importance as a novel model for studies ofC. trachomatisdisease pathogenesis.IMPORTANCEChlamydia trachomatisis a human pathogen and the leading cause of preventable blindness and sexually transmitted diseases in the world. CertainC. trachomatisstrains cause ocular disease, while others cause upper genital tract pathology. However, little is known about the cellular or immunologic basis for these differences. Here, we compared the abilities of the strain types to infect, replicate, and initiate an immune response in primary human ocular and urogenital epithelial cells, as well as in fibroblasts from the underlying stroma. While there were no significant differences in infection rates or intracellular growth for any strain in any cell type, proinflammatory responses were driven not by the epithelial cells but by fibroblasts and were distinct between ocular and urogenital strains. Our findings suggest that primary fibroblasts are a novel and more appropriate model for studies of immune responses that will expand our understanding of the differential pathological disease outcomes caused by variousC. trachomatisstrain types.

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Section: Discussionmentioning

confidence: 64%

Stromal Fibroblasts Drive Host Inflammatory Responses That Are Dependent on Chlamydia trachomatis Strain Type and Likely Influence Disease Outcomes

Jolly

Rau

Chadha

et al. 2019

mBio

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“…As it is shown in the images, there was a complete recovery of the size of the inclusions when the inhibitor was removed (Figure 2E,F). Chlamydial inclusion expansion precedes bacterial replication (Engström et al, 2015), therefore to directly assess bacterial viability and development after the strongest iAkt treatment (10 μM, 24 h, 37°C), we performed progeny/reinfection assays. Results show a significant recovery in the amount of infectious organisms after the removal of the inhibitor, notwithstanding, the inclusion forming units did not reach the levels of untreated cells (Figure 2G).…”

Section: Resultsmentioning

confidence: 99%

Akt/AS160 Signaling Pathway Inhibition Impairs Infection by Decreasing Rab14-Controlled Sphingolipids Delivery to Chlamydial Inclusions

et al. 2019

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Chlamydia trachomatis , an obligate intracellular bacterium, intercepts different trafficking pathways of the host cell to acquire essential lipids for its survival and replication, particularly from the Golgi apparatus via a Rab14-mediated transport. Molecular mechanisms underlying how these bacteria manipulate intracellular transport are a matter of intense study. Here, we show that C. trachomatis utilizes Akt/AS160 signaling pathway to promote sphingolipids delivery to the chlamydial inclusion through Rab14-controlled vesicular transport. C. trachomatis provokes Akt phosphorylation along its entire developmental life cycle and recruits phosphorylated Akt (pAkt) to the inclusion membrane. As a consequence, Akt Substrate of 160 kDa (AS160), also known as TBC1D4, a GTPase Activating Protein (GAP) for Rab14, is phosphorylated and therefore inactivated. Phosphorylated AS160 (pAS160) loses its ability to promote GTP hydrolysis, favoring Rab14 binding to GTP. Akt inhibition by an allosteric isoform-specific Akt inhibitor (iAkt) prevents AS160 phosphorylation and reduces Rab14 recruitment to chlamydial inclusions. iAkt further impairs sphingolipids acquisition by C. trachomatis- inclusion and provokes lipid retention at the Golgi apparatus. Consequently, treatment with iAkt decreases chlamydial inclusion size, bacterial multiplication, and infectivity in a dose-dependent manner. Similar results were found in AS160-depleted cells. By electron microscopy, we observed that iAkt generates abnormal bacterial forms as those reported after sphingolipids deprivation or Rab14 silencing. Taken together, our findings indicate that targeting the Akt/AS160/Rab14 axis could constitute a novel strategy to limit chlamydial infections, mainly for those caused by antibiotic-resistant bacteria.

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“…This is in agreement with a recent report indicating that chlamydial protein synthesis, but not chlamydial replication, is required for normal expansion of C . trachomatis inclusions [ 40 ]. It can thus be speculated that the DAMP-dependent reduction of inclusion size observed for C .…”

Section: Discussionmentioning

confidence: 99%

Damage/Danger Associated Molecular Patterns (DAMPs) Modulate Chlamydia pecorum and C. trachomatis Serovar E Inclusion Development In Vitro

2015

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Persistence, more recently termed the chlamydial stress response, is a viable but non-infectious state constituting a divergence from the characteristic chlamydial biphasic developmental cycle. Damage/danger associated molecular patterns (DAMPs) are normal intracellular components or metabolites that, when released from cells, signal cellular damage/lysis. Purine metabolite DAMPs, including extracellular ATP and adenosine, inhibit chlamydial development in a species-specific manner. Viral co-infection has been shown to reversibly abrogate Chlamydia inclusion development, suggesting persistence/chlamydial stress. Because viral infection can cause host cell DAMP release, we hypothesized DAMPs may influence chlamydial development. Therefore, we examined the effect of extracellular ATP, adenosine, and cyclic AMP exposure, at 0 and 14 hours post infection, on C. pecorum and C. trachomatis serovar E development. In the absence of de novo host protein synthesis, exposure to DAMPs immediately post or at 14 hours post infection reduced inclusion size; however, the effect was less robust upon 14 hours post infection exposure. Additionally, upon exposure to DAMPs immediately post infection, bacteria per inclusion and subsequent infectivity were reduced in both Chlamydia species. These effects were reversible, and C. pecorum exhibited more pronounced recovery from DAMP exposure. Aberrant bodies, typical in virus-induced chlamydial persistence, were absent upon DAMP exposure. In the presence of de novo host protein synthesis, exposure to DAMPs immediately post infection reduced inclusion size, but only variably modulated chlamydial infectivity. Because chlamydial infection and other infections may increase local DAMP concentrations, DAMPs may influence Chlamydia infection in vivo, particularly in the context of poly-microbial infections.

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Expansion of the Chlamydia trachomatis inclusion does not require bacterial replication

Cited by 15 publications

References 25 publications

Stromal Fibroblasts Drive Host Inflammatory Responses That Are Dependent on Chlamydia trachomatis Strain Type and Likely Influence Disease Outcomes

Stromal Fibroblasts Drive Host Inflammatory Responses That Are Dependent on Chlamydia trachomatis Strain Type and Likely Influence Disease Outcomes

Akt/AS160 Signaling Pathway Inhibition Impairs Infection by Decreasing Rab14-Controlled Sphingolipids Delivery to Chlamydial Inclusions

Damage/Danger Associated Molecular Patterns (DAMPs) Modulate Chlamydia pecorum and C. trachomatis Serovar E Inclusion Development In Vitro

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