Activation of Lipid Metabolism Contributes to Interleukin-8 Production during<i>Chlamydia trachomatis</i>Infection of Cervical Epithelial Cells

Fukuda, Elaine Y.; Lad, Sonya P.; Mikolon, David; Iacobelli-Martinez, Milena; Li, Erguang

doi:10.1128/iai.73.7.4017-4024.2005

Cited by 36 publications

(36 citation statements)

References 47 publications

(53 reference statements)

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“…For instance, Staphylococcus aureus has been shown to induce the production of PGE 2 in primary osteoblasts (31). Chlamydia trachomatis infection also induces COX-2 expression and PGE 2 production in cultured epithelial cells (8). The infection of cultured macrophages with Salmonella has also been shown to induce the expression of COX-2 mRNA and protein, as well as the production of PGE 2 and PGI 2 (29,36).…”

Section: Discussionmentioning

confidence: 99%

Impact of Salmonella Infection on Host Hormone Metabolism Revealed by Metabolomics

et al. 2011

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The interplay between pathogens and their hosts has been studied for decades using targeted approaches, such as the analysis of mutants and host immunological responses. Although much has been learned from such studies, they focus on individual pathways and fail to reveal the global effects of infection on the host. To alleviate this issue, high-throughput methods, such as transcriptomics and proteomics, have been used to study host-pathogen interactions. Recently, metabolomics was established as a new method to study changes in the biochemical composition of host tissues. We report a metabolomic study of Salmonella enterica serovar Typhimurium infection. Our results revealed that dozens of host metabolic pathways are affected by Salmonella in a murine infection model. In particular, multiple host hormone pathways are disrupted. Our results identify unappreciated effects of infection on host metabolism and shed light on mechanisms used by Salmonella to cause disease and by the host to counter infection.Salmonella enterica serovar Typhimurium has been used as a model organism to study host-pathogen interactions for decades (12, 18, 37). Although much is known regarding the effects of Salmonella on the host, most studies have focused on the analysis of individual host metabolic pathways. A few global studies on the effect of Salmonella infection on the host have been performed, using both transcriptomic and proteomic techniques (29,40). However, the effect of Salmonella on the biochemical composition of host tissues remains unknown. Recently, techniques that detect and quantify multiple small metabolites in complex biological samples have been developed, giving rise to the field of metabolomics (19,25,39). Metabolomic studies have relied mainly on the use of chromatography coupled to mass spectrometry (MS) or nuclear magnetic resonance spectroscopy to identify and quantify metabolites in biological samples. Because these techniques require extensive sample preparation and, in some cases, have limited sensitivity, high-throughput studies have been impractical. More powerful techniques, such as direct-infusion ultrahighresolution Fourier transform ion cyclotron resonance (DI-FT-ICR) MS, have been developed with the potential to identify and quantify hundreds of metabolites with higher mass accuracy and without the need for extensive sample preparation, thus allowing comprehensive metabolic fingerprinting (11). We used DI-FT-ICR MS to investigate the impact of Salmonella infection on host metabolism using a murine typhoid infection model. To our knowledge, this is the first comprehensive metabolomic analysis of the effect of bacterial infection on host metabolism. Our study revealed a profound impact of Salmonella on host metabolism, with dozens of pathways being affected. Interestingly, some of the most impacted pathways are involved in host hormone signaling. Hormones are important mammalian signaling molecules and are fundamental for host metabolic and immune homeostasis (5, 9). The disruption of such pathways by ...

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Section: Discussionmentioning

confidence: 99%

Impact of Salmonella Infection on Host Hormone Metabolism Revealed by Metabolomics

et al. 2011

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“…3B). Nonetheless, cPLA 2 knockdown cell lines displayed enhanced levels of ERK phosphorylation and COX2 expression, another ERK-dependent response (6), in response to chlamydial infection, suggesting a potential regulatory role for cPLA 2 in ERK signaling in HeLa cells (Fig. 3C).…”

Section: Erk and Ras Activation Are Uncoupled In Chlamydia-infectedmentioning

confidence: 99%

“…For example, infection with Chlamydia trachomatis, an obligate intracellular Gram-negative bacterial pathogen, leads to sustained activation of the MEK/ERK 2 mitogen-activated protein kinases (MAPK) signaling pathway (2)(3)(4)(5). ERK has emerged as a focal point of signaling during Chlamydia infection, with roles as a regulator of bacterial nutrient acquisition (5), IL-8 synthesis (2,6) and the expression antiapoptotic factors early in infection (4). Indeed, ERK-mediated signaling is required for the robust induction of inflammatory responses responsible for the bulk of the pathology (e.g.…”

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confidence: 99%

cPLA2 Regulates the Expression of Type I Interferons and Intracellular Immunity to Chlamydia trachomatis

Vignola

Kashatus

Taylor

et al. 2010

Journal of Biological Chemistry

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Infection with the obligate bacterial intracellular pathogenChlamydia trachomatis leads to the sustained activation of the small GTPase RAS and many of its downstream signaling components. In particular, the mitogen-activated protein kinase ERK and the calcium-dependent phospholipase cPLA 2 are activated and are important for the onset of inflammatory responses. In this study we tested if activation of ERK and cPLA 2 occurred as a result of RAS signaling during infection and determined the relative contribution of these signaling components to chlamydial replication and survival. We provide genetic and pharmacological evidence that during infection RAS, ERK, and, to a lesser extent, cPLA 2 activation are uncoupled, suggesting that Chlamydia activates individual components of this signaling pathway in a non-canonical manner. In human cell lines, inhibition of ERK or cPLA 2 signaling did not adversely impact C. trachomatis replication. In contrast, in murine cells, inhibition of ERK and cPLA 2 played a significant protective role against C. trachomatis. We determined that cPLA 2 -deficient murine cells are permissive for C. trachomatis replication because of their impaired expression of ␤ interferon and the induction of immunity-related GTPases (IRG) important for the containment of intracellular pathogens. Furthermore, the MAPK p38 was primarily responsible for cPLA 2 activation in Chlamydia-infected cells and IRG expression. Overall, these findings define a previously unrecognized role for cPLA 2 in the induction of cell autonomous cellular immunity to Chlamydia and highlight the many non-canonical signaling pathways engaged during infection.

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“…IL-8 is found in the human fallopian tube predominantly in the epithelial cells and is present in greater amounts in the distal tube, a region that coincides with severe tissue damage of Chlamydia infection. Cervical epithelial cells, a primary target of Chlamydia infection, produce IL-6 and IL-8 (5,6).…”

mentioning

confidence: 99%

Cleavage of p65/RelA of the NF-κB pathway by Chlamydia

Lad

Correia

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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107

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Chlamydia trachomatis is a bacterial pathogen that infects the eyes and urogenital tract. Ocular infection by this organism is the leading cause of preventable blindness worldwide. The infection is also a leading cause of sexually transmitted disease in the United States. As obligate intracellular pathogens, chlamydiae have evolved sophisticated, yet undefined, mechanisms to maintain a favorable habitat for intracellular growth while avoiding harm to the host. We show here that chlamydiae have the ability to interfere with the NF-B pathway of host inflammatory response. We found that Chlamydia infection did not promote I B␣ degradation, a prerequisite for NF-B nuclear translocation/activation, nor induce p65/RelA nuclear redistribution. Instead, it caused p65 cleavage into an N terminus-derived p40 fragment and a p22 of the C terminus. The activity was specific because no protein cleavage or degradation of NF-B pathway components was detected. Moreover, murine p65 protein was resistant to cleavage by both human and mouse biovars. The chlamydial protein that selectively cleaved p65 was identified as a tail-specific protease (CT441). Importantly, expression of either this protease or the p40 cleavage product could block NF-B activation. A hallmark of chlamydial STD is its asymptomatic nature, although inflammatory cellular response and chronic inflammation are among the underlying mechanisms. The data presented here demonstrate that chlamydiae have the ability to convert a regulatory molecule of host inflammatory response to a dominant negative inhibitor of the same pathway potentially to minimize inflammation.CT441 ͉ inflammation ͉ protease

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Activation of Lipid Metabolism Contributes to Interleukin-8 Production duringChlamydia trachomatisInfection of Cervical Epithelial Cells

Cited by 36 publications

References 47 publications

Impact of Salmonella Infection on Host Hormone Metabolism Revealed by Metabolomics

Impact of Salmonella Infection on Host Hormone Metabolism Revealed by Metabolomics

cPLA2 Regulates the Expression of Type I Interferons and Intracellular Immunity to Chlamydia trachomatis

Cleavage of p65/RelA of the NF-κB pathway by Chlamydia

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