Up-Regulation of the JAK/STAT1 Signal Pathway during <i>Chlamydia trachomatis</i> Infection

Lad, Sonya P.; Fukuda, Elaine Y.; Li, Jiali; Maza, Luis M. de la; Li, Erguang

doi:10.4049/jimmunol.174.11.7186

Cited by 68 publications

(64 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using Stat-1-null or Stat-1 knockdown cells, Lad et al could previously show that selectively induced Stat-1 was essential for restricting chlamydial growth in epithelial cells (12). In our hands, reduced Stat-1 (Y701) phosphorylation under hypoxia did not depend on the suppressors of cytokine signaling (SOCS) regulatory pathway, as SOCS-1/-3 mRNA levels were not significantly altered between normoxic and hypoxic conditions.…”

Section: Resultsmentioning

confidence: 47%

Hypoxia abrogates antichlamydial properties of IFN-γ in human fallopian tube cells in vitro and ex vivo

Roth

König

Zandbergen

et al. 2010

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

View full text Add to dashboard Cite

IFN-γ has an important role in the adaptive immune response against intracellular pathogens. In urogenital tract (UGT) infections with the obligate intracellular pathogen Chlamydia trachomatis, IFN-γ-mediated control of chlamydial growth implies the JAK-STAT signaling cascades and subsequent induction of the indoleamine 2,3-dioxygenase (IDO). As oxygen concentrations in the UGT are low under physiological conditions (O 2 < 5%) and further decrease during an inflammatory process, we wondered whether antibacterial properties of IFN-γ are maintained under hypoxic conditions. Using primary cells that were isolated from human fallopian tubes and an ex vivo human fallopian tube model (HFTM), we found that even high IFN-γ concentrations (200 units/mL) were not sufficient to limit growth of C. trachomatis under hypoxia. Reduced antibacterial activity of IFN-γ under hypoxia was restricted to the urogenital serovars D and L 2 , but was not observed with the ocular serovar A. Impaired effectiveness of IFN-γ on chlamydial growth under hypoxia was accompanied by reduced phosphorylation of Stat-1 on Tyr701 and diminished IDO activity. This study shows that IFN-γ effector functions on intracellular C. trachomatis depend on the environmental oxygen supply, which could explain inadequate bacterial clearance and subsequent chronic infections eventually occurring in the UGT of women.Chlamydia trachomatis | hypoxia | persistence | urogenital tract infections

show abstract

Section: Resultsmentioning

confidence: 47%

Hypoxia abrogates antichlamydial properties of IFN-γ in human fallopian tube cells in vitro and ex vivo

Roth

König

Zandbergen

et al. 2010

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

View full text Add to dashboard Cite

show abstract

“…Total RNA was isolated from infected and uninfected wild-type and cPLA2 Ϫ/Ϫ MEFs and the levels of IFN-␤ mRNAs assessed by RT-PCR. As previously reported, Chamydia infection led to the induction of IFN-␤ mRNAs (55,56). However, this increase in expression was significantly lower in infected cPLA2 Ϫ/Ϫ MEFs (Fig.…”

Section: Controls the Expression Of The P47 Family Of Immuneregulatedmentioning

confidence: 46%

“…C. trachomatis and C. muridarum infection of both human and murine cells leads to the secretion of type I interferons (55,56,(65)(66)(67). How chlamydial products activate this innate immune pathway is less clear.…”

Section: Discussionmentioning

confidence: 99%

“…How chlamydial products activate this innate immune pathway is less clear. In HeLa cells it requires the JAK/STAT1 signaling pathway (55) and in murine cells the adaptor protein TRIF and the transcription factor IRF3 (54). TRIF can interact with TLR3 and TLR4 in endosomal compartments to activate IRFs in response to nucleic acids and lipopolysaccharide, respectively (68,69) and Ly6C-positive monocytes, have been reported to induce the expression of type I interferons upon recognition of non-nucleic acid viral components by TLR2 (70).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Vignola

Kashatus

Taylor

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

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.

show abstract

“…To this end, monolayers of HeLa 229 cells were infected with C. trachomatis lymphogranuloma venereum 2 (LGV2) at 1 inclusion-forming unit (IFU) per cell for various time points (15). As controls, the cells were infected with invasive or noninvasive Salmonella typhimurium for 2 h or treated with TNF-␣ to induce I B␣ degradation (16,17).…”

Section: To Investigate Whethermentioning

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.

Self Cite

107

View full text Add to dashboard Cite

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

show abstract

Up-Regulation of the JAK/STAT1 Signal Pathway during Chlamydia trachomatis Infection

Cited by 68 publications

References 55 publications

Hypoxia abrogates antichlamydial properties of IFN-γ in human fallopian tube cells in vitro and ex vivo

Hypoxia abrogates antichlamydial properties of IFN-γ in human fallopian tube cells in vitro and ex vivo

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

Contact Info

Product

Resources

About