Differential transcriptional responses between the interferon-γ- induction and iron-limitation models of persistence for Chlamydia pneumoniae
Chlamydia spp. are important pathogens of humans and animals that cause a wide range of acute and chronic infections. A persistence model has been developed in which Chlamydia spp. do not complete their developmental cycle, have significantly reduced infectivity for new host cells, and exhibit abnormal inclusion and reticulate body morphology. This study was performed to compare the interferon-gamma (IFN-gamma) induction and iron-limitation models of persistence for Chlamydia spp. to investigate the common and unique transcriptional pathways involved.
A quantitative real time-polymerase chain reaction approach was used to compare the IFN-gamma induction and iron-limitation models of Chlamydia pneumoniae persistence at the transcriptional level by analyzing selected genes in each of 5 distinct, functionally relevant subcategories.
The models showed minimal evidence of a general transcriptional stress response in persistence, with only 1 of the 7 genes analyzed in the IFN-gamma induction model (htrA) and 4 of the genes in the iron-limitation model (htrA, clpB, clpP1, ahpC) showing increased mRNA levels. Both models showed similar responses in relation to the genes associated with lack of reticulate body to elementary body conversion (ctcB, lcrH1, and hctB levels were all unchanged or downregulated). The models also showed similar responses to the key cell wall/envelope genes, ompA, omcB, and crpA, exhibiting lower mRNA levels in both models.
These data show that several key transcriptional pathways (lack of late developmental cycle completion, key cell wall components) respond similarly between the models. However, other pathways appear to differ depending on the persistence-inducing mechanism. This result suggests that Chlamydia spp. have evolved more than 1 mechanism to respond to different persistence-inducing conditions, but ultimately the pathways probably converge through a common persistence regulon.
Available from: Christopher Charles Thompson
- "modulation of host protein synthesis results in pleiotropic effects that likely influence chlamydial growth via means independent of iron starvation. Others have eliminated this need for cyclohexamide through the use of long-term DFO pre-treatment protocols in order to deplete host cells of intracellular iron stores prior to chlamydial invasion (Al-Younes et al., 2001; Peters et al., 2005; Mukhopadhyay et al., 2006; Dill et al., 2009; Timms et al., 2009). While the effects of this protocol could presumably be attributed solely to iron-deprivation, it is tedious and requires the infection of a compromised host cell population. "
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ABSTRACT: Iron is an essential cofactor in a number of critical biochemical reactions, and as such, its acquisition, storage, and metabolism is highly regulated in most organisms. The obligate intracellular bacterium, Chlamydia trachomatis experiences a developmental arrest when iron within the host is depleted. The nature of the iron starvation response in Chlamydia is relatively uncharacterized because of the likely inefficient method of iron depletion, which currently relies on the compound deferoxamine mesylate (DFO). Inefficient induction of the iron starvation response precludes the identification of iron-regulated genes. This report evaluated DFO with another iron chelator, 2,2'-bipyridyl (Bpdl) and presented a systematic comparison of the two across a range of criteria. We demonstrate that the membrane permeable Bpdl was superior to DFO in the inhibition of chlamydia development, the induction of aberrant morphology, and the induction of an iron starvation transcriptional response in both host and bacteria. Furthermore, iron starvation using Bpdl identified the periplasmic iron-binding protein-encoding ytgA gene as iron-responsive. Overall, the data present a compelling argument for the use of Bpdl, rather than DFO, in future iron starvation studies of chlamydia and other intracellular bacteria.
Available from: Rey Carabeo
- "As with most living organisms, chlamydia absolutely requires iron. Iron limitation under in vitro conditions induces aberrant growth, growth arrest, and a transcriptional response in chlamydia (Timms et al., 2009; Wehrl et al., 2004; Wyrick, 2010). In vivo, interferon-γ, being a potent anti-chlamydial cytokine also modulates iron acquisition of and metabolism in the host to starve intracellular pathogens of this essential metal (Beekhuizen and van de Gevel, 2007; Sow et al., 2007; Nairz et al., 2008). "
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ABSTRACT: An inhibitor of host cell lysophospholipid acyltransferase, an enzyme involved in lipid metabolism blocked growth of the obligate intracellular pathogen Chlamydia through its action on the transport of transferrin (Tf) via the slow pathway of recycling. A detailed characterization of this inhibition revealed that Tf accumulated in vesicles positive for Rab11, with a concomitant reduction in the level of Tf found within the transport intermediate Rab4/11 hybrid vesicles. The net result was the failure to be recycled to the plasma membrane. In chlamydiae-infected cells, the Tf-containing Rab11-positive vesicles were typically found intimately associated with the inclusion, and treatment with the inhibitor caused their accumulation, suggesting that the timely progression and completion of Tf recycling was necessary for proper chlamydial growth. Growth inhibition by the compound could be negated by the simple removal of the Tf-containing fraction of the serum, a further indication that accumulation of Tf around the chlamydial inclusion was deleterious to the pathogen. Thus, it appears that manipulating the slow recycling pathway can have biological consequences for Chlamydia and implies the need to regulate carefully the interaction of the inclusion with this host trafficking pathway.
Available from: Alison J Carey
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ABSTRACT: Citation Carey AJ, Beagley KW. Chlamydia trachomatis, a hidden epidemic: effects on the female reproduction and options for treatment. Am J Reprod Immunol 2010
The number of genital tract Chlamydia trachomatis infections is steadily increasing worldwide, with approximately 50–70% of infections asymptomatic. There is currently no uniform screening practice, current antibiotic treatment has failed to prevent the increased incidence, and there is no vaccine available. We examined studies on the epidemiology of C. trachomatis infections, the effects infections have on the female reproductive tract and subsequent reproductive health and what measures are being taken to reduce these problems. Undetected or multiple infections in women can lead to the development of severe reproductive sequelae, including pelvic inflammatory disease and tubal infertility. There are two possible paradigms of chlamydial pathogenesis, the cellular and immunological paradigms. While many vaccine candidates are being extensively tested in animal models, they are still years from clinical trials. With no vaccine available and antibiotic treatment unable to halt the increased incidence, infection rates will continue to increase and cause a significant burden on health care systems.
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