74 research outputs found
Small molecule inhibitors of type III secretion and their effect on chlamydia development
No full textChlamydiae are obligate intracellular pathogens that cause a variety of diseases with clinical and public health importance. Like many Gram-negative bacteria, Chlamydiae employ a type III secretion (T3S) system for invasion and establishment of a protected intracellular niche for successful replication and survival within host cells. Understanding the role of T3S and bacterial effector proteins in Chlamydia infection will provide new insights into chlamydial pathogenesis and is important to identify novel therapeutic targets for drug intervention.In this thesis we employed different small molecule inhibitors of T3S activity in Yersinia, named INPs, and analyzed their effect on Chlamydia development. In addition, we identified and characterized a new family of T3S effector proteins.In paper I, we assessed the effect of INP0400 on C. trachomatis development and invasion. INP0400 caused a dose and growth phase-dependent inhibition of RB multiplication at micromolar concentrations. When INP0400 was given at different stages during the infectious cycle, we observed a partial inhibition of Chlamydia entry, inhibition of translocation of IncG and IncA and a bacterial detachment from the inclusion membrane during the late stage of infection concomitant with an inhibition of RB to EB conversion causing a marked decrease in infectivity. Our data suggest that INPs impair progression through the infectious cycle suggesting that the T3S system is essential for Chlamydia pathogenesis.In paper II, we found that INP0010 displays a strong growth inhibitory effect on C. pneumoniae development, affects translocation of the C. pneumoniae effector proteins IncB and IncC and leads to down-regulation of T3S associated genes collectively suggesting that INP0010 impairs T3S activity in C. pneumoniae.In paper III, we further investigated the effect of INPs on Chlamydia invasion. We show that INPs impair Chlamydia development after entry into host cells because the efficiency of C. trachomatis L2 and C. caviae entry into epithelial cells was not altered in the presence of INPs. Moreover, entry appeared normally with recruitment of actin and the small GTPases Rac, Cdc42 and Arf6 to the bacterial entry site.Finally, in paper IV we set out to identify novel T3S effectors in Chlamydia. We found a family of chlamydial proteins, represented by a C-terminal domain of unknown function referred to as DUF582 that contains an amino-terminal T3S signal. C. trachomatis members of this family were expressed late during the infectious cycle and found to be secreted into the lumen of the inclusion and the cytoplasm of infected cells.List of scientific papersI. Muschiol S, Bailey L, Gylfe A, Sundin C, Hultenby K, Bergström S, Elofsson M, Wolf-Watz H, Normark S, Henriques-Normark B (2006). A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis. Proc Natl Acad Sci USA. 103(39): 14566-71. Epub 2006 Sep 14 https://pubmed.ncbi.nlm.nih.gov/16973741II. Bailey L, Gylfe A, Sundin C, Muschiol S, Elofsson M, Nordström P, Henriques-Normark B, Lugert R, Waldenström A, Wolf-Watz H, Bergström S (2007). Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle. FEBS Lett. 581(4): 587-95. Epub 2007 Jan 17 https://pubmed.ncbi.nlm.nih.gov/17257594III. Muschiol S, Normark S, Henriques-Normark B, Subtil A (2009). Small molecule inhibitors of the Yersinia type III secretion system impair the development of Chlamydia after entry into host cells. BMC Microbiol. 9: 75 https://pubmed.ncbi.nlm.nih.gov/19383140IV. Muschiol S, Boncompain G, Dehoux P, Normark S, Henriques-Normark B, Subtil A (2009). A new family of secreted proteins in Chlamydia. [Manuscript]</p
Small molecule inhibitors of type III secretion in Yersinia block the Chlamydia pneumoniae infection cycle
No full textAbstractIntracellular parasitism by Chlamydiales is a complex process involving transmission of metabolically inactive particles that differentiate, replicate, and re-differentiate within the host cell. A type three secretion system (T3SS) has been implicated in this process. We have here identified small molecules of a chemical class of acylated hydrazones of salicylaldehydes that specifically blocks the T3SS of Chlamydia. These compounds also affect the developmental cycle showing that the T3SS has a pivotal role in the pathogenesis of Chlamydia. Our results suggest a previously unexplored avenue for development of novel anti-chlamydial drugs
Small molecule inhibitors of the <it>Yersinia </it>type III secretion system impair the development of <it>Chlamydia </it>after entry into host cells
No full textAbstract Background Chlamydiae are obligate intracellular pathogens that possess a type III secretion system to deliver proteins into the host cell during infection. Small molecule inhibitors of type III secretion in Yersinia, termed INPs (Innate Pharmaceuticals AB) were reported to strongly inhibit Chlamydia growth in epithelial cells. In this study we have analyzed the effect of these drugs on bacterial invasiveness. Results We demonstrate that INPs affect Chlamydia growth in a dose dependent manner after bacterial invasion. The efficiency of C. trachomatis L2 and C. caviae GPIC entry into host cells was not altered in the presence of INPs. In C. caviae, entry appears to proceed normally with recruitment of actin and the small GTPases Rac, Cdc42 and Arf6 to the site of bacterial entry. Conclusion INPs have a strong inhibitory effect on Chlamydia growth. However, bacterial invasion is not altered in the presence of these drugs. In the light of these results, we discuss several hypotheses regarding the mode of action of INPs on type III secretion during the Chlamydia infectious cycle.</p
Infection of Human Enteroendocrine Cells With C. Trachomatis as a Model for Irritable Bowel Syndrome
No full text
Human enteroendocrine cell responses to infection with Chlamydia trachomatis: a microarray study
No full textAccess to finance and venture capital for industrial SMEs
No full textSMEs play a crucial role for European economies. The numbers show the high importance of SMEs for national economies. Accordingly, it is no surprise that the regulatory framework SMEs are imbedded in is the subject of an important political discussion. In the discussion it is frequently mentioned by representatives of SMEs as well as associations of SMEs, that the access to finance for SMEs is still inferior. Based on the importance of SMEs for national economies and the discussion on the accessibility of financial resources for SMEs, it is the main objective of this study to provide solid data on the access of SMEs to financial resources. To provide the data, the study is focusing on four main issues. First of all, the importance of SMEs for national economies will be shown. After that the financing of SMEs in selected countries will be analysed. Then the availability of venture capital for SMEs will be discussed. Finally the tax regimes and the influence of the tax system on the access to finance for SMEs will be analysed. Since there is still a large variety among the tax systems of the European Union member states, the study has focused on Austria, France, Germany, Poland and the United Kingdom. --SME,financial structure,venture capital,tax framework,accounting standards
Gold in the investment portfolio
No full textThe paper examines the key drivers of gold investment. Since 2000 the gold price has risen drastically, making gold an interesting add-on to a portfolio. As gold futures have negative roll returns, gold pool accounts are characterized by high credit risk and physical possession of gold means high transaction costs, Xetra-Gold might be the most efficient way to enter the market. Xetra-Gold is a product created by the Deutsche Börse in 2007, which is handled like a security but can be exchanged into physical gold any time. In the portfolio context gold has had a positive impact on Euro and USD portfolios between 2000 and 2006 due to considerable returns and low correlation to other assets. However, this has not been true for almost all other periods, the correlation was always low but the returns of gold were almost zero, overriding the positive diversification effect. --Investing in gold,gold in the portfolio,correlation of gold,returns of gold,Xetra-Gold
Vanna-volga pricing
No full textThe vanna-volga method, also called the traders rule of thumb is an empirical procedure that can be used to infer an implied-volatility smile from three available quotes for a given maturity. It is based on the construction of locally replicating portfolios whose associated hedging costs are added to corresponding Black-Scholes prices to produce smile-consistent values. Besides being intuitive and easy to implement, this procedure has a clear financial interpretation, which further supports its use in practice. --
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