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Browsing Posts published in July, 2012

Belgian scientists of the Institute of Tropical Medicine (ITM) in Antwerp, Belgium made a breakthrough in bridging high tech molecular biology research on microbial pathogens and the needs of the poorest of the poor. After sequencing the complete genome of Leishmania donovani (a parasite causing one of the most important tropical diseases after malaria) in hundreds of clinical isolates, they identified a series of mutations specific of ‘superparasites’ and developed a simple assay that should allow tracking them anywhere. This EU-funded research was done in collaboration with the Wellcome Trust Sanger Institute in UK and clinical partners of the Banaras Hindu University (India) and the BP Koirala Institute of Health Sciences (Nepal); it is published in the last issue of the Journal of Infectious Diseases.

Leishmania is a unicellular parasite that is transmitted through the bite of sandflies and occurs mainly in Latin-America, East-Africa, Asia and countries around the Mediterranean Sea.  The parasite causes a disease called leishmaniasis which can range from self-healing cutaneous to deadly visceral disease, depending on the infecting species. Recently, the World Health Organisation estimated up to 1,6 million of new cases of leishmaniasis every year, affecting essentially the poorest of the poor. In comparison to these figures, the hundreds of imported cases reported among travelers appear a drop of water in the ocean. Some of these parasites are more dangerous than others, among them those causing visceral leishmaniasis, a clinical form which is lethal in the absence of treatment.

Recently, the same group of scientists reported among these (already) dangerous microbes, the existence of  ‘superparasites’ in the Indian sub-continent, which are drug resistant and at the same time also better equipped to cope with our immune system. To our knowledge, it is the first time such a doubly armed organism is found in nature. These superparasites could jeopardize current efforts to control this devastating disease.

The European Commission currently supports a series of research projects to develop new drugs against this type of parasites or to protect the few existing ones against the development of resistance (See http://www.leishrisk.net/leishrisk/). In the context of the Kaladrug project, the Belgian scientists of ITM, together with British colleagues of the Wellcome Trust Sanger Institute and Indian and Nepalese clinical colleagues, unraveled the DNA code of Leishmania using state-of-the-art genomic technologies while aiming to discover features allowing to track superparasites.  The scientists found a series of mutations that were specific for these drug resistant and more virulent microbes and developed an easy-to-apply assay that would allow to detect them rapidly. “Thanks to the discovery of these mutations, made possible through funding by the European Commission, the spread and emergence of these drug resistant parasites can be more efficiently monitored, contributing to a better and more adequate control of the parasite and the disease it causes.” says Dr Manu Vanaerschot (ITM), first author of the paper. “We hope that this finding will ultimately pave the way to a field applicable drug resistance detection device not only for pentavalent antimonials but for all antileishmanial drugs. This is an important breakthrough which will help immensely in the control of the menace of leishmaniasis”, says Shyam Sundar, from the Banaras Hindu University, a world authority in clinical research.

Technological revolutions during the last years have allowed a huge effort of sequencing the genome of hundreds of microbes. This type of research provides an unprecedented potential for new solutions to fight these pathogens by revealing their Achilles heal, so to say. These technologies can reveal the microbes true identity, offering new targets for drugs or vaccines and allowing scientists to track them.  “Through the application of the latest technologies on precious clinical material to identify easy-to-use markers we strengthen our position among the world top in the field of translational research for infectious diseases and at the same time benefit those, often poor, patients that are usually most neglected in the society”, says Prof Dujardin (ITM), coordinator of the Kaladrug project. “This project also clearly highlights the inestimable value of involving local clinical partners in the affected regions. Here, the European Commission plays an important role by funding fundamental research that at the same time provides solutions for clinical or epidemiological challenges.”

This article is reprinted from alphagalileo.org

The plague, bacterial dysentery, and cholera have one thing in common: These dangerous diseases are caused by bacteria which infect their host using a sophisticated injection apparatus. Through needle-like structures, they release molecular agents into their host cell, thereby evading the immune response. Researchers at the Max Planck Institute for Biophysical Chemistry in Göttingen in cooperation with colleagues at the Max Planck Institute for Infection Biology in Berlin and the University of Washington in Seattle (USA) have now elucidated the structure of such a needle at atomic resolution. Their findings might contribute to drug tailoring and the development of strategies which specifically prevent the infection process.

Hundreds of tiny hollow needles sticking out of the bacterial membrane – it is a treacherous tool that makes pathogens causing plague or cholera so dangerous. Together with a base, embedded in the membrane, these miniature syringes constitute the so-called type III secretion system – an injection apparatus through which the pathogens introduce molecular agents into their host cell. There, these substances manipulate essential metabolic processes and disable the immune defines of the infected cells. The consequences are fatal as the pathogens can now spread within the organism without hindrance. To date, traditional antibiotics are prescribed to fight the infection. However, as some bacterial strains succeed in developing resistances, researchers worldwide seek to discover more specific drugs.

The exact structure of the 60 to 80 nanometre (60 to 80 millionths of a millimetre) long and about eight nanometre wide needles has so far been unknown. Classical methods such as X-ray crystallography or electron microscopy failed or yielded wrong model structures. Not crystallisable and insoluble, the needle resisted all attempts to decode its atomic structure. Therefore Adam Lange and Stefan Becker at the Max Planck Institute for Biophysical Chemistry together with a team of physicists, biologists and chemists chose a completely novel approach. In cooperation with David Baker at the University of Washington, and Michael Kolbe at the Max Planck Institute for Infection Biology, the scientists successfully combined the production of the needle in the laboratory with solid-state NMR spectroscopy, electron microscopy, and computer modelling. The researchers deciphered the structure of the needle atom by atom and visualised its molecular architecture for the first time in the angstrom range, a resolution of less than a tenth of a millionth of a millimetre.

This required progresses in several fields. “We have made big steps forward concerning sample production as well as solid-state NMR spectroscopy,” says Adam Lange. “Finally, we were also able to use one of the presently most powerful solid-state NMR spectrometers in Christian Griesinger’s NMR-based Structural Biology Department at our Institute.” With 20 tesla, the magnetic field of this 850 megahertz spectrometer is about 400,000 times as strong as that of the earth.

“We were surprised to see how the needles are constructed,” says Lange. As expected, the needles of pathogens causing diseases as diverse as food poisoning, bacterial dysentery, or the plague show striking similarities. However, in contrast to prevailing assumptions, the similarities are found in the inner part of the needles whereas the surface is astonishingly variable. According to the scientist, this variability might be a strategy of the bacteria to evade immune recognition by the host. Changes on the surface of the needle make it difficult for the host’s immune system to recognize the pathogen.

The scientists Lange, Kolbe, Becker, and their Max Planck colleagues Christian Griesinger und Arturo Zychlinsky, have focused on the bacterial injection apparatus for several years. Together with the Federal Institute for Materials Research and Testing they already showed in 2010 how bacteria assemble their miniature syringes. The discovery of their structure in atomic detail not only enables researchers to  gain new insights into how these pathogens outwit their host cells, it also offers the prospect to block the syringe assembly and the delivery of the bacterial factors using tailored molecules. Such substances, referred to as antiinfectives, could act more specifically and much earlier during infection than traditional antibiotics. “Thanks to our new technique, we can produce large amounts of needles in the lab. Our aim is now to develop a high-throughput method. This will allow us to search for new agents that prevent the formation of the needle,” explains Stefan Becker.

This Article has been reprinted from alphagalileo.org

Original Publication :

Antoine Loquet, Nikolaos G. Sgourakis, Rashmi Gupta, Karin Giller, Dietmar Riedel, Christian Goosmann, Christian Griesinger, Michael Kolbe, David Baker, Stefan Becker, and Adam Lange

Atomic Model of the Type III Secretion System Needle.

Nature advance online publication 20 May 2012. doi:10.1038/nature11079

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