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News Article | February 23, 2017
Site: www.eurekalert.org

Researchers determine that a protein required for sperm-egg fusion is identical to a protein viruses use to invade host cells; discovery could help fight parasitic diseases like malaria Sexual reproduction and viral infections actually have a lot in common. According to new research, both processes rely on a single protein that enables the seamless fusion of two cells, such as a sperm cell and egg cell, or the fusion of a virus with a cell membrane. The protein is widespread among viruses, single-celled protozoans, and many plants and arthropods, suggesting that the protein evolved very early in the history of life on Earth. The discovery, published on February 23, 2017 in the journal Cell, reveals new details about the evolution of sex. The protein acts as a nearly universal, biochemical "key" that enables two cell membranes to become one, resulting in the combination of genetic material--a necessary step for sexual reproduction. New details about the protein's function could help fight parasitic diseases, such as malaria, and boost efforts to control insect pests. "Our findings show that nature has a limited number of ways it can cause cells to fuse together into a single cell," said William Snell, a senior author of the study and a research professor in the University of Maryland Department of Cell Biology and Molecular Genetics. Snell joined UMD in June 2016, but performed the majority of the work at his previous institution, the University of Texas Southwestern Medical Center. "A protein that first made sex possible -- and is still used for sexual reproduction in many of Earth's organisms -- is identical to the protein used by dengue and Zika viruses to enter human cells," Snell said. "This protein must have really put the spice in the primordial soup." Snell and his colleagues studied the protein, called HAP2, in the single-celled green alga Chlamydomonas reinhardtii. HAP2 is common among single-celled protozoans, plants and arthropods -- although it is not found in fungi or vertebrates such as humans. Prior results from Snell and his collaborators, as well as other research groups, indicated that HAP2 is necessary for sex cell fusion in the organisms that possess the protein. But the precise mechanism remained unclear. For the current study, Snell and his colleagues at UT Southwestern used sophisticated computer analysis tools to compare the amino acid sequence of Chlamydomonas HAP2 with that of known viral fusion proteins. The results suggested a striking degree of similarity, especially in a region called the "fusion loop" that enables the viral proteins to successfully invade a cell. If HAP2 functioned like a viral fusion protein, Snell reasoned, then disrupting HAP2's fusion loop should block its ability to fuse sex cells. Sure enough, when Snell's team changed just a single amino acid in the fusion loop of Chlamydomonas HAP2, the protein entirely lost its function. The sex cells were able to stick together -- a process that depends on other proteins--but they were not able to complete the final fusion of their cell membranes. Similarly, the cells could not fuse when the researchers introduced an antibody that covered up the HAP2 fusion loop. "We were thrilled with these results, because they supported our new model of HAP2 function," Snell said. "But we needed to visualize the three-dimensional structure of the HAP2 protein to be sure it was similar to viral fusion proteins." Snell reached out to Felix Rey, a structural biologist at the Pasteur Institute in Paris who specializes in viruses. Coincidentally, Rey and his colleagues had just determined the structure of Chlamydomonas HAP2 using X-ray crystallography. Rey's results demonstrated that, indeed, HAP2 was functionally identical to dengue and Zika viral fusion proteins. "The HAP2 protein from Chlamydomonas is folded in an identical fashion to the viral proteins," Rey said, referring to the molecular folding that creates the three-dimensional structure of all proteins from a simple chain of amino acids. "The resemblance is unmistakable." HAP2 appears to be necessary for cell fusion in a wide variety of organisms, including disease-causing protozoans, invasive plants and destructive insect pests. So far, every known version of HAP2 shares the one critical amino acid in the fusion loop region. As such, HAP2 could provide a promising target for vaccines, therapies and other control methods. Snell is particularly encouraged by the possibility of controlling malaria, which is caused by the single-celled protozoan Plasmodium falciparum. "Developing a vaccine that blocks the fusion of Plasmodium sex cells would be a huge step forward," Snell said, noting that Plasmodium has a complex life cycle that depends on both mosquito and human hosts. "Our findings strongly suggest new strategies to target Plasmodium HAP2 that could disrupt the mosquito-borne stage of the Plasmodium life cycle." In addition to Snell and Rey, co-authors of the study include: Juliette Fedry, Gerard Péhau-Arnaudet, M. Alejandra Tortorici, Francois Traincard and Annalisa Meola (Pasteur Institute); Yanjie Liu, Jimin Pei, Wenhao Li and Nick Grishin (UT Southwestern); Gerard Bricogne (Global Phasing, Ltd.); and Thomas Krey (Pasteur Institute, Hannover Medical School and German Center for Infection Research). The research paper, "The ancient gamete fusogen HAP2 is a eukaryotic class II fusion protein," Juliette Fedry, Yanjie Liu, Gerard Péhau-Arnaudet, Jimin Pei, Wenhao Li, M. Alejandra Tortorici, Francois Traincard, Annalisa Meola, Gerard Bricogne, Nick Grishin, William J. Snell, Félix A. Rey and Thomas Krey, was published February 23, 2017 in the journal Cell. This work was supported by the United States National Institutes of Health (Award Nos. GM56778 and GM094575), the Welch Foundation (Award No. I-1505), the European Research Council, the Pasteur Institute and the French National Center for Scientific Research. The content of this article does not necessarily reflect the views of these organizations. University of Maryland College of Computer, Mathematical, and Natural Sciences 2300 Symons Hall College Park, MD 20742 http://www. @UMDscience About the College of Computer, Mathematical, and Natural Sciences The College of Computer, Mathematical, and Natural Sciences at the University of Maryland educates more than 7,000 future scientific leaders in its undergraduate and graduate programs each year. The college's 10 departments and more than a dozen interdisciplinary research centers foster scientific discovery with annual sponsored research funding exceeding $150 million.


News Article | February 15, 2017
Site: www.eurekalert.org

University of Tübingen researchers in collaboration with the biotech company Sanaria Inc. have demonstrated in a clinical trial that a new vaccine for malaria called Sanaria® PfSPZ-CVac has been up to 100 percent effective when assessed at 10 weeks after last dose of vaccine. For the trial, Pro-fessor Peter Kremsner and Dr. Benjamin Mordmüller of the Institute of Tropical Medicine and the German Center for Infection Research (DZIF) used malaria parasites provided by Sanaria. The vac-cine incorporated fully viable - not weakened or otherwise inactivated - malaria pathogens together with the medication to combat them. Their research results have been published in the latest edition of Nature. DOI: 10.1038/nature21060 Malaria parasites are transmitted by the bite of female Anopheles mosquitoes. The Plasmodium falciparum parasite is responsible for most malaria infections and almost all deaths caused by the disease worldwide. Most of the previous vaccines which have been tried involved the use of individual molecules found in the pathogen. However, they were unable to provide sufficient immunity to the disease. The Tuebingen study involved 67 healthy adult test persons, none of whom had previously had malaria. The best immune response was shown in a group of nine test persons who received the highest dose of the vaccine three times at four-week intervals. At the end of the trial, all nine of these individuals had 100 percent protection from the disease. "That protection was probably caused by specific T-lymphocytes and antibody responses to the parasites in the liver," Professor Peter Kremsner explained. The researchers analyzed the bodies' immune reactions and identified protein patterns which will make it possible to further improve malaria vaccines, Kremsner added. The researchers injected live malaria parasites into the test subjects, at the same time preventing the development of the disease by adding chloroquine - which has been used to treat malaria for many years. This enabled the researchers to exploit the behavior of the parasites and the properties of chloroquine. Once the person is infected, the Plasmodium falciparum parasite migrates to the liver to reproduce. During its incubation period there, the human immune system could respond; but at this stage, the pathogen does not make the person sick. On top of that, chloroquine does not take effect in the liver - so it is unable to prevent the parasite from reproducing. Malaria only breaks out when the pathogen leaves the liver, entering the bloodstream and going into the red corpuscles, where it continues to reproduce and spread. As soon as the pathogen enters the bloodstream, however, it can be killed by chloroquine - and the disease cannot break out. "By vaccinating with a live, fully active pathogen, it seems clear that we were able to set of a very strong immune response," said study leader Benjamin Mordmueller, "Additionally, all the data we have so far indicate that what we have here is relatively stable, long-lasting protection." In the group of test persons who demonstrated 100 percent protection after receiving a high dose three times, Mordmueller said, the protection was reliably still in place after ten weeks - and remained measurable for even longer. He added that the new vaccine showed no adverse effects on the test persons. The next step is to further test the vaccine's effectiveness over several years in a clinical study in Gabon funded by DZIF. Malaria is one of the biggest health threats in the African nation. The University of Tuebingen has worked with the Albert Schweitzer Hospital in the Gabonese town of Lambaréné and with the neighboring research institute, the Centre de Recherches Médicales de Lambaréné, for many years. Malaria is one of the deadliest infectious diseases worldwide. The World Health Organization reports that some 214 million people became infected with malaria in the year 2015 alone. Approximately 438,000 died of the disease. Around 90 percent of those malaria deaths were in Africa. Nearly three-quarters of those who succumb to the disease are children under five. The search for a vaccine has been going on for more than a century. An effective vaccine would make it easier to control malaria; vaccination campaigns could be conducted in severely affected areas to eliminate the pathogen. Such a vaccine could also help to stop the spread of resistance to the treatment, and to better protect travelers.


News Article | November 4, 2016
Site: www.sciencedaily.com

Tuberculosis (TB) is a major global public health problem. Treatment often takes many months and till this day there is no effective vaccine. Various TB bacterial strains exist globally, with different geographical spread. Only the so-called Lineage 4 occurs on all continents. It is responsible for the majority of the 10 million new infections and 2 million deaths annually. Under the lead of Sébastien Gagneux at the Swiss Tropical and Public Health Institute (Swiss (TPH), and DZIF scientist Stefan Niemann, Research Center Borstel, a team of 75 scientists at 56 institutions analyzed the genetic make-up of TB bacteria from several thousand patients. Surprisingly, it was found that Lineage 4 can be genetically further subdivided into several sublineages. Some of these sublineages occur all over the world, others are geographically highly restricted. According to the study in the journal Nature Genetics, TB bacteria can be divided into generalists with worldwide distribution and specialists that have focused on localized ecological niche. While ecologists have been differentiating between generalists and specialists, especially in plants, for a pathogen that transmits exclusively from human to human, such a subdivision is new. Generalists are immunologically more versatile than specialists TB bacteria have a unique property: they hardly vary their antigens, and are thus efficiently recognized by the human immune system. As a result, a fierce immune reaction occurs, which affects the lungs in particular, and promotes coughing. Thanks to this strategy, TB bacteria is transmitted very efficiently from human to human. The researchers show that the generalists pursue an additional strategy. They show a slightly increased diversity of their antigens compared to the specialists. "Generalists are thus able to react more specifically to the immune system of different human populations," says Stefan Niemann, who coordinates the research field "Tuberculosis" at DZIF. They have adapted their molecular strategy and are able to push through and spread much more globally. These new findings have implications for the development of new TB vaccines. The more TB bacteria can adapt their antigens, the more difficult it will be to design a vaccine that is equally effective in all human populations across the world. Hence, the development of a broadly active TB vaccine might be delayed even further. The international cooperation has made these results possible; for the German Center for Infection Research scientists from the sites Hamburg-Lübeck-Borstel, Munich and Tübingen have contributed to it as well as scientists from the African Partner Institutions. "National and international networks are the basis for the global fight against infectious diseases as HIV and TB," says DZIF Prof Michael Hoelscher, Director of the Tropical Institute in Munich, LMU. "This has been the concept for the successful work of DZIF in the research field "Tuberculosis."


News Article | November 3, 2016
Site: www.eurekalert.org

Tuberculosis (TB) is a major global public health problem. Treatment often takes many months and till this day there is no effective vaccine. Various TB bacterial strains exist globally, with different geographical spread. Only the so-called Lineage 4 occurs on all continents. It is responsible for the majority of the 10 million new infections and 2 million deaths annually. Under the lead of Sébastien Gagneux at the Swiss Tropical and Public Health Institute (Swiss (TPH), and DZIF scientist Stefan Niemann, Research Center Borstel, a team of 75 scientists at 56 institutions analyzed the genetic make-up of TB bacteria from several thousand patients. Surprisingly, it was found that Lineage 4 can be genetically further subdivided into several sublineages. Some of these sublineages occur all over the world, others are geographically highly restricted. According to the study in the journal Nature Genetics, TB bacteria can be divided into generalists with worldwide distribution and specialists that have focused on localized ecological niche. While ecologists have been differentiating between generalists and specialists, especially in plants, for a pathogen that transmits exclusively from human to human, such a subdivision is new. TB bacteria have a unique property: they hardly vary their antigens, and are thus efficiently recognized by the human immune system. As a result, a fierce immune reaction occurs, which affects the lungs in particular, and promotes coughing. Thanks to this strategy, TB bacteria is transmitted very efficiently from human to human. The researchers show that the generalists pursue an additional strategy. They show a slightly increased diversity of their antigens compared to the specialists. "Generalists are thus able to react more specifically to the immune system of different human populations," says Stefan Niemann, who coordinates the research field "Tuberculosis" at DZIF. They have adapted their molecular strategy and are able to push through and spread much more globally. These new findings have implications for the development of new TB vaccines. The more TB bacteria can adapt their antigens, the more difficult it will be to design a vaccine that is equally effective in all human populations across the world. Hence, the development of a broadly active TB vaccine might be delayed even further. The international cooperation has made these results possible; for the German Center for Infection Research scientists from the sites Hamburg-Lübeck-Borstel, Munich and Tübingen have contributed to it as well as scientists from the African Partner Institutions. "National and international networks are the basis for the global fight against infectious diseases as HIV and TB", says DZIF Prof Michael Hoelscher, Director of the Tropical Institute in Munich, LMU. "This has been the concept for the successful work of DZIF in the research field „Tuberculosis".


News Article | February 15, 2017
Site: www.eurekalert.org

After an infection with the Epstein-Barr virus (EBV), the virus persists in the body throughout a person's lifetime, usually without causing any symptoms. About one third of infected teenagers and young adults nevertheless develop infectious mononucleosis, also known as glandular fever or kissing disease, which usually wears off after a few weeks. In rare cases, however, the virus causes cancer, particularly lymphomas and cancers of the stomach and of the nasopharynx. Scientists have been trying for a long time to elucidate how the viruses reprogram cells into becoming cancer cells. "The contribution of the viral infection to cancer development in patients with a weakened immune system is well understood" says Henri-Jacques Delecluse, a cancer researcher at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg. "But in the majority of cases, it remains unclear how an EBV infection leads to cancer development." In their present publication, Delecluse, in collaboration with Ingrid Hoffmann, also from the DKFZ, and their respective groups present a new and surprising explanation for this phenomenon. The scientists have shown for the first time that a protein component of the virus itself promotes the development of cancer. When a dividing cell comes in contact with Epstein-Barr viruses, a viral protein present in the infectious particle called BNRF1 frequently leads to the formation of an excessive number of spindle poles (centrosomes). As a result, the chromosomes are no longer divided equally and accurately between the two daughter cells -- a known and acknowledged cancer risk factor. By contrast, Epstein-Barr viruses that had been made deficient of BNRF1 did not interfere with chromosome distribution to the daughter cells. EBV, a member of the herpes virus family, infects B cells of the immune system. The viruses normally remain silent in a few infected cells, but occasionally they reactivate to produce viral offspring that infects nearby cells. As a consequence, these cells come in close contact with the harmful viral protein BNRF1, thus having a greater risk of transforming into cancer cells. "The novelty of our work is that we have uncovered a component of the viral particle as a cancer driver," Delecluse said. "All human tumors viruses that have been studied so far cause cancer in a completely different manner. Usually, the genetic material of the viruses needs to be permanently present in the infected cell, thus causing the activation of one or several viral genes that cause cancer development. However, these gene products are not present in the infectious particle itself". Delecluse and his colleagues therefore suspect that EBV could cause the development of additional tumors. These tumors might have previously not been linked to the virus because they do not carry the viral genetic material. For Delecluse, the consequence that follows from his findings is immediate: "We must push forward with the development of a vaccine against EBV infection. This would be the most direct strategy to prevent an infection with the virus. Our latest results show that the first infection could already be a cancer risk and this fits with earlier work that showed an increase in the incidence of Hodgkin's lymphoma in people who underwent an episode of infectious mononucleosis." Experts estimate that an EBV vaccine could prevent two percent of all cancer cases worldwide. Delecluse and his group already developed a vaccine prototype in 2005. It is based on so-called 'virus-like particles', or VLPs. These are empty virus shells that mimic an EBV infectious particle, thus prompting the body to mount an immune response. Henri-Jacques Delecluse is a medical researcher and, since 2012, he has been director of a research unit (Unité Inserm 1074) that was established at the DKFZ by the French 'Institut National de la Santé et de la Recherche Médicale' (Inserm). In addition, the DKFZ is a member of the German Center for Infection Research (DZIF), one of six German Centers for Health Research that the German government has established with the goal of fighting major common diseases. The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.


Stecher B.,Ludwig Maximilians University of Munich | Stecher B.,German Center for Infection Research | Berry D.,University of Vienna | Loy A.,University of Vienna
FEMS Microbiology Reviews | Year: 2013

The highly diverse intestinal microbiota forms a structured community engaged in constant communication with itself and its host and is characterized by extensive ecological interactions. A key benefit that the microbiota affords its host is its ability to protect against infections in a process termed colonization resistance (CR), which remains insufficiently understood. In this review, we connect basic concepts of CR with new insights from recent years and highlight key technological advances in the field of microbial ecology. We present a selection of statistical and bioinformatics tools used to generate hypotheses about synergistic and antagonistic interactions in microbial ecosystems from metagenomic datasets. We emphasize the importance of experimentally testing these hypotheses and discuss the value of gnotobiotic mouse models for investigating specific aspects related to microbiota-host-pathogen interactions in a well-defined experimental system. We further introduce new developments in the area of single-cell analysis using fluorescence in situ hybridization in combination with metabolic stable isotope labeling technologies for studying the in vivo activities of complex community members. These approaches promise to yield novel insights into the mechanisms of CR and intestinal ecophysiology in general, and give researchers the means to experimentally test hypotheses in vivo at varying levels of biological and ecological complexity. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.


LMU researchers have shown that a defined set of 15 bacterial species protects mice from Salmonella infections as effectively as does the natural gut microbiota. The system will facilitate studies of host-pathogen interactions in the gut. MÜNCHEN, 25-Nov-2016 — /EuropaWire/ — The mammalian gut harbors thousands of microbial species – collectively known as the microbiota or microbiome – that interact with each other and with their host to form a complex ecosystem. In healthy organisms, this community provides an effective shield against infection by many pathogenic organisms, such as Clostridium difficile (which is responsible for antibiotic-associated diarrhea) and various Salmonellaspecies. Researchers led by LMU microbiologist Professor Bärbel Stecher, in cooperation with colleagues from the University of Vienna and the Technical University of Munich, now show that, in the mouse, a defined group of 15 bacterial species confers the same degree of protection against Salmonella infections as does the host’s natural microbiota. The work establishes a new model system for the investigation of the interaction between the gut microbiome and infectious pathogens, which could in turn provide new approaches to the treatment of gastrointestinal infections. The new findings appear in the journal Nature Microbiology. The protective effect provided by the gut microbiota against infection by invasive pathogens is referred to as colonization resistance. Exposure to antibiotics can disrupt this mechanism because these drugs typically alter the composition of the bacterial population in the gastrointestinal tract. “However, the contribution made by individual bacterial species to colonization resistance remains unclear,” says Stecher, who is also member of the German Center for Infection Research (DZIF). “In order to gain a better understanding of the functions of the gut microbiota in this context, we had already established in my laboratory a minimal consortium comprising 12 bacterial species which are representative for the gut microbiome of the mouse.” This set of species, which is referred to as Oligo-MM-12, can be introduced into germ-free mice and is stably maintained over several generations. However, while mice colonized by the Oligo-MM-12 species are more resistant to infection by Salmonella enterica than their germ-free relatives, they are not as well protected as mice with a normal microbiome. The team then went on to develop a new strategy, called genome-guided microbiota design, to identify species required to confer the same measure of protection as the natural gut microbiome of the mouse. “We compared DNA sequences from the 12 species represented in Oligo-MM-12 with homologous sequences derived from the total mouse microbiome, and were able to identify groups of genes that were missing from our set,” Stecher explains. Some of these genes turned out to be characteristic for so-called facultative anaerobes, i.e. bacterial species that grow best in the presence in oxygen, but are nevertheless capable of proliferating in its absence. Indeed, the genus Salmonellaconsists of facultative anaerobes, while almost all the species that make up the Oligo-MM-12 consortium are obligate anaerobes – for which oxygen is toxic. “We therefore supplemented our original consortium with three facultatively anaerobic species that are found in the microbiota of healthy mice,” Stecher says, “and we were able to demonstrate experimentally that this combination confers the same level of colonization resistance against Salmonella as that observed in mice that have a natural microbiota.” Stecher and her colleagues believe that their new “mini-microbiota”, together with the use of genome-guided microbiota design, provides a powerful new tool for the identification of hitherto unknown functions mediated by natural microbiota. This opens a route to the identification of specific bacterial species that could ameliorate the effects of disease-dependent dysfunction of the gut microbiota. Nature Microbiology 2016


News Article | February 6, 2017
Site: www.biosciencetechnology.com

Scientists from the Heidelberg University Hospital and the German Center for Infection Research (DZIF) have developed a new substance that has cured severe malaria in humanized mice. Severe malaria, caused by the Plasmodium falciparum parasite, causes dangerous circulatory disorders and neurological complications. If the affected person is not treated immediately, the disease will inevitably lead to death. On the one hand, the currently used drugs artesunate and quinine have unwanted side effects and, on the other, more and more plasmodia are becoming resistant to them. Developing new drugs with other mechanisms of action is therefore essential. “New drugs for treating severe malaria are indeed urgently needed,” emphasizes Prof Michael Lanzer, DZIF scientist at the Heidelberg University Hospital. In a DZIF project, he developed the first promising candidate together with his research team: SC83288, the promising substance with a somewhat prosaic name has the required properties, and has already been successfully used to treat severe malaria in humanised mice. The starting point of the drug development was benzamidine derivatives, which had been effective against different parasites in veterinary medicine but were not used as they have severe side effects. The scientists have now tried to modify these substances so that they become suitable to treat severe malaria. The substance was chemically modified to make it more tolerable without forfeiting its effect against parasites. “The new chemical structure is very well tolerated, is metabolised rapidly in the body and the crucial factor: in animal models, it can kill the severe malaria parasites in a short period of time,” explains Lanzer. For their tests, the scientists used mice with human blood cells and that had been infected with severe malaria. In this model system, SC83288 was effective in the late stages of malaria, during which the parasites are in the blood cells where they cause severe damage. Detailed preclinical studies on pharmacokinetics and toxicology showed consistent positive results for the substance which is to be administered intravenously. “We are now in the process of conducting the regulatory preclinical procedures and hope to initiate the clinical trials in 2018,” says Lanzer.


Diepold A.,University of Oxford | Wagner S.,University of Tübingen | Wagner S.,German Center for Infection Research
FEMS Microbiology Reviews | Year: 2014

Many bacteria that live in contact with eukaryotic hosts, whether as symbionts or as pathogens, have evolved mechanisms that manipulate host cell behaviour to their benefit. One such mechanism, the type III secretion system, is employed by Gram-negative bacterial species to inject effector proteins into host cells. This function is reflected by the overall shape of the machinery, which resembles a molecular syringe. Despite the simplicity of the concept, the type III secretion system is one of the most complex known bacterial nanomachines, incorporating one to more than hundred copies of up to twenty different proteins into a multi-MDa transmembrane complex. The structural core of the system is the so-called needle complex that spans the bacterial cell envelope as a tripartite ring system and culminates in a needle protruding from the bacterial cell surface. Substrate targeting and translocation are accomplished by an export machinery consisting of various inner membrane embedded and cytoplasmic components. The formation of such a multimembrane-spanning machinery is an intricate task that requires precise orchestration. This review gives an overview of recent findings on the assembly of type III secretion machines, discusses quality control and recycling of the system and proposes an integrated assembly model. This review discusses the assembly of the type III secretion injectisome, a cell envelope spanning macromolecular machine used by Gram-negative bacteria to translocate bacterial effector proteins into host cells. © 2014 Federation of European Microbiological Societies.


Rockstroh J.K.,University of Bonn | Rockstroh J.K.,German Center for Infection Research
Liver International | Year: 2015

The development of direct acting antivirals (DAAs) against the hepatitis C virus (HCV) has revolutionized treatment paradigms for HCV in HIV co-infected subjects. In the era of DAAs, HIV/HCV co-infected patients have the same cure rates of over 90% with interferon (IFN)-free DAA combinations. Therefore, guidelines no longer separate mono- and co-infected subjects. Indications for HCV therapy and DAA drug selection have become the same for all patients. The only special consideration in HIV/HCV co-infected subjects is the need to check for drug-drug interactions between HIV and HCV drugs, especially HIV and HCV protease inhibitors which have a high risk of clinically significant drug interactions. Because of the faster progression of fibrosis and the higher risk of hepatic decompensation in co-infected subjects, even with combination antiretroviral (ART) therapy, the availability of modern HCV treatments needs to be extended and HCV therapy should be discussed in all co-infected patients. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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