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Archive for May, 2006

New Pathways For Autoimmune Treatment Identified

Posted by tumicrobiology on May 30, 2006

A rare genetic defect that can trigger a host of diseases from type 1 diabetes to alopecia has helped explain the imbalance of immune regulator and killer cells in autoimmune disease.

Mutation in the Aire gene causes APS1, a disease causing two out of three problems – an underactive parathyroid, yeast infection of the skin and/or mucous membrane and adrenal gland insufficiency – by age 5 and up to 16 autoimmune diseases over a lifetime.

The same mutation causes a defect in iNKT cells, a type of regulatory cell that helps the immune system fight infections while suppressing errant T cells bent on attacking the body, Medical College of Georgia researchers say.

This finding opens new pathways for treating or preventing APS1, or autoimmune polyglandular syndrome type 1, and potentially other autoimmune diseases as well, researchers report in the June issue of Nature Medicine.

“The body should maintain a balance between killing and suppression,” says Dr. Qing-Sheng Mi, immunologist and lead and co-senior author. “If you are killing too hard, it can induce autoimmune disease. If you regulate suppression too hard, you can get cancer. iNKT cells help maintain a healthy balance. But patients with autoimmune disease may not have enough functional iNKT cells.”

“Aire controls the development and function of iNKT cells,” says Drs. Jin-Xiong She, director of the MCG Center for Biotechnology and Genomic Medicine and co-senior author. “This relationship means that iNKT cells are critical to most autoimmune diseases and manipulating the iNKT cell population is one possible way to cure autoimmune disease.”

A lipid purified from sea plants, called alpha-GalCer, is already under study as a way to boost iNKT cell numbers and fight autoimmune disease as well as cancer. iNKT cells’ reactivity to alpha-GalCer, prompted the scientists to use it as a marker to examine the status of these cells in a mouse missing the Aire gene. That Aire knockout is a good model for humans with APS1.

They found significantly fewer iNKT cells in the thymus, spleen, liver and bone marrow and severely impaired maturation of those cells in mice missing the Aire gene. And the mice given alpha-GalCer had significantly reduced autoantibody production.

In 2001, Dr. Terry L. Delovitch and his colleagues at Canada’s Robarts Research Institute, including Dr. Mi, reported in Nature Medicine that using alpha-GalCer to boost iNKT cells and re-establish a healthy balance of good and bad immune cells prevented development of type 1 diabetes in an animal model for the disease.

But Drs. Mi and She say new iNKT boosters likely are needed because the action of alpha-GalCer somehow depends on individual genetic architecture as well as other factors. Under certain conditions, the drug can help or worsen an autoimmune disease by producing good or bad cytokines. That’s why it also has worked for some cancers and why a modified version of the glycolipid or totally different drugs may work better, Dr. She says. “By understanding more, we are better able to come up with better targets,” he says.

“iNKT development is still the big question,” says Dr. Mi. “Not only how they develop, but how they develop properly.”

The researchers watched the key regulatory cells come out of the bone marrow and go to the thymus where all T cells go for a process of positive and negative selection and maturation. Positive selection eliminates cells that are dysfunctional. Negative selection is eliminating T-cells that recognize the body’s own proteins, Dr. She says.

Other researchers recently confirmed that the Aire gene is involved in negative selection by controlling some protein expression in the thymus, Dr. Mi says. The thymus is supposed to express most body proteins so any T cells that would react to them can be eliminated through negative selection, he says. “But Aire’s role in protein expression is not sufficient to explain all the clinical symptoms of patients with APS1,” Dr. Mi says. “The Aire gene must have other immune functions.”

iNKT cells also go through a development process but via a somewhat different path than that of other T cells. MCG researchers have learned medullary epithelial cells in the thymus are critical to proper iNKT cell development. A defective Aire gene disrupts this natural nurturing relationship by disrupting medullary epithelial cell function, leading to insufficient numbers of iNKT cells.

“Whether or not you develop autoimmune disease to a large degree depends on the balance of these bad T cells that recognize the body’s own protein and regulatory T cells,” Dr. She says. “It’s all about balance.”
Source: Medical College of Georgia

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New Potential Drug Target In Tuberculosis

Posted by tumicrobiology on May 30, 2006

Tuberculosis remains one of the deadliest threats to public health. Every year two million people die of the disease, which is caused by the microorganism Mycobacterium tuberculosis. Roughly one third of the world’s population is infected and more and more bacterial strains have developed resistance to drugs. Researchers from the Hamburg Outstation of the European Molecular Biology Laboratory (EMBL) and the Max Planck Institute for Infection Biology (MPIIB) in Berlin have now obtained a structural image of a protein that the bacterium needs for survival in human cells. This image reveals features of the molecule that could be targeted by new antibiotic drugs. The results appear in this week’s online issue of the Proceedings of the National Academy of Sciences (PNAS).
Tuberculosis is dangerous because it hides and persists in the immune cells of our bodies. “It can only persist there because of the activity of key molecules,” says Matthias Wilmanns, Head of EMBL Hamburg. “We are investigating the functions of tuberculosis proteins and determining their atomic structures, in hopes of finding weak points and new inhibitors.”

A protein called LipB is essential for the organism because it activates cellular machines that drive the bacterium’s metabolism. Stefan Kaufmann’s department at the MPIIB has specialised in the biology of M. tuberculosis infection and its ability to survive in immune cells. They discovered that LipB is highly active in acutely infected cells, particularly in patients infected by multidrug-resistant forms of M. tuberculosis.

“In these cells we see a 70-fold increase in the production of LipB when compared to other cells,” says Stefan Kaufmann, Director at the MPIIB. “This strongly indicates an involvement in pathogenesis and makes it a particularly interesting target where traditional drugs have lost their efficacy.”

A structural picture of the protein – a kind of technical diagram of its building plan – has yielded important clues about its activity. Qingjun Ma from Wilmanns’ group purified LipB and obtained crystals of the molecule. Using the high-energy synchrotron radiation beamlines at EMBL Hamburg, on the campus of the German Electron Synchrotron Radiation Facility (DESY), he created an atom-by-atom map of the protein’s structure. A high-resolution picture of the active site of LipB bound to a lipid inhibitor helped to determine the function of the enzyme. In collaboration with EMBL’s Proteomics Core Facility in Heidelberg and researchers from the University of Illinois (USA), the Hamburg group discovered how LipB attaches specific fatty acids onto other proteins.

“LipB is a very promising drug target,” Wilmanns says, “because it belongs to a vital pathway. Unlike other organisms M. tuberculosis has no backup mechanism that could take over LipB’s role. This means that an inhibitor blocking its active site would shut down key processes the bacterium needs to survive and replicate. This would be a very effective strategy for a drug.”

The scientists will now search for compounds that can do so. At the same time, they are continuing to look for other proteins as drug targets. Wilmanns and his colleagues from various other institutes are now focusing on structures of molecules that help M. tuberculosis to persist in its dormant state and could become drug targets.

Over the past three years, EMBL has coordinated an “M. tuberculosis structural proteomics” consortium, supported by the German Ministry of Education and Research (BMBF), and produced high resolution images of more than 30 proteins. “Structure-based drug discovery has been a big success in the battle against many other diseases. We are now applying these tools to tuberculosis, one of the most devastating infectious diseases of mankind,” Wilmanns concludes.

Source: European Molecular Biology Laboratory

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New Treatment For Food Poisoning

Posted by tumicrobiology on May 12, 2006

A team of researchers working at the University of Bristol has found a potential new treatment for listeriosis, a deadly form of food poisoning. Their work is reported in Nature Medicine.

The group, led by Professor Jose Vazquez-Boland, has shown that one particular antibiotic — fosfomycin — can treat Listeria in the body, despite it being ineffective in laboratory conditions.

Because it was not effective in the laboratory, this drug has never been considered for the treatment of listeriosis, in spite of it reaching the infection sites more effectively than other antibiotics.

Professor Vazquez-Boland said: “Our results illustrate that antibiotic resistance in the laboratory does not always mean that the drug will not work in the infected patient. This work brings some optimism to the highly worrying problem of the increasing resistance to antibiotics.”

The Listeria bacteria causes the food-borne disease, listeriosis. It often triggers a brain infection and kills up to 30% of those affected.

To test whether antibiotics are effective, bacteria are taken from patients and tested in the laboratory. These tests measure whether antibiotics can halt the growth of Listeria in laboratory conditions. Such tests are usually a measure of how effective the drug will be in the body.

When tested this way, Listeria had been shown to be resistant to the antibiotic, fosfomycin. As a consequence, this drug has never been considered for the treatment of listeriosis.

Dr Mariela Scortti, lead author on the paper, added: “Our findings warn about the need to revise laboratory methods currently in use to determine the susceptibility or resistance of bacteria to such drugs, so that the tests reflect better what actually happens in the body.”
Source: University of Bristol

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How Bad Is Malaria Anemia? It May Depend On Your Genes

Posted by tumicrobiology on May 12, 2006

Cell and animal studies conducted jointly by scientists at Johns Hopkins, Yale and other institutions have uncovered at least one important contributor to the severe anemia that kills almost half of the 2 million people worldwide who die each year of malaria. The culprit is a protein cells make in response to inflammation called MIF, which appears to suppress red blood cell production in people whose red blood cells already are infected by malaria parasites.
The parasite that causes malaria – known as plasmodium – is carried through blood by mosquito bites, and in parts of the world where mosquitoes thrive, millions are infected, most of them by early childhood. Once in the bloodstream, plasmodium invades liver and red blood cells and makes more copies of itself. Eventually, as red cells break and free plasmodium to infect other cells, and as the body’s immune system works to kill infected cells, the total number of red blood cells drops, causing anemia.

But not everyone infected with malaria develops severe, lethal anemia. And there are cases where patients who have been cured of infection still develop severe anemia.

This report provides the rationale for a simple, genetic test to sort out which children may be most susceptible to this lethal complication of malarial infection and to identify treatments targeted to them especially, the study’s authors suggest.

“This is important because in places where malaria is endemic, drug treatment resources are scarce,” says the study’s primary author, Michael A. McDevitt, M.D., Ph.D., an assistant professor of medicine and hematology at the Johns Hopkins School of Medicine.

“There are many difficulties with blood transfusion safety and access in Africa, especially in rural areas where most of the malaria-related deaths occur,” says McDevitt. “That led us to search for a better way to identify those most at risk and a better way to treat the disease,” he says.

The study, published online April 24 in the Journal of Experimental Medicine, adds to a growing amount of evidence that an individual’s unique genetic makeup can affect the prevalence and outcome of diseases, in this case the individual risk of malarial anemia.

A number of human proteins, including MIF (which stands for migration inhibitory factor), were long suspected to cause malarial anemia because they are known to reduce red blood cell counts as part of the body’s normal response to such inflammatory conditions as rheumatoid arthritis or some cancers.

Using immature blood cell precursors grown in a dish, the research team showed that adding MIF to the cells decreases both the final number and maturity of red blood cells. The researchers believe this effect can lead to anemia.

When infected with plasmodium, mice genetically engineered to lack MIF experience less severe anemia and are more likely to survive. Without MIF around to prevent blood cells from maturing, the mice appear better able to maintain their oxygen carrying capacity and don’t lose as much hemoglobin, the protein found in red blood cells responsible for binding to oxygen molecules.

“Demonstrating that MIF clearly contributes to severe anemia suggests new ideas for therapies that can block MIF in malaria patients,” says the study’s senior author, Richard Bucala, M.D., Ph.D., a professor of medicine at Yale University School of Medicine.

The research team also found different versions of “promoter” DNA sequences next to the MIF gene that control how much MIF protein a cell makes in response to infection. One version of the MIF promoter leads to less MIF protein made, while cells containing another version of the MIF promoter make much more MIF protein. Differences in the MIF promoter also have been linked to the severity of other inflammatory diseases.

The researchers continue to collaborate in an effort to develop drugs that might block MIF and treat severe anemia in malaria patients.

The researchers were funded by the National Institutes of Health, the Office of Research on Minority Health, a Howard University General Clinical Research Center grant, and the Department of Medicine at Johns Hopkins.

Authors on the paper are McDevitt, Ganapathy Shanmugasundaram and Jeffrey Keefer of Johns Hopkins; Jianlin Xie and Christine Metz of the Feinstein Institute for Medical Research; Jason Griffith, Aihua Liu, Courtney McDonald, Lin Leng and Bucala of Yale; Philip Thuma of the Macha Malaria Research Institute in Choma, Zambia, a field unit of the Johns Hopkins Bloomberg School of Public Health; Victor Gordeuk of Howard University; Robert Mitchell of the James Graham Brown Cancer Center; and John David of Harvard School of Public Health.

Source: Johns Hopkins Medical Institutions

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Mars Meteorite Similar To Bacteria-etched Earth Rocks

Posted by tumicrobiology on May 12, 2006

A new study of a meteorite that originated from Mars has revealed a series of microscopic tunnels that are similar in size, shape and distribution to tracks left on Earth rocks by feeding bacteria.

And though researchers were unable to extract DNA from the Martian rocks, the finding nonetheless adds intrigue to the search for life beyond Earth.

Results of the study were published in the latest edition of the journal Astrobiology.

Martin Fisk, a professor of marine geology in the College of Oceanic and Atmospheric Sciences at Oregon State University and lead author of the study, said the discovery of the tiny burrows do not confirm that there is life on Mars, nor does the lack of DNA from the meteorite discount the possibility.

“Virtually all of the tunnel marks on Earth rocks that we have examined were the result of bacterial invasion,” Fisk said. “In every instance, we’ve been able to extract DNA from these Earth rocks, but we have not yet been able to do that with the Martian samples.

“There are two possible explanations,” he added. “One is that there is an abiotic way to create those tunnels in rock on Earth, and we just haven’t found it yet. The second possibility is that the tunnels on Martian rocks are indeed biological in nature, but the conditions are such on Mars that the DNA was not preserved.”

More than 30 meteorites that originated on Mars have been identified. These rocks from Mars have a unique chemical signature based on the gases trapped within. These rocks were “blasted off” the planet when Mars was struck by asteroids or comets and eventually these Martian meteorites crossed Earth’s orbit and plummeted to the ground.

One of these is Nakhla, which landed in Egypt in 1911, and provided the source material for Fisk’s study. Scientists have dated the igneous rock fragment from Nakhla – which weighs about 20 pounds – at 1.3 billion years in age. They believe that the rock was exposed to water about 600 million years ago, based on the age of clay found inside the rocks.

“It is commonly believed that water is a necessary ingredient for life,” Fisk said, “so if bacteria laid down the tunnels in the rock when the rock was wet, they may have died 600 million years ago. That may explain why we can’t find DNA – it is an organic compound that can break down.”

Other authors on the paper include Olivia Mason, an OSU graduate student; Radu Popa, of Portland State University; Michael Storrie-Lombardi, of the Kinohi Institute in Pasadena, Calif.; and Edward Vicenci, from the Smithsonian Institution.

Fisk and his colleagues have spent much of the past 15 years studying microbes that can break down igneous rock and live in the obsidian-like volcanic glass. They first identified the bacteria through their signature tunnels then were able to extract DNA from the rock samples – which have been found in such diverse environments on Earth as below the ocean floor, in deserts and on dry mountaintops.

They even found bacteria 4,000 feet below the surface in Hawaii that they reached by drilling through solid rock.

In all of these Earth rock samples that contain tunnels, the biological activity began at a fracture in the rock or the edge of a mineral where the water was present. Igneous rocks are initially sterile because they erupt at temperatures exceeding 1,000 degrees C. – and life cannot establish itself until the rocks cool. Bacteria may be introduced into the rock via dust or water, Fisk pointed out.

“Several types of bacteria are capable of using the chemical energy of rocks as a food source,” he said. “One group of bacteria in particular is capable of getting all of its energy from chemicals alone, and one of the elements they use is iron – which typically comprises 5 to 10 percent of volcanic rock.”

Another group of OSU researchers, led by microbiologist Stephen Giovannoni, has collected rocks from the deep ocean and begun developing cultures to see if they can replicate the rock-eating bacteria. Similar environments usually produce similar strains of bacteria, Fisk said, with variable factors including temperature, pH levels, salt levels, and the presence of oxygen.

The igneous rocks from Mars are similar to many of those found on Earth, and virtually identical to those found in a handful of environments, including a volcanic field found in Canada.

One question the OSU researchers hope to answer is whether the bacteria begin devouring the rock as soon as they are introduced. Such a discovery would help them estimate when water – and possibly life – may have been introduced on Mars.
Source: Oregon State University

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‘Coffee Ring’ Formations Found In Drying Drops Of DNA

Posted by tumicrobiology on May 12, 2006

Coffee drinkers are familiar with the ring-shaped stains that result from spilled drops that have dried, in which the brown stain is not evenly distributed, but instead concentrated at the edge. Now, a team led by Gerard Wong, a professor of materials science and engineering, physics, and bioengineering at the University of Illinois at Urbana-Champaign has found the same “coffee-ring” formation in drying drops of DNA.
To gain insights into the physics behind the ring phenomenon, Wong’s team experimentally studied the dynamics of drying DNA droplets on glass surfaces. They report their findings in a paper accepted for publication in the journal Physical Review Letters, and posted on its Web site.

“As the droplet evaporated, DNA chains were transported outward by water flow to the drop’s perimeter,” Wong said. “At the droplet edge, the DNA became increasingly concentrated and formed a liquid crystal with concentric chain orientations. (Liquid crystals are materials that flow like a liquid, but can align in a preferred direction like a crystalline solid.) During the final stages of drying, stresses propagated from the rim inward through the liquid crystal, creating cracks that formed a periodic zigzag pattern.”

To examine the structure and behavior of the DNA liquid crystal, the researchers used a relatively new imaging technique developed at Kent State University. Called fluorescence confocal polarizing microscopy, the technique imaged the DNA in the drying droplet in three dimensions.

“The DNA alignment parallel to the droplet’s edge was counterintuitive,” Wong said. “We had expected the DNA to extend along the direction of flow, which was mainly in the radial direction. But, instead of resembling the spokes of a bicycle wheel, the transported DNA resembled the rim of a bicycle wheel.”

Since nearly all the DNA is concentrated in a narrow ring with almost no DNA in the rest of the stain, these effects should be accounted for in the design of arrays in which DNA droplets are sequentially deposited onto a glass surface for hybridization studies, the researchers report.

“Without optimization of the wetting conditions, it is possible to miss all the DNA in the ring stain of a dried droplet, resulting in false negatives,” Wong said. “We need to think of strategies to minimize this effect.”

The co-authors of the paper are postdoctoral research associate Ivan Smalyukh, graduate students Olena Zribi and John Butler, and professor Oleg D. Lavrentovich, director of the Liquid Crystal Institute at Kent State.
Source: University of Bristol

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Follow The Nitrogen To Extraterrestrial Life; Narrow Search For Water May Miss Important Clues, Say USC Geobiologists

Posted by tumicrobiology on May 6, 2006

The great search for extraterrestrial life has focused on water at the expense of a crucial element, say geobiologists at the University of Southern

Writing in the Perspectives section of the May 5 issue of Science, four USC researchers propose searching for organic nitrogen as a direct indicator of the presence of life. Nitrogen is essential to the chemistry of living organisms.

Even if NASA were to find water on Mars, its presence only would indicate the possibility of life, said Kenneth Nealson, Wrigley Professor of earth sciences in the USC College of Letters, Arts and Sciences.

“It’s hard to imagine life without water, but it’s easy to imagine water without life,” Nealson said.

The discovery of nitrogen on the Red Planet would be a different story.

“If you found nitrogen in abundance on Mars, you would get extremely excited because it shouldn’t be there,” Nealson said.

The reason has to do with the difference between nitrogen and carbon, the other indispensable organic element.

Unlike carbon, nitrogen is not a major component of rocks and minerals. This means that any substantial organic nitrogen deposits found in the soil of Mars, or of another planet, likely would have resulted from biological activity.

Dimming the hopes of life-on-Mars believers is the makeup of the planet’s atmosphere. The abundant nitrogen in Earth’s atmosphere is constantly replenished through biological activity. Without the ongoing contribution of living systems, the atmosphere slowly would lose its nitrogen.

The extremely low nitrogen content in the Martian atmosphere suggests that biological nitrogen production is close to zero.

However, the authors write, it is possible that life existed on Mars at some hypothetical time when nitrogen filled the atmosphere.

Co-author Douglas Capone, Wrigley Professor of environmental biology in USC College, said NASA should establish a nitrogen detection program alongside its water- seeking effort. He noted that next-generation spacecraft will have advanced sampling capabilities.

“What we’re suggesting here is basically drilling down into geological strata, which they’re going to be doing for water anyway,” Capone said.

“The real smoking gun would be organic nitrogen.”

Said Nealson: “If your goal is to search for life, it would be wise to include nitrogen.”

In their acknowledgments, the authors thanked the students of the Spring 2004 Geobiology & Astrobiology course at USC, with whom Nealson and Capone began their discussion on how to search for life outside earth.

“That’s really what stimulated this [paper],” Nealson said.

The authors also thanked NASA, the Department of Energy and the National Science Foundation for their financial support.

Along with Nealson and Capone, USC graduate student Beverly Flood and former USC Research Professor Radu Popa (now a professor of biology at Portland State University) contributed to the Perspectives paper.
Source: University of Southern California

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The Next Flu Pandemic: When It Happens, Restricting Air Travel Won’t Help

Posted by tumicrobiology on May 6, 2006

Restricting air travel from countries where there is a serious influenza outbreak will do little to hold back the spread of the infection, according to the findings of a study conducted at the UK Health Protection Agency and published in the journal PLoS Medicine.

Sometimes a new type of influeza virus appears that causes an illness that is more serious than is usually the case for flu. This happened, for example, in 1918, when a flu pandemic killed between 20 million and 100 million people. Recently, there have been concerns about the new type of bird (avian) flu. At present the virus responsible does not pass easily from birds to humans, and it does not seem to pass from one human to another. However, the fear is that the virus might change and that human-to-human infection could then be possible. Should all this happen, the changed virus would be a major threat to human health.

With current technology, it would take several months to produce enough vaccine against such a new virus for even a small proportion of the world’s population. By that time, it would probably be too late; the virus would already have spread to most parts of the world.

Health authorities must therefore consider all the methods that might control the spread of the virus. With the increase in international travel that has taken place, the virus could spread more quickly than in previous pandemics. Restrictions on international travel might be considered necessary, particularly travel by air. However, it is important to estimate how useful restrictions on air travel might be in controlling the spread of a flu virus. Travel restrictions are usually unpopular and could themselves be harmful. If they are not effective, resources could be wasted on enforcing them.

Researchers of the Centre for Infections, Health Protection Agency, UK used the techniques of mathematical modelling. In other words, complex calculations were done using information that is already available about how flu viruses spread, particularly information recorded during a worldwide flu outbreak in 1968-1969. Using this information, virtual experiments were carried out by simulating worldwide outbreaks on a computer. The researchers looked at how the virus might spread from one city to another and how travel restrictions might reduce the rate of spread. Their calculations allowed for such factors as the time of the year, the number of air passengers who might travel between the cities, and the fact that some people are more resistant to infection than others.

From the use of their mathematical model, the researchers concluded that restrictions on air travel would achieve very little. This is probably because, compared with some other viruses, the flu virus is transmitted from one person to another very quickly and affects many people. Once a major outbreak was under way, banning flights from affected cities would be effective at significantly delaying worldwide spread only if almost all travel between cities could be stopped almost as soon as an outbreak was detected in each city. It would be more effective to take other measures that would control the spread of the virus locally. These measures could include use of vaccines and antiviral drugs if they were available and effective against the virus.

{Citation: Cooper BS, Pitman RJ, Edmunds WJ, Gay NJ (2006) Delaying the international spread of pandemic influenza. PLoS Med 3(6): e212. (http://dx.doi.org/10.1371/journal.pmed.0030212)}

Source: Public Library of Science

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Stomach Receptor For H. Pylori Discovered

Posted by tumicrobiology on May 6, 2006

Scientists have determined that decay-accelerating factor (DAF), a protein found in epithelial cells in the stomach, acts as a receptor for the bacteria Helicobacter pylori. Blocking this interaction could lead to new drugs that reduce the risk of peptic ulcer disease or gastric cancer. The research appears as the “Paper of the Week” in the May 12 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.

Helicobacter pylori are spiral shaped bacteria that live in the thick layer of mucus that covers the stomach lining. The bacteria are found everywhere in the world, but are especially prevalent in developing countries, where up to 80% of children and 90% of adults can have laboratory evidence of an H. pylori infection–usually without having any symptoms.

The vast majority of H. pylori in colonized hosts are free-living, but approximately 20% bind to gastric epithelial cells. This binding induces an immune response and alters the morphology and behavior of the epithelial cells due to injection of bacterial proteins into the cells. This interaction can lead to peptic ulcer disease, gastric adenocarcinoma, and non-Hodgkins lymphoma of the stomach.

“Ulcers are a breach in the gastric or duodenal mucosa and gastric adenocarcinoma is one type of cancer of the stomach,” explains senior author Dr. Richard M. Peek, Jr. of the Vanderbilt University School of Medicine. “H. pylori alters acid production and can lead to increased acid outputs which causes peptic ulcer disease. The means through which H. pylori causes gastric cancer are more complex but likely involve alterations in gastric epithelial cell responses that are perturbed within the context of a chronic gastric inflammatory infiltrate, which can persist for decades.”

A membrane-imbedded protein found in the stomach called decay-accelerating factor (DAF) has been shown to function as a receptor for several microbial pathogens. Peek and his colleagues were curious as to whether DAF was also involved in H. pylori adherence. To do this, the researchers measured the number of H. pylori that bound to cells that either expressed or did not express DAF. They found that the bacteria do indeed adhere to cells with DAF. They also discovered that H. pylori induce DAF expression in cultured gastric epithelial cells and that mice lacking DAF develop attenuated stomach inflammation.

“Our results indicate that H. pylori can co-opt a host protein as a receptor and that it can increase expression of this receptor in gastric epithelial cells,” says Peek. “Further, absence of this receptor abolishes the inflammatory response that H. pylori induces in infected mice, suggesting that this receptor mediates H. pylori-induced injury in the stomach.”

These findings suggest that drugs that interfere with DAF binding could be used to prevent or treat peptic ulcer disease or distal gastric adenocarcinoma. These new drugs will be a welcome alternative to the current treatment for H. pylori infections which typically involves taking 3 to 4 medications over a 10 to 14 day period.
Source: American Society for Biochemistry and Molecular Biology

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New Treatment Against Persistent Ulcer-inducing Bacteria Successful

Posted by tumicrobiology on May 6, 2006

For those who suffer from stomach ulcers, the daily routine of breakfast, lunch and dinner can be painful. A common cause of these ulcers, as well as other gastric malignancies, is a bacterium called Helicobacter pylori. For some, this infection can be persistent and difficult to treat.
Many approaches have been taken in an attempt to clear such infections, but with limited or unsuccessful outcomes. In a recent meta-analysis of therapies published in the April issue of The American Journal of Gastroenterology, Levofloxacin-based triple therapy was found to be better tolerated and more effective than bismuth-based quadruple therapy for patients with persistent H. pylori despite previous treatment attempts. Levofloxacin is commonly prescribed to treat such infections as pneumonia, bronchitis and urinary tract infections.

According to author William D. Chey, “Helicobacter pylori is a highly prevalent chronic infection with a worldwide prevalence of nearly 50% and U.S. prevalence of 20-40%.” This bacterial infection is particularly difficult to treat because of its ability to adapt to the harsh environment in the stomach. The bacterium guards itself in the lining of the stomach, which prevents the body’s natural defenses (Killer T Cells) from attacking it.

Levofloxacin-based triple therapy may offer an effective and safe treatment option for patients with persistent H. pylori infection, according to researchers. With so many people living with this infection, it has become increasingly important to achieve effective methods of treatment. Levofloxacin-based therapy may prove to be this method.

This study is published in The American Journal of Gastroenterology.

William D. Chey, MD is Associate Professor, Department of Internal Medicine and Director, Gastrointestinal Physiology Laboratory at the University of Michigan. Dr. Chey is conducting research and has extensively published in the areas of GERD and Helicobacter pylori. Dr Chey is conducting research and has published extensively in the areas of functional bowel disease, GERD, and Helicobacter pylori.
Source: Blackwell Publishing Ltd.

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New Study Reveals Structure Of E. Coli Multidrug Transporter Protein; Could Aid In Fight Against Drug-resistant Bacteria

Posted by tumicrobiology on May 6, 2006

Scientists at The Scripps Research Institute have determined the x-ray structure of EmrD, a multidrug transporter protein from Escherichia coli (E. coli), a common bacteria known to cause several food-borne illnesses. Proteins like EmrD that expel drugs from cells contribute significantly to the continued rise in multidrug resistant bacteria, and the re-emergence of drug-resistant strains of diseases such as tuberculosis that were once thought to have been eradicated.

This new study could potentially help researchers find new ways to avoid the problem of multidrug resistance and enhance the potency of existing drug compounds.

The study is being published in ScienceXpress, an advance online edition of the journal Science, on May 5.

“The development of antibiotics to treat infectious disease is being seriously undermined by the emergence of drug-resistant bacteria,” says Geoffrey A. Chang, Ph.D., a Scripps Research associate professor and a member of the Skaggs Institute for Chemical Biology, who led the study. “Multidrug resistance develops in part through the expulsion of drugs by integral membrane transporters like EmrD. Determining the structure of this transporter will add significantly to our general understanding of the mechanism of drug transport through the cell membrane and provide the structural basis for how these proteins go about selecting specific drugs to expel.”

Multidrug resistant bacterial infections raise the cost of medical treatment and are far more expensive than treating normal infections. Treating drug-resistant tuberculosis, for example, requires so-called second-line drugs if standard treatment fails. According to the Centers for Disease Control, second-line drugs can cost as much as “$33,000 per patient in industrialized countries compared to $84 for first-line drugs.” In addition, the centers noted, second-line drugs need to be taken for longer periods of time-from 18 to 36 months-and may require substantial patient monitoring, making these treatments difficult if not impossible to “be available in many of the resource-poor nations where drug-resistant tuberculosis is emerging.”

EmrD belongs to the Major Facilitator Superfamily, a group of transporters among the most prevalent in microbial genomes. These transporters are distinctive in their ability to recognize and expel a highly diverse range of amphipathic compounds. Amphipathic molecules contain both hydrophobic and hydrophilic groups-molecules that repel or are attracted to water, respectively.

The x-ray structure of the EmrD transporter-determined with data collected at the Stanford University Synchrotron Radiation Laboratory and the Advanced Light Source at the University of California, Berkeley-revealed an interior composed primarily of hydrophobic residues. This finding is consistent with its role of transporting hydrophobic or lipophilic molecules-and similar to the interior of another multidrug transporter, EmrE, which Chang and his colleagues uncovered in a study that was published last year in the journal Science.

This internal cavity is the “most notable difference” between EmrD and most non-Major Facilitator Superfamily multidrug transporters that, the new study noted, typically transport “a relatively narrow range of structurally related” compounds. The hydrophobic residues in the EmrD internal cavity are likely to contribute to the general mechanism transporting various compounds through the cell membrane, and may play “an important role in dictating a level of drug specificity” through a number of molecular interactions.

The study also suggests that EmrD intercepts and binds cyanide m-chlorophenyl hydrazone, a known efflux pump inhibitor, before it reaches the cell cytoplasm. This binding is likely facilitated by hydrophobic interactions within the internal cavity of EmrD. The researchers speculate that cyanide m-chlorophenyl hydrazone is either expelled from the bacterial cell or into the periplasmic space-the space between the outer membrane and the plasma membrane in gram-negative bacteria like E. coli.

“While EmrD and EmrE are completely different proteins from different molecular families,” Chang said, “both are multidrug transporters that help bacteria develop multidrug resistance. Together with MsbA, another MDR structure that our laboratory is studying, this new x-ray structure adds another important view of some general structural features across multi-drug resistant transporter families.”

Other authors of the study include Yong Yin, Xiao He, Paul Szewczyk, and That Nguyen of The Scripps Research Institute.

The study was supported by the National Institutes of Health and the Skaggs Institute for Chemical Biology.
Source: Scripps Research Institute

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We are back again

Posted by tumicrobiology on May 6, 2006

Dear all,
Because of the political instability and the consequences that affected all of us in Nepal and abroad, we could not update our site for a month. Now, were are back.
Let’s be together again.
Cheers
Gaffer, TUMDF

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