hacked by p@3t_b@y for turks

Qingming Xiong, Mingqun Lin, Yasuko Rikihisa*

Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, United States of America

Abstract
In eukaryotes, intracellular cholesterol homeostasis and trafficking are tightly regulated. Certain bacteria, such as Anaplasma phagocytophilum, also require cholesterol; it is unknown, however, how this cholesterol-dependent obligatory intracellular bacterium of granulocytes interacts with the host cell cholesterol regulatory pathway to acquire cholesterol. Here, we report that total host cell cholesterol increased >2-fold during A. phagocytophilum infection in a human promyelocytic leukemia cell line. Cellular free cholesterol was enriched in A. phagocytophilum inclusions as detected by filipin staining. We determined that A. phagocytophilum requires cholesterol derived from low-density lipoprotein (LDL), because its replication was significantly inhibited by depleting the growth medium of cholesterol-containing lipoproteins, by blocking LDL uptake with a monoclonal antibody against LDL receptor (LDLR), or by treating the host cells with inhibitors that block LDL-derived cholesterol egress from late endosomes or lysosomes. However, de novo cholesterol biosynthesis is not required, since inhibition of the biosynthesis pathway did not inhibit A. phagocytophilum infection. The uptake of fluorescence-labeled LDL was enhanced in infected cells, and LDLR expression was up-regulated at both the mRNA and protein levels. A. phagocytophilum infection stabilized LDLR mRNA through the 3′ UTR region, but not through activation of the sterol regulatory element binding proteins. Extracellular signal–regulated kinase (ERK) was up-regulated by A. phagocytophilum infection, and inhibition of its upstream kinase, MEK, by a specific inhibitor or siRNA knockdown, reduced A. phagocytophilum infection. Up-regulation of LDLR mRNA by A. phagocytophilum was also inhibited by the MEK inhibitor; however, it was unclear whether ERK activation is required for LDLR mRNA up-regulation by A. phagocytophilum. These data reveal that A. phagocytophilum exploits the host LDL uptake pathway and LDLR mRNA regulatory system to accumulate cholesterol in inclusions to facilitate its replication.

Citation: Xiong Q, Lin M, Rikihisa Y (2009) Cholesterol-Dependent Anaplasma phagocytophilum Exploits the Low-Density Lipoprotein Uptake Pathway. PLoS Pathog 5(3): e1000329. doi:10.1371/journal.ppat.1000329

Editor: Jenifer Coburn, Medical College of Wisconsin, United States of America
Received: September 9, 2008; Accepted: February 5, 2009; Published: March 13, 2009

Copyright: © 2009 Xiong et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This project was supported by National Institutes of Health grant R01 AI030010.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: rikihisa.1@osu.edu

To read full article: CLICK HERE

Neurol Clin. 2010 Feb;28(1):277-91.

Halperin JJ.

Department of Neurology, Madison Avenue, Mount Sinai School of Medicine, NY, USA; Department of Neurosciences, Overlook Hospital, 99 Beauvoir Avenue, Summit, NJ 07902, USA.

Only two spirochetal infections are known to cause nervous system infection and damage: neurosyphilis and neuroborreliosis (nervous system Lyme disease). Diagnosis of both generally relies on indirect tools, primarily assessment of the host immune response to the organism. Reliance on these indirect measures poses some challenges, particularly as they are imperfect measures of treatment response. Despite this, both infections are known to be readily curable with straightforward antimicrobial regimens. The challenge is that, untreated, both infections can cause progressive nervous system damage. Although this can be microbiologically cured, the threat of permanent resultant neurologic damage, often severe in neurosyphilis and usually less so in neuroborreliosis, leads to considerable concern and emphasizes the need for prevention or early and accurate diagnosis and treatment.

PMID: 19932386 [PubMed - in process]

J Infect Dis. 2009 Dec 15;200(12):1936-43.
Strle K, Drouin EE, Shen S, Khoury JE, McHugh G, Ruzic-Sabljic E, Strle F, Steere AC.

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. kstrle@partners.org

To delineate the inflammatory potential of the 3 pathogenic species of Borrelia burgdorferi sensu lato, we stimulated monocyte-derived macrophages from healthy human donors with 10 isolates each of B. burgdorferi, Borrelia afzelii, or Borrelia garinii recovered from erythema migrans skin lesions of patients with Lyme borreliosis from the United States or Slovenia. B. burgdorferi isolates from the United States induced macrophages to secrete significantly higher levels of interleukin (IL)-8, CCL3, CCL4, IL-6, IL-10, and tumor necrosis factor than B. garinii or B. afzelii isolates. Consistent with this response in cultured macrophages, chemokine and cytokine levels in serum samples of patients from whom the isolates were obtained were significantly greater in B. burgdorferi-infected patients than in B. afzelii- or B. garinii-infected patients. These results demonstrate in vitro and in vivo that B. burgdorferi has greater inflammatory potential than B. afzelii and B. garinii, which may account in part for variations in the clinical manifestations of Lyme borreliosis.

PMID: 19909078 [PubMed - in process]

The National Research Fund for Tick-Borne Diseases (NRFTD) announced that it has awarded grants totaling $240,000 to four investigators to study key aspects of Lyme disease and Rocky Mountain spotted fever. The NRFTD is the nation’s only non-profit organization dedicated primarily to funding scientific research in the rapidly expanding field of tick-borne infections.

“We are immensely grateful to our donors for providing the resources to fund these studies,” said Carl Brenner, a member of the NRFTD’s Research Board. “Our hope is that these innovative projects will produce findings that quickly translate into benefits for patients. The NRFTD’s projects are selected not only for the immediate scientific value they offer, but also for their potential to lead to further work that will enable researchers and clinicians to find answers to these serious tick-borne illnesses.”

Grant winners were selected following a rigorous peer-review process by the NRFTD’s distinguished five-member Scientific Advisory Board using guidelines akin to those established by the National Institutes of Health. Four ad hoc reviewers from prestigious national academic institutions provided additional expertise in the review of the applications.

Dr. Stephen Barthold of the Center of Comparative Medicine at the University of California in Davis has been awarded an NRFTD grant to continue his investigations into the ability of the Lyme disease bacterium, Borrelia burgdorferi, to survive antibiotic treatment in a mouse model. Previous work by Dr. Barthold’s laboratory has shown that B. burgdorferi can persist in an infectious but non-cultivatable state in mice for at least 90 days after the animals have been treated with ceftriaxone, a powerful antimicrobial often used to treat Lyme disease in humans. These bacteria can then be acquired by ticks and subsequently transmitted to other mice. In his NRFTD project, Dr. Barthold will attempt to verify these findings with additional strains of the Lyme bacterium and investigate the long-term fate of these organisms. Special fluorescence techniques will be employed to discern the morphology and location of the spirochetes and, hopefully, lay the groundwork for determining definitively whether these bacteria are capable of causing persistent disease. It is possible that the findings from this study could have a profound impact on current conceptualizations and treatment paradigms for human Lyme disease.

Also studying the fate of B. burgdorferi in mice after antibiotic treatment is Dr. Linda Bockenstedt of Yale University’s Department of Internal Medicine. Dr. Bockenstedt’s study will employ multiphoton microscopy, a cutting-edge form of imaging that permits the visualization of cells and bacteria in tissues of living laboratory animals. Using this technique, Dr. Bockenstedt will be able to study the behavior of B. burgdorferi spirochetes in live anesthetized mice and examine in real-time the effects of antibiotics on spirochete populations within the infected animals. These studies will provide insight into how the Lyme bacteria move between the tick and the mammal, and may yield important information with implications for the treatment of Lyme disease in humans.

The third NRFTD grant has been awarded to Dr. Melissa Caimano of the Department of Medicine at the University of Connecticut Health Center. Dr. Caimano’s project will investigate in detail how B. burgdorferi transits from ticks to mammalian hosts during tick feeding. Recent work by Dr. Caimano and others has shown that the migration of the bacteria out of the ticks’ midgut is considerably more complex than previously recognized: During tick feeding, spirochetes undergo a burst of replication, forming non-motile networks that adhere to differentiating tick midgut epithelial cells and only later in the feeding process become individually motile forms. Dr. Caimano will investigate the interplay between B. burgdorferi and the tick midgut epithelium; this work will likely further the long-term objective of identifying bacterial and tick gene products and regulatory pathways that enable dissemination of the Lyme spirochete within both ticks and mammals. It is possible that this work could ultimately lead to novel vaccine strategies that block the exit of spirochetes from the tick midgut during feeding.

The fourth NRFTD grant has been awarded to Dr. Gustavo Valbuena of the University of Texas Medical Branch, who will develop and test a novel animal model of Rocky Mountain spotted fever, the most common fatal tick-borne infection in the United States. Dr. Valbuena’s objective is to create a “humanized” mouse model by transplanting human immunological cells into laboratory mice. This will make it possible to then transplant human skin into the mice, expose them to Rickettsia rickettsii, the causative agent of spotted fever in the United States, and study the pathogenesis of the disease. Because little is known about the specific processes that determine disease outcome and severity in Rocky Mountain spotted fever, the development of a viable animal model that mimics human disease is crucial for increasing understanding of these mechanisms. An additional complication in studying spotted fever is that endothelial cells, the main targets of Rickettsia bacteria, are different in culture than they are in vivo (i.e., in animals themselves). Dr. Valbuena’s model will ensure that these cells will remain in their natural state as the pathogenic processes are investigated.

All four NRFTD projects are expected to begin in May of 2009 and to be completed in one year. For more information visit http://www.nrftd.org.

About the National Research Fund for Tick-Borne Diseases, Inc.

The NRFTD is a nonprofit, tax-exempt organization devoted strictly to raising funds in support of scientific research on tick-borne diseases. It aims to advance scientific understanding of these complicated infections by sponsoring innovative research at premier institutions throughout the world.

The NRFTD was founded in 1999 to address the complex and critical research questions raised by thousands of patients afflicted with emerging tick-borne diseases, including Lyme disease, relapsing fever, babesiosis, ehrlichiosis and anaplasmosis. The need for answers has grown markedly as Lyme disease continues to spread throughout the country and as other tick-borne infections have been recognized as public health threats.

For more information about the NRFTD, or to make a tax-deductible donation, please visit http://www.nrftd.org.

Contact:

Carl Brenner, Research Board

National Research Fund for Tick-borne Diseases, Inc. (NRFTD)

800.728.7147

http://www.nrftd.org

Author Information - Carl Brenner

http://zai.qingyang88.cn/firing/415258

Medscape Conference Coverage, based on selected sessions at the: From Medscape Medical News

Infectious Disease Treatment Guidelines Weakened By Paucity of Scientific Evidence

Daniel M. Keller, PhD

November 13, 2009 (Philadelphia, Pennsylvania) — Two separate analyses presented here at the Infectious Diseases Society of America (IDSA) 47th Annual Meeting revealed that most of the society’s treatment guidelines are based on expert opinion, nonrandomized trials, and case studies. Only about 15% of the guidelines are supported by randomized controlled trials (RCTs), considered the highest level of evidence. Nonetheless, more than 40% of the guidelines’ recommendations were classified as class A, the strongest level of treatment recommendation, according to Dong Lee, MD, and colleagues from the Division of Infectious Diseases and HIV Medicine at Drexel University College of Medicine in Philadelphia, Pennsylvania.

Between 1994 and April 2009, IDSA issued 68 guidelines on 52 different topics (there have been 2 more since April). Most were published in Clinical Infectious Diseases. Of the 52 current guidelines, Dr. Lee’s team analyzed the 30 that followed IDSA’s standard grading system to evaluate the class of clinical recommendations and the strength of the supporting evidence underlying them.

“Our analysis revealed that more than half were based on expert opinion or not supported by properly controlled trials,” Dr. Lee announced. In an oral presentation, he reported that the 30 guidelines he analyzed contained a mean of 47 recommendations (range, 14 to 150).
Recommendations ranged from class A (should always be offered) to class C (optional). The quality of evidence ranged from level I, consisting of 1 or more properly conducted RCTs, to level III, the opinion of respected authorities, based on clinical experience. Level II evidence is derived from 1 or more properly controlled trials without randomization.

The guidelines revealed a total of 589 class A recommendations. “Ideally, all should be [supported by] level I evidence,” Dr. Lee said. “However, a class A recommendation was supported by level I evidence only in 25% [of cases].” The rest were based on level II (40%) or level III (35%) evidence. Of all the guidelines evaluated, a median of 41% of recommendations were class A, but level I evidence supported them only 14% of the time.

Guidelines for common conditions were often based on fairly strong evidence. The recommendations that are most supported by level I evidence are in the guidelines for tropical medicine (41% of recommendations), intra-abdominal infection (39%), and asymptomatic bacteriuria (38%). “Influenza or Group A Streptococcus guidelines had less than 20% of level III evidence,” possibly because of the high prevalence of these diseases and the ease of designing studies, Dr. Lee reported.

He explained the lack of RCTs for some conditions, saying that certain infections occur rarely or present in heterogeneous forms, making it difficult to design a study. Furthermore, in some cases it might be unethical to conduct such a trial, and at times certain knowledge based on sound clinical judgment will never be tested in RCTs. Finally, funding to do trials might be lacking.

“Although a randomized controlled trial is referred to as level I evidence, not all RCTs are created equal,” he warned. “Some choose surrogate markers, others choose patient-centered outcomes. Well-designed nonrandomized trials may provide more information than certain randomized controlled trials, but I do think that a randomized controlled trial minimizes bias and does deserve the high levels of evidence.”

Dr. Lee summarized his presentation, saying that of the 1408 guideline recommendations he reviewed, “more than half were based on level III evidence, which is from expert opinion or not supported by properly controlled trials. Level I evidence was only 15%.” He said his study should help to point out where evidence is lacking and to suggest areas for further research.

Physicians and trainees should not just look at guidelines, but should also examine the strength of the evidence on which they are based, he advised. “When clinicians are using the guidelines, they should not assume that they are all based on well-designed studies. . . . Clinicians should remain cautious when using current guidelines as the sole source for guiding patient care.”

A second presentation supported the findings of Lee and coworkers. Abdur Khan, MD, assistant consultant at King Fahad Medical City in Riyadh, Saudi Arabia, presented his results in a poster session. Of the 65 IDSA guidelines, encompassing 6667 recommendations, issued between March 1994 and July 2009, he and his colleagues evaluated the 44, comprising 4206 recommendations, that were posted on the IDSA Web site at the end of July.

They, too, found that, overall, the strength of the recommendations did not correlate with the available evidence. Level I evidence was the basis for only 15% of the guidelines, which is in agreement with the findings that Lee and colleagues reported. Thirty percent of the evidence was level II.

“Around 55% of the guidelines had a level of evidence of III, which was based on expert opinion,” Dr. Khan told Medscape Infectious Diseases, “but the class C recommendations [are] only 12%.” Guidelines for the treatment of fungal infections had the weakest supporting evidence; 46.5% to 89.5% of the recommendations were based on level III evidence.

Although the highest levels of evidence generally led to class A recommendations (25.9%), these strongest recommendations were most often based on lesser levels of evidence (36.3% on level II; 37.8% on level III).

Commenting on the studies’ findings, Richard Whitley, MD, professor of pediatrics, microbiology, medicine, and neurosurgery at the University of Alabama at Birmingham and president of IDSA, told Medscape Infectious Diseases that “one always has to be concerned when we don’t have randomized controlled trials that provide evidence-based medicine to write guidelines. Without a shadow of a doubt, the best evidence comes from controlled clinical trials that are adequately powered with a sample size to answer the targeted question.” But he noted that sometimes expert opinion or small uncontrolled studies have to suffice if there are not enough patients to conduct better trials.

In some situations, less than level I data can be powerful, Dr. Whitley observed. He cited the example that neuraminidase inhibitors can decrease mortality from influenza in elderly individuals. This finding was based on retrospective reviews of databases of Kaiser Permanente and other managed health care systems, he explained.

Looking forward, he said, “guidelines don’t necessarily just teach how to take care of patients. They identify areas for future investigation . . . because they tell us where the vagueness is and where we have to move forward.” This information can then be brought to the attention of the leadership of the National Institute of Allergy and Infectious Diseases so that they can fund studies and to the attention of the US Food and Drug Administration, which has funds to study targeted issues.

Dr. Whitley emphasized that “guidelines shouldn’t be just for patients in the United States. They should be for patients around the world.” As such, IDSA and the European Congress of Clinical Microbiology and Infectious Diseases will try to work on guidelines together, and IDSA will also work with Canadian colleagues “so that we can provide a level of care that’s standardized around the world,” he said. “Certainly, that’s optimistic.”

Neither of these studies received funding. Dr. Lee and Dr. Khan have disclosed no relevant financial relationships. Dr. Whitley reports being on the board of directors of Gilead Sciences and is a consultant for 3-V Biologics and Chimerix; his other consulting, review, advisory panel positions, investigator, or speaker honoraria relationships include Juvaris, Primus, Inhibitex, and JID.

Infectious Diseases Society of America (IDSA) 47th Annual Meeting: Abstract 1324. presented November 1, 2009; Abstract LB-31, presented
October 31, 2009.

Lyme disease is caused by the microbe Borrelia burgdorferi, which is transmitted to humans from feeding ticks. Justin Radolf and colleagues, at the University of Connecticut Health Center, Farmington, have now visualized the microbe moving through the feeding tick and determined that it has a biphasic mode of dissemination. These data provide new insight into the transmission process, detailed understanding of which is essential if new methods of preventing human infection with the Lyme disease–causing microbe are to be developed.

In this study, the midguts and salivary glands of ticks before, during, and after feeding were isolated, and the live Borrelia burgdorferi microbes imaged in real time. In the first phase of dissemination, replicating microbes formed networks of nonmotile organisms that moved by adhering to the cells lining the tick midgut. In the second phase of dissemination, the microbes became motile invasive organisms that ultimately entered the salivary glands. These data challenge the conventional viewpoint that Lyme disease–causing microbes are always motile within ticks and that this drives their dissemination.

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TITLE: Live imaging reveals a biphasic mode of dissemination of Borrelia burgdorferi within ticks

AUTHOR CONTACT:
Justin D. Radolf
University of Connecticut Health Center, Farmington, Connecticut, USA.
Phone: (860) 679-8480; Fax: (860) 679-1358; E-mail: jradolf@up.uchc.edu.

View this article at: http://www.jci.org/articles/view/39401?key=HnLk45JRxih3aqbS4YCQ

By Aleena Lakhanpal
Issue date: 11/5/09

Antibacterial soap, hand sanitizer and antibiotics are all substances that we use in an attempt to kill bacteria that might make us sick.Whether we are concerned about getting strep throat, bacterial meningitis or something else, these prevention methods can offer protection.

However, some bacteria, such as those that cause Staph and MRSA infections, are becoming increasingly resistant to antibiotics. Since the 1930s, researchers have been aware that bacteria may be able to resist treatment because they can morph into the L-form, or bacteria lacking cell walls.

Until the 1980s, not much else could be known about the L-form, but now, researchers at the Bloomberg School of Public Health have used a wide variety of modern molecular tools to learn more about the origin and biological functions of the L-form bacteria.

Ying Zhang, a professor of molecular microbiology and immunology at Bloomberg, is the senior author of the study, which was published in PLoS ONE last month.

Not all bacteria can transform into the L-form, but those that can include Bacillus anthracis (anthrax), Treponema pallidum (syphilis), Mycobacterium tuberculosis (tuberculosis), Heliobacter pylori (stomach ulcers and cancer), Borrelia burgdorferi (Lyme disease) and Escherichia coli (food poisoning). Zhang’s team used E. coli to create a culture of L-form bacteria.

Although it had been difficult to culture L-form bacteria before, Zhang and his team created a new method that more closely simulated the in vivo conditions in which these bacteria form.

“The presence of antibiotic stress is cell wall inhibiting, like penicillin,” Zhang said. To prevent the cells from bursting because of this increased stress, Zhang’s team added sucrose to the cell media.

This culture represented the mechanism that occurs in the body. “L forms are formed in response to stress,” Zhang said. “They have a different mode of survival and replication from classical bacteria.” The cell wall-deficient bacteria cluster together in the shape of a fried egg rather than the smooth, homogeneous appearance of wild-type bacteria cultures.

Not only are L-form bacteria difficult to culture and therefore study, but this “fried egg” cluster is part of what makes the L-form bacteria resistant to antibiotics, in addition to the fact that they do not have cell walls for commonly used antibiotics to disintegrate.

Once Zhang and his team were able to successfully culture L-form E. coli, they screened for and identified mutants that fail to grow at the L-form. From these mutants, they were able to discover a series of genes that were linked with the inability to grow in the L-form.

“These fall into four to five different categories involving extracellular matrix synthesis, membrane proteins, membrane biogenesis, DNA repair as well as iron metabolism and energy metabolism,” Zhang said.

Their identification of these genes and their effect on L-form bacterial expression is a resounding discovery because it was impossible to do before, what with the difficulty of culturing the L-forms of various bacteria. Zhang noted, however, that although his team managed to create and study a culture of L-form bacteria, their study cannot be universal.

“What we can culture is only a small percentage - probably less than 1 percent - of all bacteria on earth,” Zhang said.
“They exist in nature and grow easily, but we’re limited to what we can grow and the form of bacteria that can grow. Bacteria can grow a variety of different forms even for the same species, and can change forms under different conditions. L-forms are one example of changing under antibiotic stress.”

These L-forms of various bacteria may be the underlying reason for chronic resistant and recurring diseases, such as sarcoidosis, various forms of inflammatory bowel diseases and rheumatoid arthritis. Zhang is confident that there will be many practical applications of this discovery.

“It is possible, with our discovery of the L-form genes to develop new antibiotics and more effective ones that can be used with current ones as well as new vaccines to . . . allow these forms to be eliminated by the immune system,” he said.
 

Public release date: 27-Oct-2009
Contact: Randi Triant
617-636-9845
Tufts University, Health Sciences

The Tufts Clinical and Translational Science Institute (CTSI) and Tufts University today announced they are the recipients of four supplemental grant awards from the National Institutes of Health. These new awards, totaling approximately $1.73 million, are supplements to the original Clinical and Translational Science Award (CTSA) grant, UL1 RR025752 that Tufts University received in 2008 from the National Center for Research Resources.

“Community Engagement Research” is a two-year project that will expand the scope of Tufts CTSI’s current community engagement program by enhancing the ability of community partners to participate more effectively in the development of research plans and outcomes. Begun in September 2009, the project has already established an alliance between the Tufts CTSI, the Harvard Clinical and Translational Science Center, and two pivotal community partners, the Center for Community Health Education, Research, and Service (CCHERS) and the Immigrant Service Providers Group/Health (ISG/H). This alliance is creating a curriculum and evaluation for a self-study and face-to-face program entitled “Fostering Community Partners in Translational Research (FCPTR)” that will target community agencies and health centers. The Program Director is Laurel Leslie, MD, MPH, Associate Professor of Medicine at Tufts University School of Medicine.

“Improving BPD Predictors and Outcomes for Clinical Trials” builds on prior landmark research that identified a constellation of signs and symptoms in high risk newborns to accurately define bronchopulmonary dysplasia (BPD) and predict the subsequent development of chronic respiratory morbidity (CRM) later in childhood and adolescence. While treatment with recombinant human superoxide dismutase to premature newborns has been proven to have a 55% reduction in CRM compared to placebo controls, current definitions of BPD may be unreliable predictors of CRM and a more robust reduction in CRM is needed. Superoxide dismutase is an enzyme that converts superoxide radicals (highly reactive oxygen molecules produced during metabolism and capable of damaging body tissues) into less toxic agents. This one-year study is a prospective, longitudinal, observational study in 85 preterm infants 24-29 weeks gestation. The Program Director is Jonathan Davis, MD, Chief of Newborn Medicine, The Floating Hospital for Children at Tufts Medical Center, Program Director at the Clinical and Translational Research Center, and Professor of Pediatrics, Tufts University School of Medicine. Partners in this study include Brigham and Women’s Hospital (Harvard University), Beth Israel Hospital (Harvard University), Nationwide Children’s Hospital (Ohio State), and King’s College in London.

“Searching for Persistence of Infection in Lyme Disease” is a highly innovative Bench-to- Bedside research project that could have an extraordinarily significant impact on the field of Lyme disease. Although antibiotic therapy is clinically effective in treating the symptoms of Lyme disease for most patients early in the course of disease, a significant number of patients who receive therapy report persistent symptoms. A range of theories have been proposed for why this occurs. Moreover, commonly available tests for human Lyme disease are not able to determine persistent infection after antibiotic therapy. Program Director, Linden Hu, MD (Associate Professor of Medicine, Tufts University School of Medicine and Associate Professor of Microbiology, Sackler School of Biomedical Graduate Sciences) has begun an unconventional study examining whether xenodiagnosis (the feeding of uninfected Ixodes ticks on infected animals) can be used to determine when persistent infection occurs in humans. Xenodiagnosis has been used for other difficult to diagnose diseases such as Chagas disease and can sometimes definitively identify the presence of an organism in animals where other techniques cannot. Whether xenodiagnosis is effective in humans is unknown. This two-year project seeks to test the utility of xenodiagnosis for identifying persistence of B. burgdorferi, the spirochetal bacteria that cause Lyme disease, after antibiotic treatment of the disease. Dr. Linden’s team will test subjects with elevated C6 antibody levels or persistent symptoms after antibiotic therapy and patients with Lyme arthritis. Evidence that B. burgdorferi can be identified by xenodiagnosis after antibiotic therapy in subjects with continued symptoms would significantly change the current paradigm for potential mechanisms of disease and provide researchers and clinicians with a novel tool for identifying patients with persistent infection.

Tufts CTSI currently has a Pilot Studies Program that funds new interdisciplinary research teams, seeds novel ideas, and provides the means to acquire necessary preliminary data for larger, multi-year grant applications. A new supplemental project, The Pilot Project Mechanism, is led by Susan K. Parsons, MD, MRP, Director, The Health Institute, Institute for Clinical Research and Health Policy Studies and Associate Professor of Medicine and Pediatrics, Tufts University School of Medicine, and Amy Yee, PhD, Professor of Biochemistry, Sackler School of Biomedical Graduate Sciences. This two-year project expands the current program to influence research not just within the Tufts enterprise, but also throughout the Commonwealth of Massachusetts and into New England via Tufts CTSI’s forty-three collaborating partners by soliciting interinstitutional and multidisciplinary applications. Many of the identified programs will hire and support undergraduate and graduate students and postdoctoral fellows, thereby creating jobs throughout New England and also increasing the pipeline for translational researchers.
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About Tufts Clinical and Translational Science Institute (CTSI)

Tufts CTSI was established in August 2008 with Grant Number UL1 RR025752 from the National Center for Research Resources (NCRR), National Institutes of Health (NIH). A collaboration of organizations, founded by Tufts Medical Center and Tufts University, Tufts CTSI accelerates the translation of laboratory research into clinical use, medical practice and health policy. It connects people to research resources, consultation, and education, and fosters collaboration with scholars of all disciplines and with community members, with the ultimate goal of improving the health of the public. Website: www.tuftsctsi.org.

About NCRR and the CTSA Consortium

The National Center for Research Resources (NCRR), a part of the National Institutes of Health (NIH), provides laboratory scientists and clinical researchers with the tools and training they need to understand, detect, treat, and prevent a wide range of diseases. NCRR supports all aspects of clinical and translational research, connecting researchers, patients, and communities across the nation. Through programs such as the Clinical and Translational Science Awards, NCRR brings together innovative research teams and equips them with essential tools and critical resources needed to tackle the nation’s complex health problems.

About the NIH

The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting medical research. Helping to lead the way toward important medical discoveries that improve people’s health and save lives, NIH scientists investigate ways to prevent disease as well as the causes, treatments, and even cures for common and rare diseases. Composed of 27 Institutes and Centers, the NIH provides leadership and financial support to researchers in every state and throughout the world. For more information about NIH and its programs, visit www.nih.gov.

http://www.eurekalert.org/pub_releases/2009-10/tuhs-tca102709.php

The Lancet Infectious Diseases, Volume 4, Issue 9, Pages 575-583
S.Kumar Singh, H.Josef Girschick

Abstract
Lyme disease is a tick-transmitted disease caused by the spirochete Borrelia burgdorferi. The bacterium adopts different strategies for its survival inside the immunocompetent host from the time of infection until dissemination in different parts of body tissues. The success of this spirochete depends on its ability to colonise the host tissues and counteract the host’s defence mechanisms. During this process borrelia seems to maintain its vitality to ensure long-term survival in the host. Borrelia’s proteins are encoded by plasmid and chromosomal genes. These genes are differentially regulated and expressed by different environmental factors in ticks as well as in the mammalian host during infection. In addition, antigenic diversity enables the spirochete to escape host defence mechanisms and maintain infection. In this review we focus on the differential expression of proteins and genes, and further molecular mechanisms used by borrelia to maintain its survival in the host. In light of these pathogenetic mechanisms, further studies on spirochete host interaction are needed to understand the complex interplay that finally lead to host autoimmunity.

http://linkinghub.elsevier.com/retrieve/pii/S1473309904011326
 

MU researchers use Lyme disease as model

COLUMBIA, Mo. – According to the National Center for Chronic Disease Prevention and Health Promotion, 46 million Americans have arthritis. Many of these people take over-the-counter anti-inflammatory medications that block production of certain molecules, known as bioactive lipids, to reduce pain and swelling. Yet, the role of these lipids is not yet understood completely, and medications may have adverse side effects. Recently, University of Missouri researchers completed the first comprehensive analysis of bioactive lipids in an inflammatory response triggered by the Lyme disease agent, Borrelia burgdorferi. This analysis could shed light on the role bioactive lipids play in inflammatory diseases.

“Many diseases, such as arthritis, cardiovascular disease and diabetes are associated with chronic inflammation,” said Charles Brown, associate professor of veterinary pathobiology in the MU College of Veterinary Medicine. “The first step in finding an effective treatment is to understand the basics of an inflammatory response, including the role of bioactive lipids. Understanding how bioactive lipids regulate the disease processes will lead to the development of drugs that have more specific targets and less adverse side effects.”

In the study, researchers investigated the role of certain bioactive lipids in mice infected with Borrelia burgdorferi, the bacteria responsible for Lyme disease. Eicosanoids, which are bioactive lipids that play an important role in inflammatory disease, were extracted from mice that displayed symptoms of Lyme arthritis and from mice who showed no symptoms. The researchers found differences in the amounts of specific eicosanoids in the samples, which correlated with the severity of arthritis in the mice.

“The process of inflammation is not a passive event, but instead is a coordinated, orderly process actively signaled by specific protein and lipid molecules,” Brown said. “Previous studies investigating eicosanoids have focused on singular pathways or phases of the inflammatory response. These studies provided an incomplete picture and gave the impression that some bioactive lipids function in isolation. In our study, we were able to measure virtually all of the known eicosanoids at the same time and examine a more complete picture of the inflammatory response.”

The findings from this study also could translate into a diagnostic tool for assessing individual patients, assist with the development of more disease-specific therapies, and facilitate the progress of individualized medicine, resulting in more effective treatments for inflammatory diseases with fewer side effects.

Lyme arthritis occurs in 60 to 80 percent of individuals not treated with antibiotics at the time of their infection, and patients are typically given anti-inflammatory drugs to treat their pain and swelling. Arthritis in mice caused by Lyme disease is a good model for how bioactive lipids regulate the process of inflammation, because researchers can observe the process from start to finish, Brown said.
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The study, “Lipidomic Analysis of Dynamic Eicosaniod Responses During the Induction and Resolution of Lyme Arthritis,” was published in the June issue of The Journal of Biological Chemistry. It was co-authored by Brown; Victoria Blaho, post doctoral researcher in the MU College of Veterinary Medicine; Matthew Buczynski, researcher at the University of California; and Edward Dennis, researcher at the University of California.

http://www.eurekalert.org/pub_releases/2009-09/uom-idt090109.php