Health Research Report #171 27 DEC 2013

Health Research Report

 #171

Latest Health Research Report Click Image for Report

27 DEC 2013 /  White paper draft

Compiled by Ralph Turchiano

 

 

In this issue:

1.       Research shows how household dogs protect against asthma and infection
2.       Pain drugs used in prostate gland removal linked to cancer outcome, Mayo Clinic-led study finds
3.       An apple a day keeps the doctor away
4.       Diet rich in tomatoes may lower breast cancer risk
5.       A new — and reversible — cause of aging
6.       Government’s voluntary approach to improving hospital food is not working, argues expert
7.       Research linking autism symptoms to gut microbes called ‘groundbreaking’
8.       Chewing Gum is Often the Culprit for Migraine Headaches in Teens
9.       Inosine treatment safely elevates urate levels in Parkinson’s disease patients
10.   Antioxidant drug knocks down multiple sclerosis-like disease in mice Continue reading “Health Research Report #171 27 DEC 2013”

AIDS guidelines for children may not improve death rates but may improve treatment access ( Yes, you read that right )

Contact: Fiona Godwin medicinepress@plos.org Public Library of Science

Recent changes to World Health Organization guidelines for starting anti-AIDS drugs (antiretroviral therapy—ART)  in young children are unlikely to improve death rates but may increase the numbers of children receiving ART by simplifying access to treatment,  according to a study by international researchers published in this week’s PLOS Medicine.

Continue reading “AIDS guidelines for children may not improve death rates but may improve treatment access ( Yes, you read that right )”

Large HIV study stopped after safety review found more study participants who received the vaccine later became infected

HIV vaccine study halted by US government over unsuccessful shots

Associated Press in Washington

guardian.co.uk,  Thursday 25 April 2013 17.52 EDT

A pharmaceutical machine loaded with ARV medicine at the Themba Lethu HIV/Aids clinic, Johannesburg

A 2009 study in Thailand is the only HIV/Aids study ever to show a modest success. Photograph: Denis Farrell/AP

The US government halted a large HIV vaccine study on Thursday, saying the experimental shots were not successful in preventing infection.

Nor did the shots reduce the amount of the Aids virus in the blood when people who had been vaccinated later became infected, the National Institutes of Health said.

“It’s disappointing,” said Dr Anthony Fauci, head of NIH’s National Institute of Allergy and Infectious Diseases. But he said there was “important information” gained from the study that will help determine what to try next.

The study had enrolled 2,504 volunteers, mostly gay men, in 19 cities since 2009. Half received dummy shots, and half received a two-part experimental vaccine developed by the NIH. All were provided free condoms and given extensive counseling about the risks of HIV.

It’s a strategy known as “prime-boost”. A DNA-based vaccine made with genetically engineered HIV material is given to prime the immune system to attack the Aids virus. Then a different vaccine, encasing the same material inside a shell made of a disabled cold virus, acts as a booster shot to strengthen that response. Neither vaccine could cause HIV.

The idea was to train immune cells known as T cells to spot and attack the very earliest HIV-infected cells in someone’s body. The hope was that the vaccine could either prevent HIV infection, or help those infected anyway to fight it.

A safety review this week found that slightly more study participants who had received the vaccine later became infected with HIV. It’s not clear why. But the difference wasn’t statistically significant, meaning it may be due to chance. Overall, there were 41 HIV infections in the vaccinated group and 30 among placebo recipients. When researchers examined only participants diagnosed after being in the study for at least 28 weeks – long enough for the shots to have done their job – there were 27 HIV infections among the vaccinated and 21 among the placebo recipients.

The NIH said Thursday that it is stopping vaccinations in the study, known as HVTN 505, but that researchers will continue to study the volunteers’ health.

Josh Robbins, 30, of Nashville, Tennessee, was one of the participants who became infected with HIV. He said he was glad he had taken part because its close monitoring meant he was diagnosed and treated much sooner than most people.

“We’ve got to keep moving forward,” Robbins said. The study “certainly can lead us down a new direction to hopefully find something that might work.”

Multiple attempts at creating an Aids vaccine have failed over the years. A 2009 study in Thailand is the only one ever to show a modest success, using a somewhat different prime-boost approach. Newer research suggests another approach – to try creating powerful antibodies that could work a step earlier than the T-cell attack, before HIV gets inside the first cell.

Both approaches need continued research funding, said Mitchell Warren of the international Aids Vaccine Advocacy Coalition.  “Clearly an Aids vaccine remains critical,” he said.

http://www.guardian.co.uk/society/2013/apr/25/hiv-aids-vaccine-study-us-government

 

Newly identified natural protein blocks HIV, other deadly viruses

EEV:  25-hydroxycholesterol/Statin?

Contact: Enrique Rivero erivero@mednet.ucla.edu 310-794-2273 University of California – Los Angeles Health Sciences

A team of UCLA-led researchers has identified a protein with broad virus-fighting properties that potentially could be used as a weapon against deadly human pathogenic viruses such as HIV, Ebola, Rift Valley Fever, Nipah and others designated “priority pathogens” for national biosecurity purposes by the National Institute of Allergy and Infectious Disease.

In a study published in the January issue of the journal Immunity, the researchers describe the novel antiviral property of the protein, cholesterol-25-hydroxylase (CH25H), an enzyme that converts cholesterol to an oxysterol called 25-hydroxycholesterol (25HC), which can permeate a cell’s wall and block a virus from getting in.

Interestingly, the CH25H enzyme is activated by interferon, an essential antiviral cell-signaling protein produced in the body, said lead author Su-Yang Liu, a student in the department of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA.

“Antiviral genes have been hard to apply for therapeutic purposes because it is difficult to express genes in cells,” said Liu, who performed the study with principal investigator Genhong Cheng, a professor of microbiology, immunology and molecular genetics. “CH25H, however, produces a natural, soluble oxysterol that can be synthesized and administered.

“Also, our initial studies showing that 25HC can inhibit HIV growth in vivo should prompt further study into membrane-modifying cholesterols that inhibit viruses,” he added.

The discovery is particularly relevant to efforts to develop broad-spectrum antivirals against an increasing number of merging viral pathogens, Liu said.

Working with Jerome Zack, a professor of microbiology, immunology and molecular genetics and an associate director of the UCLA AIDS Institute, the researchers initially found that 25HC dramatically inhibited HIV in cell cultures. Next, they administered 25HC in mice  implanted with human tissues and found that it significantly reduced their HIV load within seven days. The 25HC also reversed the T-cell depletion caused by HIV.

By contrast, mice that had the CH25H gene knocked out were more susceptible to a mouse gammaherpes virus, the researchers found.

In collaboration with Dr. Benhur Lee, a professor of pathology and laboratory medicine and a member of the UCLA AIDS Institute, they discovered that 25HC inhibited HIV entry into the cell. Furthermore, in cell cultures, it was found to inhibit the growth of other deadly viruses, such as Ebola, Nipah and the Rift Valley Fever virus.

Intriguingly, CH25H expression in cells requires interferon. While interferon has been known for more than 60 years to be a critical part of the body’s natural defense mechanism against viruses, the protein itself does not have any antiviral properties. Rather, it triggers the expression of many antiviral genes. While other studies have identified some antiviral genes that are activated by interferon, this research gives the first description of an interferon-induced antiviral oxysterol through the activation of the enzyme CH25H. It provides a link to how interferon can cause inhibition of viral membrane fusion, Liu said.

He noted some weaknesses in the research. For instance, 25HC is difficult to deliver in large doses, and its antiviral effect against Ebola, Nipah and other highly pathogenic viruses have yet to be tested in vivo. Also, the researchers still need to compare 25HC’s antiviral effect against other HIV antivirals.

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Additional study co-authors were Roghiyh Aliyari, Kelechi Chikere, Matthew D. Marsden and Olivier Pernet, of UCLA; Jennifer K. Smith, Rebecca Nusbaum and Alexander N. Frieberg, of the University of Texas–Galveston; and Guangming Li, Haitao Guo and Lishan Su, of the University of North Carolina–Chapel Hill.

The National Institutes of Health (grants R01 AI078389, AI069120, AI080432, AI095097, AI077454, AI070010 and AI028697), the Warsaw Fellowship, the UCLA Center for AIDS Research (CFAR), the UCLA AIDS Institute, the UCLA Clinical and Translational Science Institute (CTSI), and the Pacific Southwest Regional Center of Excellence (PSWRCE) for Biodefense and Emerging Infectious Diseases funded this study.

The UCLA AIDS Institute, established in 1992, is a multidisciplinary think tank drawing on the skills of top-flight researchers in the worldwide fight against HIV and AIDS, the first cases of which were reported in 1981 by UCLA physicians. Institute members include researchers in virology and immunology, genetics, cancer, neurology, ophthalmology, epidemiology, social sciences, public health, nursing and disease prevention. Their findings have led to advances in treating HIV, as well as other diseases, such as hepatitis B and C, influenza and cancer.

For more news, visit the UCLA Newsroom and follow us on Twitter.

Could probiotics help HIV patients?

Contact: Jillian Hurst press_releases@the-jci.org Journal of Clinical Investigation

Antiretroviral (ARV) drugs are the first line therapy for patients with HIV; however, ARV-treated, HIV-infected individuals still have a higher mortality rate than uninfected individuals. During the course of infection, HIV patients develop inflammation that damages the walls of the intestines, known as the gut mucosa, allowing intestinal microbes to escape and enter the blood stream to cause a life-threatening systemic infection. The health of the gut mucosa is significantly influenced by the complement of bacteria in the gut and there is mounting evidence that probiotic supplements benefit patients intestinal disorders, such as irritable bowel syndrome, C. difficile infection, and inflammatory bowel disease.

In this issue of the Journal of Clinical Investigation, researchers led by Jason Brenchley at the National Institute of Allergy and Infectious Disease, demonstrated that probiotic supplementation may also be beneficial for ARV-treated HIV patients. Brenchley and colleagues treated SIV-infected macaques (a model of human HIV-infection) with either ARV alone or ARV in combination with a mixture of probiotics. Macaques treated with probiotics had enhanced gastrointestinal immune function and decreased inflammation compared to macaques treated with ARV alone. In a companion article, Judith Aberg and colleagues at New York University School of Medicine discuss how these findings could benefit HIV patients.

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TITLE: Probiotic/prebiotic supplementation of antiretrovirals improves gastrointestinal immunity in SIV-infected macaques

AUTHOR CONTACT: Jason M. Brenchley NIAID NIH, Bethesda, MD, USA Phone: 301-496-1498; E-mail: jbrenchl@mail.nih.gov

View this article at: http://www.jci.org/articles/view/66227?key=1cff041937d9040dfed7

ACCOMPANYING THE ATTENDING PHYSICIAN

TITLE: Clash of the microbes: let’s bring back the good guys

AUTHOR CONTACT: Judith Aberg New York University School of Medicine, New York, NY, USA Phone: 2122637300; Fax: ; E-mail: judith.aberg@nyumc.org

View this article at: http://www.jci.org/articles/view/66736?key=64b158b04e2a168811a3

Research on enhanced transmissibility in H5N1 influenza: Should the moratorium end?

Public Release: 9-Oct-2012

Contact: Jim Sliwa jsliwa@asmusa.org 202-942-9297 American Society for Microbiology

How can scientists safely conduct avian flu research if the results could potentially threaten, as well as save, millions of lives? In a series of commentaries appearing on Tuesday, October 9 in mBio®, the online open-access journal of the American Society for Microbiology, prominent microbiologists and physicians argue the cases both for and against lifting a voluntary moratorium on experiments to enhance the ability of the H5N1 virus to move from mammal to mammal, so-called “gain-of-function” research, and discuss the level of biosecurity that would be appropriate for moving that research forward.

In January 2012, in response to the controversy caused by the unprecedented recommendation iof an advisory board to the government to redact methods sections  of two research studies showing how genetic changes could make H5N1 become transmissible between mammals, a group of influenza researchers agreed to a voluntary pause on any research involving highly pathogenic avian influenza H5N1 viruses leading to the generation of viruses that are more transmissible in mammals. Despite both articles eventually being published in full in May and June 2012, the research moratorium remains in place.

“The scientific community and the greater society that it serves are currently engaged in a vigorous debate on whether and how to carry out experiments that could provide essential information for preparedness against a pandemic of avian influenza. To foster discussion and to provide a venue to record the arguments for or against this moratorium, mBio® has commissioned a series of views from experts in the field,” write Arturo Casadevall of the Albert Einstein School of Medicine, editor-in-chief of mBio®; and Thomas Shenk of Princeton University, Chair of the ASM Publications Board, in an introductory editorial.

Enhancing and analyzing the transmissibility of the H5N1 virus could, on the one hand, provide insights that could help prevent or treat a future outbreak of H5N1 , or, on the other hand, it may provide a roadmap for a “bad actor” to deliberately bring about an influenza pandemic or lead to an inadvertent release of a virus with enhanced transmissibility.

Authors of the commentaries are prominent scientists, including:

  • Ron Fouchier of Erasmus MC Rotterdam in The Netherlands, Adolfo García-Sastre of the Mount Sinai School of Medicine, and Yoshihiro Kawaoka of the University of Wisconsin-Madison, lead authors of the two papers that began the controversy, argue that in the eight months since the moratorium was agreed upon, the international research community has had sufficient time to review biosafety and biosecurity measures and that H5N1 transmission studies ought to proceed. 
  • Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases contributes his voice as a representative of an organization that is a key funder of influenza research. Although Fauci acknowledges that the benefits of gain-of-function research outweigh the risks, he argues that scientists have yet to fully meet their responsibility for engaging the public in weighing these matters and making the case for proceeding. He outlines how the U.S. government plans to augment policy guidelines related to “dual use research of concern” like the experiments on enhanced influenza transmission. 
  • Marc Lipsitch and Barry R. Bloom of the Harvard School of Public Health explain why they view H5N1 with enhanced transmissibility as a “potential pandemic pathogen,”representing an even greater threat to global health than Ebola and other biosafety level 4 (BSL-4) pathogens. They argue that research on enhanced H5N1 and other potential pandemic pathogens requires a new, more stringent set of guidelines for safety, thorough public discussion of the risks and benefits involved, and global guidelines for laboratory procedures, among other measures to minimize the risk of laboratory-released infections or epidemics. 
  • Ian Lipkin of Columbia University argues that once research on enhanced strains of H5N1 continues it may be advisable to conduct the work only in BSL-3 Ag laboratories that meet additional, enhanced guidelines for handling agents with pandemic potential. Lipkin proposes that any course should be charted in consultation with and oversight from the global scientific and regulatory community. 
  • Stanley Falkow of Stanford University provides perspective on the H5N1 research moratorium based on his own experiences with a similar situation in the 1970s, when research in recombinant DNA techniques was halted while a committee of scientists and non-scientists could establish a set of guidelines for conducting the work safely. Falkow argues that research on H5N1 viruses with enhanced transmissibility should move forward once scientists work with the public to establish standardized guidelines using common sense and scientific creativity.

“This is a historic time in science,” says Casadevall. mBio® has solicited the views of experts in the field, he says, in order to provide a venue for recording the arguments for and against continuing H5N1 gain-of-function research. “Society is asking for a pause of research that is perhaps the best defense against pandemics because of concern about both biosafety and biosecurity.” With the research moratorium continuing well past the 60-days originally planned, it is time these conflicting views were aired in a public forum, he says.

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mBio® is an open access online journal published by the American Society for Microbiology to make microbiology research broadly accessible. The focus of the journal is on rapid publication of cutting-edge research spanning the entire spectrum of microbiology and related fields. It can be found online at http://mBio.asm.org.

The American Society for Microbiology is the largest single life science society, composed of over 39,000 scientists and health professionals. ASM’s mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide

Reconstructed 1918 influenza virus has yielded key insights, scientists say

Contact: Nalini Padmanabhan
padmanabhannm@niaid.nih.gov
301-402-1663
NIH/National Institute of Allergy and Infectious Diseases

WHAT:

 

The genetic sequencing and reconstruction of the 1918 influenza virus that killed 50 million people worldwide have advanced scientists’ understanding of influenza biology and yielded important information on how to prevent and control future pandemics, according to a new commentary by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and several other institutions.

By sequencing the 1918 virus, researchers were able to confirm that the viruses that caused influenza pandemics in 1957, 1968, and 2009 were all descended in part from the 1918 virus. Studies showed that the 2009 pandemic virus had structural similarities with the 1918 virus and explained why younger people, who had never been exposed to the 1918 virus or its early descendants, were most vulnerable to infection by the 2009 influenza virus. As a result, public health officials were able to target limited vaccine supplies to predominantly younger people, who needed vaccine protection most, rather than the elderly, who were at lower risk of infection in 2009, but are traditionally the most important target group for vaccination. Further, determining the physical structure of parts of the 1918 virus, particularly the portions that are consistent across influenza viruses, has informed the ongoing development of candidate “universal” influenza vaccines that may be given infrequently yet protect broadly against multiple influenza viruses. In addition, by comparing the 1918 virus to related influenza viruses found in animals, scientists have learned some of the changes necessary for influenza viruses to adapt from an animal to a human host. This has led to more targeted surveillance of certain influenza viruses in animals that may be more likely to move to humans.

More generally, the authors say that reconstruction of the 1918 influenza virus has furthered scientific understanding of how novel influenza viruses emerge and evolve. Additionally, study of the 1918 influenza virus has helped clarify the critical effects of the human immune system’s response to viral infection and the importance of bacterial co-infections that often follow the influenza infection. In sum, the authors write, learning more about the 1918 pandemic influenza virus has led to important insights that could help prevent or mitigate seasonal and pandemic influenza.

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ARTICLE:

 

JK Taubenberger et al. Reconstruction of the 1918 influenza virus: Unexpected rewards from the past. mBio DOI: 10.1128/mBio.00201-12 (2012).

WHO:

 

Study co-authors Jeffery K. Taubenberger, M.D., Ph.D., section chief in NIAID’s Laboratory of Infectious Diseases; and David M. Morens, M.D., senior advisor to the NIAID Director, are available to discuss this study.

CONTACT:

 

To schedule interviews, please contact Nalini Padmanabhan, (301) 402-1663, padmanabhannm@niaid.nih.gov.

For more information about NIAID’s research involving the 1918 influenza virus, see NIAID’s web page on the History of the 1918 Pandemic (http://www.niaid.nih.gov/topics/Flu/1918/Pages/1918History.aspx).

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov/.

NIH…Turning Discovery Into Health

La Jolla Institute unlocks mystery of potentially fatal reaction to smallpox vaccine

Contact: Bonnie Ward contact@liai.org 619-303-3160 La Jolla Institute for Allergy and Immunology

Research team is part of NIH network working toward new smallpox vaccine for eczema sufferers

SAN DIEGO – (May 25, 2009) Researchers from the La Jolla Institute for Allergy & Immunology have pinpointed the cellular defect that increases the likelihood, among eczema sufferers, of developing eczema vaccinatum, a severe and potentially fatal reaction to the smallpox vaccine.  The research, conducted in mouse models, was funded under a special research network created by the National Institutes of Health in 2004.  The network is working toward the development of a new smallpox vaccine that could be administered to the millions of Americans who suffer from atopic dermatitis, a chronic, itchy skin condition commonly referred to as eczema.

The La Jolla Institute’s Toshiaki and Yuko Kawakami, M.D.s, Ph.D.s., a husband and wife scientific team, led the research group which found that activity levels of Natural Killer (NK) cells played a pivotal role in the development of eczema vaccinatum in the mice.  The activity of the NK cells, which are disease fighting cells of the immune system, was significantly lower in the mice that developed eczema vaccinatum than in normal mice that also received the smallpox vaccine.  This knowledge opens the door to one day developing therapies that could potentially boost NK cell activity in eczema sufferers.

“Since atopic dermatitis affects as many as 17 percent of children in the U. S. and since eczema vaccinatum carries a fatality rate of 5-10 percent, therapies that prevent or treat eczema vaccinatum successfully are crucial should the need for mass vaccination against smallpox arise in response to bioterrorism,” said Harvard pediatrics professor Raif S. Geha, M.D., chief of immunology at Boston Children’s Hospital and a principal investigator in the NIH funded network investigating eczema vaccinatum. “The discovery of the Kawakami team, who are participants in the NIH network, is an important step towards this goal.”

People with active atopic dermatitis (eczema), or who have outgrown atopic dermatitis, and the people they live with currently cannot receive smallpox vaccinations because of the risk of eczema vaccinatum.  While uncommon, eczema vaccinatum can develop when atopic dermatitis patients are given the smallpox vaccine or come into close personal contact with people who recently received the vaccine.  It is estimated that a significant portion of the U.S. population is currently not eligible for smallpox vaccination.

“This discovery answers an important question that has long eluded the scientific community, “why people with atopic dermatitis were susceptible to developing eczema vaccinatum upon receiving the smallpox vaccine, while the general population was not,” said Mitchell Kronenberg, the La Jolla Institute’s president & scientific director.  “It marks a significant advance toward the goal of ensuring that everyone can one day be protected against the smallpox virus.”

The finding was published today in the online version of the Journal of Experimental Medicine in a paper entitled, “Inhibition of NK cell activity by IL-17 allows vaccinia virus to induce severe skin lesions in a mouse model of eczema vaccinatum.”  La Jolla Institute scientist Shane Crotty, Ph.D., also contributed to the study.

Regarded as the deadliest disease ever known to man, smallpox was officially eradicated worldwide in 1980 and routine vaccinations against the disease ended in the U.S in 1972.   However, bioterrorism concerns have arisen over recent years regarding the deliberate distribution of the smallpox virus, which might make smallpox vaccinations once again necessary.  Such concerns led to the creation of the Atopic Dermatitis and Vaccinia Network (ADVN), a consortium of medical and research institutions nationwide developed by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.  The network, which provided grant funding for the Kawakami’s studies under NIH contact N01-AI40030C, was launched in 2004 with the goal of developing a new smallpox vaccine that would be safe for atopic dermatitis sufferers.  It includes three consortiums, involving data, clinical testing and animal studies, of which Drs. Kawakami and the La Jolla Institute are members.

The Animal Studies Consortium was created to establish animal models of atopic dermatitis and investigate their immune responses to vaccinia — the virus used in smallpox vaccine.  Drs. Kawakami were invited to join the consortium due to their creation of a new, more effective atopic dermatitis mouse model in 2004.

In their study, Drs. Kawakami showed that eczema-infected mice had higher levels of IL-17 cells, which are known to inhibit NK cell activity.  “This higher level of IL-17 cells slowed down the ability of the NK cells to kill the vaccinia virus,” said Yuko Kawakami, noting people with atopic dermatitis are also known to have higher numbers of IL-17 producing cells.  “This led to the development of eczema vaccinatum when these mice received the smallpox vaccine.”

Drs. Kawakami tested their theory by stimulating more NK cell activity in the eczema-infected mice.  The higher activity led to the elimination of the eczema vaccinatum infection.  “We are very excited by these findings, ” said  Toshiaki Kawakami.  “Developing a safer smallpox vaccine is the most important thing in this field.”

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About La Jolla Institute

Founded in 1988, the La Jolla Institute for Allergy & Immunology is a nonprofit medical research center dedicated to increasing knowledge and improving human health through studies of the immune system. Scientists at the institute carry out research searching for cures for cancer, allergy and asthma, infectious diseases, and autoimmune diseases such as diabetes, inflammatory bowel disease and arthritis. La Jolla Institute’s research staff includes more than 100 Ph.Ds and M.D.s.

Reposted at request

Study illuminates how the plague bacteria causes disease

Contact: Heidi Hardman hhardman@cell.com 617-397-2879 Cell Press

The bacteria responsible for the plague and some forms of food poisoning “paralyze” the immune system of their hosts in an unexpected way, according to a new study in the September 8, 2006 issue of the journal Cell, published by Cell Press.

The researchers found that these bacteria, which belong to the genus Yersinia, harbor a protein that mimics an apparently unrelated mammalian enzyme. That copycat protein blocks host cells’ capacity to change shape and move, abilities important for cells of the immune system to track down and “eat” foreign invaders, the researchers explained.

The discovery marks the second way in which this protein, called YpkA, compromises the immune system. Earlier studies suggested that another portion of YpkA–which may have been derived from a mammalian enzyme and later co-opted by Yersinia–has activity that also influences cell shape by a separate, though incompletely understood mechanism.

The findings offer important new insight into the factors that lend Yersinia their ability to spawn disease, the researchers said. The results might also contribute to new strategies for fighting the bug.

“Yersinia injects several virulence factors into its host,” said C. Erec Stebbins of Rockefeller University. “If we can discover which ones are critical, we might identify the pathogen’s Achilles heel–an attractive target for antibacterial or anti-virulence compounds.”

“We were quite excited to see such a critical and unexpected factor in the virulence of Yersinia–a bacteria historically responsible for some of the worst diseases,” he added. Although improvements in sanitation have eliminated acute problems from diseases caused by Yersinia, concerns remain about the possibility that an untreatable strain might arise or that the bacteria might come into use as a biological weapon, he said.

Nearly 200 million people are estimated to have died in the plague epidemics that devastated the ancient world, the researchers said. The successful weaponization of plague in the former Soviet Union bioweapons program also made the pathogen a primary biodefense concern. Additional medical concerns have arisen from the evolution of multidrug-resistant strains of the plague bacterium found in patients from several locations.

The plague bacterium Yersinia pestis is closely related to Y. enterocolitica and Y. pseudotuberculosis, which are food-borne agents that cause inflammation of the stomach and intestines. All Yersinia bacteria have a virulence plasmid, which is necessary to cause disease. Plasmids are extra DNA molecules frequently found in bacteria containing genes that can be passed from one bacterial strain to another and that may confer an evolutionary advantage, such as antibiotic resistance.

In the case of Yersinia, the plasmid harbors numerous genes, including a large number that contribute to the ability of diverse pathogens to deliver virulence factors into host cells. One of these genes is YpkA, a protein with multiple domains, including one closely related to an enzyme, a type of kinase, not typically found in bacteria. Earlier studies found that mutations that eliminate this activity reduce but do not eliminate YpkA’s ability to disrupt cell shape by modifying their cytoskeletal support system.

In the current study, the researchers solved the high-resolution crystal structure of a second YpkA domain, the “Rho-GTPase binding domain” along with the host protein, “Rac1,” with which it interacts.

“The Yersinia structure was doing things to Rac1 that the host proteins normally do,” Stebbins said, suggesting that the domain acted as a mimic.

Further examination confirmed the domain to be a mimic of mammalian “guanidine nucleotide dissociation inhibitor” (GDI) proteins with a critical role in the bacteria’s ability to disrupt cell structure. The domain paralyzes cells by acting as an “off-switch” for host proteins involved in modifying cell shape, Stebbins said.

Mutations that prevented the bacterial proteins’ interaction with the host protein significantly impaired YpkA’s ability to disrupt the cytoskeleton. Moreover, a mutant strain of Y. pseudotuberculosis that lacked the GDI activity caused significantly fewer problems for infected mice compared to normal bacteria.

“Earlier studies that focused only on the protein’s kinase activity had missed half the picture,” Stebbins said. “The GDI domain seems to have an even bigger effect on host cells in culture, and a significant impact on virulence.”

The results also add to broader themes in the evolution of bacterial diseases, the researchers added.

“It is becoming increasingly clear that a common strategy used by bacterial pathogens to manipulate host cell biology is the mimicry of their own biochemical processes,” Stebbins said.

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The researchers include Gerd Prehna and C. Erec Stebbins of Rockefeller University in New York, NY; Maya I. Ivanov and James B. Bliska and of Stony Brook University in Stony Brook, NY.

This work was funded in part by research funds to C.E.S. from the Rockefeller University and PHS grants 1U19AI056510 (to C.E.S) and RO1AI433890 (to J.B.B) from the National Institute of Allergy and Infectious Diseases.

Prehna et al.: “Virulence in Yersinia Is Dependent on a Bacterial Mimic of Host Rho-Family Nucleotide Dissociation Inhibitors.” Publishing in Cell 126, 869–880, September 8, 2006. DOI 10.1016/j.cell.2006.06.056 http://www.cell.com

Repost at Request 2006

Protein enhances lethality of influenza virus – PB1-F2

Contact: Nancy Wampler nwampler@cell.com 617-386-2121 Cell Press

Clues from the past may influence preparations for the future

Often called the most devastating epidemic in the recorded history of the world, the 1918 influenza virus pandemic was responsible for more than 40 million deaths across the globe. The incredible lethality of the 1918 flu strain is not well understood, despite having been under intense scrutiny for many years. Now, a new study published by Cell Press in the October issue of the journal Cell Host & Microbe unravels some of the mystery surrounding the devastating 1918 pandemic and provides key information that will help prepare for future pandemics.

It is relatively rare for an influenza virus to be virulent enough to cause death in healthy humans. Many deaths associated with influenza are caused by the combined influence of viral disease and the following secondary bacterial infection. Although the 1918 pandemic strain was one of the few influenza viruses capable of killing healthy victims on its own, the majority of fatal cases from the “Spanish Flu” can be attributed to secondary bacterial pathogens rather than primary viral disease. This important interaction between influenza viruses and bacteria is not well understood.

Dr. Jonathan A. McCullers from the Department of Infectious Diseases at St. Jude Children’s Research Hospital in Memphis, Tennessee and colleagues examined this interaction by studying a newly discovered influenza A virus (IAV) protein, called PB1-F2. The gene encoding PB1-F2 is present in nearly all IAVs, including highly pathogenic avian IAVs that have infected humans and the IAV associated with the 1918 pandemic. “PB1-F2 was recently shown to enhance viral pathogenicity in a mouse infection model, raising questions about its effects on the secondary bacterial infections associated with high levels of influenza morbidity and mortality,” explains Dr. McCullers.

The researchers found that expression of PB1-F2 increased the incidence of and exacerbated secondary bacterial pneumonia in a mouse model. Intranasal delivery of a synthetic peptide derived from a portion of PB1-F2 had the same effects. Further, an influenza virus engineered to express a version of PB1-F2 identical to that in the 1918 pandemic strain was more virulent in mice and led to more severe bacterial pneumonia, explaining in part both the unparalleled virulence of the 1918 strain and the high incidence of fatal pneumonia during the pandemic.

The finding that PB1-F2 promotes lung pathology in primary viral infection and secondary bacterial infection also provides critical information for the future. “Given the importance of IAV as a leading cause of virus-induced morbidity and mortality year in and year out, and its potential to kill tens of millions in the inevitable pandemic that may have its genesis in the viruses currently circulating in southeast Asia, it is imperative to understand the role of PB1-F2 in IAV pathogenicity in humans and animals,” says Dr. McCullers. “These findings also reinforce the recent suggestion of the American Society for Microbiology that nations should stockpile antibiotics for the next pandemic, since many of the deaths during this event are likely to be caused by bacterial super-infections.”

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The researchers include Julie L. McAuley of Department of Infectious Diseases,  St. Jude Children’s Research Hospital in Memphis; Felicita Hornung of Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases in Bethesda; Kelli L. Boyd of Animal Resources Center, St. Jude Children’s Research Hospital in Memphis; Amber M. Smith of Department of Mathematics, University of Utah in Salt Lake City; Raelene McKeon of Department of Infectious Diseases,  St. Jude Children’s Research Hospital in Memphis; Jack Bennink and Jonathan W. Yewdell of Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases in Bethesda; and Jonathan A. McCullers of Department of Infectious Diseases,  St. Jude Children’s Research Hospital in Memphis.

This work was supported by the NIH (grants AI-66349 and AI-54802), the NIAID intramural research program, and the American Lebanese Syrian Associated Charities (ALSAC).

McAuley et al.: “Expression of the 1918 Influenza A Virus PB1-F2 Enhances the Pathogenesis of Viral and Secondary Bacterial Pneumonia.” Publishing in Cell Host & Microbe 2, 240–249, October 2007. DOI 10.1016/j.chom.2007.09.001 www.cellhostandmicrobe.com

* Reposted For Filing

A small genetic change makes flu virus deadly ( H5N1 2001 Requested Repost)

Contact: Jeff Minerd jminerd@niaid.nih.gov 301-402-1663 NIH/National Institute of Allergy and Infectious Diseases

A small genetic change makes flu virus deadly

A tiny change in one of the influenza virus’s 10 genes is key to making certain strains of the virus especially virulent to humans, scientists report in the Sept. 7 issue of Science. This discovery helps explain why an influenza outbreak four years ago in Hong Kong killed an unusually high proportion of the people it infected – six out of 18, says lead researcher Yoshihiro Kawaoka, D.V.M., Ph.D., of the University of Wisconsin-Madison.

“We have found that a limited number of very tiny genetic changes in a specific gene, one called PB2, can have a big effect on how potent the influenza virus is,” says Dr. Kawaoka, a grantee of the National Institute of Allergy and Infectious Diseases (NIAID).  “Because the influenza virus constantly mutates, and because only a few changes can make a non-pathogenic virus highly pathogenic, we should assume that an outbreak of any new strain or subtype is potentially dangerous to humans.”

“To prepare for future influenza pandemics, NIAID has supported efforts to understand how new virus strains potentially harmful to humans appear,” says Anthony S. Fauci, M.D., NIAID director. “This study is an elegant example of research that provides insight into the emergence of virulent viruses and can help us develop better strategies for detecting future outbreaks.”

Wild waterfowl are natural reservoirs for the influenza virus; these birds transmit the virus to pigs or chickens, which then pass it on to people. The deadly outbreak of influenza virus subtype H5N1 in Hong Kong in 1997 was the first documented case of an influenza virus jumping directly from chickens to people.  Public health authorities responded by ordering the slaughter of more than 1 million live poultry to prevent further spread of the virus to humans.

Dr. Kawaoka and colleagues obtained samples of the H5N1 viruses that had infected Hong Kong residents during the 1997 outbreak. Testing these viruses in laboratory mice, the researchers found good correlation between how sick certain H5N1 strains made mice and how sick they had made humans.  The researchers divided the H5N1 strains into two groups: one that caused systemic lethal infection in the mice and one that was relatively benign.  Mice are a good model for studying H5N1, Dr. Kawaoka says, because this virus affects mice and humans similarly.

Next, Dr. Kawaoka used a technology that allows him to genetically engineer “designer” influenza viruses from scratch.  By systematically swapping the genes from the harmful and benign viruses, then testing how those engineered viruses affected mice, he discovered that the PB2 gene from the harmful group gives the virus its potency.  Then, through testing viruses that contained variations of this PB2 gene, he further identified a tiny change within the gene – a change of just one unit of RNA – that appears to be key to the virus’s virulence.

The function of the PB2 gene is not completely understood, but scientists believe it codes for an enzyme that helps force the host cell’s molecular machinery to make more viruses, Dr. Kawaoka explains.  “We don’t know if the mutation we studied is involved in that process, but our next step will be to find out,” he says.

Just over 10 years ago, researchers developed the ability to genetically engineer influenza viruses, a process known as reverse genetics.  In 1999, Dr. Kawaoka, with support from NIAID, streamlined this technology, making it much more efficient.  Without the ability to engineer influenza viruses through the reverse genetics system, it would not have been possible to create and study variations of the H5N1 virus, Dr. Kawaoka says.  “Just a few years ago, this discovery would not have been possible,” says Carole Heilman, Ph.D., director of NIAID’s Division of Microbiology and Infectious Diseases. “We believe this is the first of many more important discoveries that will arise from this technology.”

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For more information on Dr. Kawaoka’s work in this field, other NIAID-supported influenza research, and background on the virus itself, visit Focus on the Flu on the NIAID Web site at http://www.niaid.nih.gov/newsroom/focuson/flu00.  Focus on the Flu also contains information on NIAID-sponsored efforts to prepare for future influenza pandemics.  Such efforts include helping to fund ongoing monitoring of influenza virus strains circulating through live poultry markets in Hong Kong, a project that could nip future outbreaks in the bud.  Other NIAID-supported researchers are examining the history of influenza virus evolution for clues about which new strains might emerge next.

NIAID is a component of the National Institutes of Health (NIH).  NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

Reference:

Hatta M et al.  Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses.  Science 293(5536):1840-42 (2001).

Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.