TAG: "Infectious disease"

Malaria’s clinical symptoms fade on repeat infections


UCSF-led team finds that this might be in part to loss of immune cells.

Researchers have been studying immune responses to the malaria parasite in Tororo, Uganda, where infection is now more prevalent than Kampala, the Ugandan capital.

Children who repeatedly become infected with malaria often experience no clinical symptoms with these subsequent infections, and a team led by UC San Francisco researchers has discovered that this might be due at least in part to a depletion of specific types of immune cells.

Working in Uganda, one of the most malaria-plagued nations in Africa and one in which individuals are repeatedly exposed to the malaria parasite, UCSF scientists found that a depletion of immune cells known as gamma delta T cells diminishes inflammatory responses in infected children — responses that when unabated can become debilitating or deadly.

“These inflammatory immune cells are depleted in children with repeated malaria exposure, and those that remain behave differently than the same cell types in children who have not previously been infected,” said Prasanna Jagannathan, M.D., an assistant professor of medicine at UCSF, who conducted the lab analysis as part of a study team led by Margaret Feeney, M.D., a UCSF professor of experimental medicine and pediatrics. The study was published online today (Aug. 27) in the journal Science Translational Medicine.

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Protein ID’d that helps prevent active TB in infected patients


Discovery could help doctors identify people at greatest risk for the disease.

A UCLA-led study has identified a protein that appears to play a key role in protecting people infected with Mycobacterium tuberculosis — the bacterium that causes tuberculosis — from developing the active form of the disease. The protein, interleukin-32, was discovered to be one biomarker of adequate host defense against TB.

The discovery could help doctors identify people who are at the greatest risk for the highly contagious and potentially fatal lung disease, and it could point the way toward new treatment strategies for TB.

The study, conducted in partnership with researchers from Harvard University School of Public Health and the University of Michigan School of Medicine, was published in the Aug. 20 online edition of the journal Science Translational Medicine.

The findings underscore the importance of maintaining sufficient levels of vitamin D to effectively combat the pathogen that causes TB. The researchers found that the protective protein, interleukin-32, can induce the killing of the TB bacterium only in the presence of sufficient levels of vitamin D.

An estimated one-third of the world’s population is infected with tuberculosis, but the disease is latent in 90 to 95 percent of infected people, meaning that they experience no symptoms and are not contagious. Interleukin-32 contributes to maintaining that latent state and preventing active infection. In 2012, nearly 9 million people worldwide became sick with TB and there were 1.3 million TB-related deaths, according to the U.S. Centers for Disease Control and Prevention.

A new urgency for developing new approaches to identify individuals at risk, maintain immunity and treat active disease has arisen in recent years as TB has re-emerged as a global health threat — thanks in part to the rise of extremely drug-resistant bacteria.

“Until now, there had been no way to predict, based on biological factors, why latently infected individuals do not develop active tuberculosis,” said Dennis Montoya, a postdoctoral scholar in the division of dermatology at the David Geffen School of Medicine at UCLA and the study’s lead author. “We were surprised to find many differences between people with latent TB and healthy people, suggesting that people with latent TB may have activated immune systems that are protecting them from developing active infection.”

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New vaccine may be stronger weapon against both TB and leprosy


Research finds variant of existing vaccine offers stronger protection against both diseases.

Antigen 85B structure

In many parts of the world, leprosy and tuberculosis live side-by-side. Worldwide there are approximately 233,000 new cases of leprosy per year, with nearly all of them occurring where tuberculosis is endemic.

The currently available century-old vaccine Bacille Calmette-Guerin, or BCG, provides only partial protection against both tuberculosis and leprosy, so a more potent vaccine is needed to combat both diseases. UCLA-led research may have found a stronger weapon against both diseases.

In a study published in the September issue of the peer-reviewed journal Infection and Immunity, the researchers found that rBCG30, a recombinant variant of BCG that overexpresses a highly abundant 30 kDa protein of the tuberculosis bacterium known as Antigen 85B, is superior to BCG in protecting against tuberculosis in animal models, and also cross protects against leprosy. In addition, they found that boosting rBCG30 with the Antigen 85B protein, a protein also expressed by the leprosy bacillus, provides considerably stronger protection against leprosy.

“This is the first study demonstrating that an improved vaccine against tuberculosis also offers cross-protection against Mycobacterium leprae, the causative agent of leprosy,” said Dr. Marcus A. Horwitz, professor of medicine and microbiology, immunology and molecular genetics, and the study’s senior author. “That means that this vaccine has promise for better protecting against both major diseases at the same time.

“It is also the first study demonstrating that boosting a recombinant BCG vaccine further improves cross-protection against leprosy,” he added.

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Antimalarial drug shipped to Africa


Project begun by Berkeley Lab’s Jay Keasling to benefit millions of people.

Jay Keasling with children in a village outside Nairobi, Kenya. (Photo by Gabrielle Tenenbaum)

A project begun some 13 years ago by Jay Keasling, the associate laboratory director for biosciences at Berkeley Lab and the CEO of the Joint BioEnergy Institute (JBEI), was culminated with an announcement on Aug. 12 from the partnership of Sanofi, the multinational pharmaceutical company, and PATH, the nonprofit global health organization. Sanofi/PATH announced the shipment of 1.7 million treatments of semi-synthetic artemisinin to malaria-endemic countries in Africa. Unlike conventional artemisinin, which is derived from the bark of the sweet wormwood plant, this synthetic version of the World Health Organization’s frontline antimalarial drug is derived from yeast. The addition of a microbial-based source of artemisinin to the botanical source provides a stable new option for treating the millions of victims who are stricken with malaria each year, most of them children.

Sanofi has produced enough of the drug for 70 million treatments, and has the capacity to produce up to 150 million treatments annually. It was Keasling and his research group, using the tools of synthetic biology, who engineered the genes and metabolic pathways that enabled first E. coli and later yeast to produce artemisinic acid, the precursor to artemisin. This led to a $42.6 million grant from the Bill and Melinda Gates Foundation for further basic research that ultimately led to yesterday’s announcement by Sanofi/PATH. Keasling, who is also the Hubbard Howe Jr. Distinguished Professor in Biochemical Engineering at UC Berkeley, among other titles, has been recognized for leading this groundbreaking research with numerous awards including the Biotechnology Industry Organization’s first Biotech Humanitarian Award.

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Grant will advance research on African malaria mosquito


UC Riverside’s Bradley White will produce critical tool aimed at crippling Anopheles gambiae.

Bradley White, UC Riverside

Malaria, the most deadly mosquito-borne disease, kills more than 500,000 people each year, with more than 90 percent of the deaths occurring in sub-Saharan Africa.  While poverty and poor medical care contribute to the African malaria burden, the importance of the uniquely efficient mosquito vectors present in Africa cannot be overlooked.

One particularly promising area of research involves genetic engineering of mosquitoes to prevent transmission.  Although great progress has been made in developing mosquitoes that cannot transmit malaria, more knowledge is needed before such mosquitoes can be released.

Bradley White, an assistant professor of entomology at UC Riverside, has received a five-year grant of more than $1.8 million from the National Institute of Allergy and Infectious Diseases, one of the many institutes that make up the National Institutes of Health (NIH). The grant will allow his lab to produce fine-scale recombination rate maps for the African malaria mosquito, Anopheles gambiae.

The grant is a NIH “R01” grant, RO1 being an NIH activity code.  At 31, White is one of the youngest NIH R01 principal investigators in the country (well less than 1 percent of NIH principal investigators are 31 or younger).

“By the end of the project, we will have produced these recombination rate maps that can be used to model and predict the efficacy of various novel vector control strategies,” said White, who joined UC Riverside in 2011.  “Ultimately, this project will provide a critical tool in the ongoing fight against one of humanity’s ancient foes.”

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A key step toward a safer strep vaccine


UC San Diego gene discovery identifies molecular pathway to potential preventive treatment.

Electron micrograph, false color, of group A Streptococcus bacteria

An international team of scientists, led by researchers at the UC San Diego School of Medicine, have identified the genes encoding a molecule that famously defines Group A Streptococcus (strep), a pathogenic bacterial species responsible for more than 700 million infections worldwide each year.

The findings, published online in today’s (June 11) issue of Cell Host & Microbe, shed new light on how strep bacteria resists the human immune system and provides a new strategy for developing a safe and broadly effective vaccine against strep throat, necrotizing fasciitis (flesh-eating disease) and rheumatic heart disease.

“Most people experience one or more painful strep throat infections as a child or young adult,” said senior author Victor Nizet, M.D., professor of pediatrics and pharmacy. “Developing a broadly effective and safe strep vaccine could prevent this suffering and reduce lost time and productivity at school and work, estimated to cost $2 billion annually.”

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Just-in-time diagnosis


UCSF uses advanced DNA sequencing technology to diagnose infection, save critically ill boy.

Joshua Osborn, 15, flips on the trampoline in the backyard of his home in Cottage Grove, Wis., on May 31. (Photo by John Maniaci)

A mysterious ailment sent an active teenage boy into a medically induced coma, and no one could figure out the cause.

As precious time passed, a team at UC San Francisco employed advanced DNA sequencing technology to find a needle-in-the-haystack answer. What they found led them to a life-saving, and surprisingly simple, treatment.

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Faster DNA sleuthing saves critically ill boy


UCSF genome experts show value of ‘next-generation sequencing’ in diagnosing infection.

Charles Chiu, UC San Francisco

A 14-year-old boy’s turnaround and quick recovery after mysteriously being stricken by brain-inflaming encephalitis – which led to him being hospitalized for six weeks and put into a medically induced coma after falling critically ill – shows that the newest generation of DNA analysis tools can be harnessed to reveal the cause of a life-threatening infection even when physicians have no suspects.

The quick diagnosis and successful treatment of the adolescent just 48 hours after cerebrospinal spinal fluid and blood were received for analysis portends the broader application of powerful, “next-generation sequencing” (NGS) techniques in solving infectious disease mysteries, not only in cutting-edge research labs, but also in clinical laboratories accessible to hospital physicians everywhere, according to Charles Chiu, M.D., Ph.D., a professor of laboratory medicine at UC San Francisco. Chiu is senior author of the case study, published online in the New England Journal of Medicine (NEJM) today (June 4).

The workflow pipeline developed in Chiu’s UCSF laboratory to streamline genetic sleuthing of disease pathogens with NGS dramatically cut the time between sample collection and actionable diagnosis and helped a medical team at the University of Wisconsin save the young patient’s life.

The NEJM study reflects the convergence of faster DNA sequencing, ever-growing genome databases for identifying pathogens and other organisms, and more sophisticated computational analysis tools to quickly analyze millions of data points. The protocol enabled rapid sequencing and simultaneous identification of all DNA in the patient samples without culturing or targeting for specific infectious disease agents.

“From the perspective of cost and turnaround time, this is a very powerful technology that has become practical to implement routinely in clinical laboratories,” Chiu said. Some clinical labs now offer NGS testing to identify cancer mutations in clinical trials and to identify mutations underlying birth defects, but until now NGS has been regarded as too slow and laborious to be useful for routine infectious disease diagnosis.

Study co-author Joseph DeRisi, Ph.D., chair of biochemistry and biophysics at UCSF, a Howard Hughes Medical Institute (HHMI) investigator, and a leader in using new genomics techniques to identify previously unknown pathogens, such as the SARS coronavirus, said that at a cost of a few thousand dollars, essentially any pathogen now can be detected with a single test.

“This is one test to rule them all,” DeRisi said.

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Research targets three neglected tropical diseases


UC, partner researchers receive $6M to target Chagas’ disease, dengue, onchocerciasis.

Researchers at UC San Francisco, UC Berkeley and partner institutions are receiving $6 million to speed development of new tools and technologies that will address three neglected tropical diseases that place a huge health and economic burden on people in Central and South America: Chagas’ disease, dengue and onchocerciasis.

Led by scientists at UCSF Global Health Sciences and funded jointly by the Bill & Melinda Gates Foundation and the Instituto Carlos Slim de la Salud (the Carlos Slim Health Institute), the two-year project is titled FIRST (Fighting Infections through Research, Science, and Technology). The research, which is already under way, will focus on Mesoamerica, which comprises the Southern states of Mexico and Central America from Guatemala to Panama. A significant number of people, mainly of indigenous descent, live in poverty in these countries, making them vulnerable to illness and death.

FIRST promises to address three diseases that collectively affect billions of people worldwide, and have significant health and economic effects, by helping to find better treatments, more effective vaccines and other ways to prevent them.

“We are selecting projects that will give us quick wins, allowing us to make a huge impact immediately, as well as game-changing, high-risk research that will make a significant impact in the long term,” said Jaime Sepulveda, M.D., M.P.H., M.Sc., Dr.Sc., the executive director of UCSF Global Health Sciences.

“Although transmission of onchocerciasis has been interrupted in Mesoamerica, many indigenous communities are still at high-risk because current treatments do not kill the adult worms,” said Jim McKerrow, the principal investigator on the onchocerciasis project and a UCSF professor of pathology. “We will carry out a clinical trial with collaborators in Cameroon and the UK to determine whether Auranofin, an FDA approved drug, can be repurposed as a macrofilaricide to kill adult worms.”

The aims of the other projects in the FIRST portfolio include developing:

  • Low-cost diagnostic tools for early detection of dengue
  • Information systems that will provide early warnings of dengue outbreaks
  • New tests to guide dengue vaccine development
  • A cell phone app for crowdsourcing mosquito control
  • New, less toxic drugs for Chagas’ disease
  • Better biomarkers to monitor treatment of Chagas’ disease.

In addition to UCSF, researchers whose work will be funded by this project are affiliated with Blood Systems Research Institute, Liverpool School of Tropical Medicine, Sustainable Sciences Institute in San Francisco and Nicaragua, UC Berkeley, UC San Diego, UC Santa Cruz, University of North Carolina, and University of Sao Paulo.

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Why dengue fever prevention efforts often fail


Twelve-year study provides insights.

Studies on dengue fever infections took UC Davis researcher Robert Reiner (foreground) to Iquitos, Peru.

Newly published research involving a 12-year study of dengue infections in Iquitos, Peru, helps explain why interventions to prevent the mosquito-borne disease are frequently unsuccessful.

The research, headed by professor Thomas Scott of the UC Davis Department of Entomology and Nematology, is published today (May 19) in the Proceedings of the National Academy of Sciences.

“Defining variation in the risk of dengue transmission has been a roadblock to understanding disease dynamics and designing more realistic and effective disease prevention programs,” said Scott, a noted dengue researcher and a senior author of the paper, “Time-Varying, Serotype-Specific Force of Infection of Dengue Virus.”

“This study is an important step toward overcoming that obstacle,” Scott said. “We hope our results will help reduce the burden of this increasingly devastating disease.”

Dengue, a mosquito-borne virus infecting nearly 400 million people a year, is difficult to model not only because the majority of all infections are hidden, but also because there are four distinct serotypes, or versions, of dengue, each having unique characteristics, said lead author Robert Reiner, a Research and Policy for Infectious Disease Dynamics (RAPIDD) postdoctoral fellow in Scott’s Mosquito Research Laboratory.

“Typically, most infections go unnoticed and as such, measuring and modeling transmission intensity is problematic,” Reiner said.

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UC Davis Children’s Hospital opens recurrent MRSA clinic


Clinic will be accepting referrals from primary care physicians.

Pediatric patients with recurrent MRSA (methicillin-resistant Staphylococcus aureus) can find the help they seek at UC Davis Children’s Hospital’s new clinic.

The Recurrent MRSA Clinic will open Tuesday, May 6, and will be accepting referrals from primary care physicians.

Dean Blumberg, chief of pediatric infectious diseases at UC Davis, has been caring for patients with MRSA for over a decade and has seen an increase in cases over the past five years. He has developed a tried-and-tested line of defense to help treat and prevent future outbreaks.

“I see the frustration that families face every day when battling community-associated MRSA. I developed this clinic to provide parents with the right resources to fight it once and for all, so they can get back to their day-to-day lives,” said Blumberg.

Blumberg has been able to reduce MRSA recurrences, if not eliminate them, in more than 95 percent of his pediatric patients. In most cases, no further MRSA infections occur after one clinic visit.

According to the U.S. Centers for Disease Control and Prevention, two in 100 people carry MRSA. MRSA is a bacteria that is resistant to many antibiotics. People can transmit MRSA through direct contact with an infected wound or by sharing personal items, such as towels or razors, that have touched someone’s infection. MRSA is frequently spread in places that involve crowding, skin-to-skin contact, and shared equipment or supplies. Most community-associated MRSA infections are skin infections.

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Declines in large wildlife lead to increases in disease risk


Research shows biodiversity loss heightens risk of animal-to-human disease transmission.

A plains zebra in front of the Kenya Long-Term Exclosure experiment.

In the Middle Ages, fleas carried by rats were responsible for spreading the Black Plague. Today in East Africa, they remain important vectors of plague and many other diseases, including Bartonellosis, a potentially dangerous human pathogen.

Research by Hillary Young, assistant professor in UC Santa Barbara’s Department of Ecology, Evolution and Marine Biology, directly links large wildlife decline to an increased risk of human disease via changes in rodent populations. The findings appear today (April 28) in the Proceedings of the National Academy of Sciences Early Online Edition.

With an East African savanna ecosystem as their research site, Young and her colleagues examined the relationship between the loss of large wildlife — defaunation — and the risk of human disease. In this case, they analyzed Bartonellosis, a group of bacterial pathogens which can cause endocarditis, spleen and liver damage and memory loss.

“We were able to demonstrate that declines in large wildlife can cause an increase in the risk for diseases that are spread between animals and humans,” said Young. “This spike in disease risk results from explosions in the number of rodents that benefit from the removal of the larger animals.”

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