TAG: "Infectious disease"

NIH funds projects to develop tools to detect drug-resistant microbes


UC Berkeley, Irvine investigators to work to rapidly detect antimicrobial-resistant bacteria.

By Sarah Yang, UC Berkeley

UC Berkeley researchers will receive $5.8 million over five years from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, to develop tools to quickly spot and identify drug-resistant pathogens.

The UC Berkeley project is among nine announced today (April 9) by NIAID as part of the agency’s effort to develop diagnostics to rapidly detect antimicrobial-resistant bacteria. A total of $11 million was awarded to six academic institutions and three companies for the first of five years of funding. Awardees included UC Irvine, whose project is led by Weian Zhao.

Over the past 70 years, antimicrobials have become increasingly ineffective as organisms develop resistance to the drugs that are supposed to kill them. According to the U.S. Centers for Disease Control and Prevention (CDC), more than 2 million people are infected and 23,000 people are killed each year as a result of antibiotic-resistant microbes.

The UC Berkeley team consists of researchers from the School of Public Health and the Department of Bioengineering. Leading the team are Dr. Lee Riley, professor of infectious diseases, and Luke Lee and Niren Murthy, both professors of bioengineering.

Their goal is to develop a diagnostic system to determine in blood, urine and other clinical samples the species of bacteria and its resistance to drugs in a matter of minutes. That would be a huge improvement over the current process, which can take up to three days and often involves sending patient samples to off-site labs.

“Delay in diagnosis not only contributes to increased patient mortality, but also to the wrong choice of drugs that can further select for drug resistance,” Riley said.

The researchers will focus on so-called “Gram negative” bacteria, a class of bacteria that includes Escherichia coli and Pseudomonas aeruginosa, which have been designated by the CDC as “urgent threat” and “serious threat” pathogens.

“Antimicrobial resistance is a serious global health threat that is undermining our ability to effectively detect, treat and prevent infections,” said Dr. Anthony S. Fauci, NIAID’s director, in the announcement. “One way we can combat drug resistance is by developing enhanced diagnostic tests that rapidly identify the bacteria causing an infection and their susceptibility to various antimicrobials. This will help physicians determine the most effective treatments for infected individuals and thereby reduce the use of broad-spectrum antibiotics that can contribute to the drug-resistance problem.”

More information is available from the NIAID press release.

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Cigarette smoke makes superbugs more aggressive


In experiments, cigarette smoke helps drug-resistant bacteria fight off the immune system.

By Heather Buschman, UC San Diego

Methicillin-resistant Staphylococcus aureus (MRSA), an antibiotic-resistant superbug, can cause life-threatening skin, bloodstream and surgical site infections or pneumonia. Researchers at the UC San Diego School of Medicine now report that cigarette smoke may make matters worse. The study, published March 30 by Infection and Immunity, shows that MRSA bacteria exposed to cigarette smoke become even more resistant to killing by the immune system.

“We already know that smoking cigarettes harms human respiratory and immune cells, and now we’ve shown that, on the flipside, smoke can also stress out invasive bacteria and make them more aggressive,” said senior author Laura E. Crotty Alexander, M.D., assistant clinical professor of medicine at UC San Diego and staff physician at the Veterans Affairs San Diego Healthcare System.

Crotty Alexander is a pulmonologist who sees many patients who smoke cigarettes. She also sees many MRSA infections, and that got her wondering if one might influence the other. To test the hypothesis, Crotty Alexander and her team infected macrophages, immune cells that engulf pathogens, with MRSA. Some of the bacteria were grown normally and some were grown with cigarette smoke extract. They found that while the macrophages were equally able to take up the two bacterial populations, they had a harder time killing the MRSA that had been exposed to cigarette smoke extract.

To better understand why, the Crotty Alexander team tested the bacteria’s susceptibility to individual mechanisms macrophages typically employ to kill bacteria. Once inside macrophages, smoke-exposed MRSA were more resistant to killing by reactive oxygen species, the chemical burst that macrophages use to destroy their microbial meals. The team also discovered that smoke-exposed MRSA were more resistant to killing by antimicrobial peptides, small protein pieces the immune system uses to poke holes in bacterial cells and trigger inflammation. The effect was dose-dependent, meaning that the more smoke extract they used, the more resistant the MRSA became.

MRSA treated with cigarette smoke extract were also better at sticking to and invading human cells grown in the lab. In a mouse model, MRSA exposed to cigarette smoke survived better and caused pneumonia with a higher mortality rate.

The data suggest that cigarette smoke strengthens MRSA bacteria by altering their cell walls in such a way that they are better able to repel antimicrobial peptides and other charged particles.

“Cigarette smokers are known to be more susceptible to infectious diseases. Now we have evidence that cigarette smoke-induced resistance in MRSA may be an additional contributing factor,” Crotty Alexander said.

Study co-authors include Elisa K. McEachern, John H. Hwang, Katherine M. Sladewski, UC San Diego and Veterans Affairs San Diego Healthcare System; Shari Nicatia, UC San Diego, Veterans Affairs San Diego Healthcare System and Utrecht University; Carola Dewitz, UC San Diego, Veterans Affairs San Diego Healthcare System and University of Veterinary Medicine, Hannover, Germany; Denzil P. Mathew, Veterans Affairs San Diego Healthcare System; and Victor Nizet, UC San Diego.

This research was funded, in part, by the U.S. Department of Veterans Affairs.

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Scientists link unexplained childhood paralysis to eneterovirus D68


UCSF-led team rules out other pathogens with comprehensive sequencing.

By Laura Kurtzman, UC San Francisco

A research team led by UC San Francisco scientists has found the genetic signature of enterovirus D68 (EV-D68) in half of the California and Colorado children diagnosed with acute flaccid myelitis – sudden, unexplained muscle weakness and paralysis – between 2012 and 2014, with most cases occurring during a nationwide outbreak of severe respiratory illness from EV-D68 last fall.

The finding strengthens the association between EV-D68 infection and acute flaccid myelitis, which developed in only a small fraction of those who got sick. The scientists could not find any other pathogen capable of causing these symptoms, even after checking the cerebrospinal fluid for every known infectious agent.

Researchers analyzed the genetic sequences of EV-D68 in children with acute flaccid myelitis and discovered that they all corresponded to a new strain of the virus, designated strain B1, which emerged about four years ago and had mutations similar to those found in poliovirus and another closely related nerve-damaging virus, EV-D70. The B1 strain was the predominant circulating strain detected during the 2014 EV-D68 respiratory outbreak, and the researchers found it both in respiratory secretions and – for the first time – in a blood sample from one child as his acute paralytic illness was worsening.

The study also included a pair of siblings, both of whom were infected with genetically identical EV-D68 virus, yet only one of whom developed acute flaccid myelitis.

“This suggests that it’s not only the virus, but also patients’ individual biology that determines what disease they may present with” said Charles Chiu, M.D., Ph.D., an associate professor of Laboratory Medicine and director of UCSF-Abbott Viral Diagnostics and Discovery Center. “Given that none of the children have fully recovered, we urgently need to continue investigating this new strain of EV-D68 and its potential to cause acute flaccid myelitis.”

Among the 25 patients with acute flaccid myelitis in the study, 16 were from California and nine were from Colorado. Eleven were part of geographic clusters of children in Los Angeles and in Aurora, Colorado, who became symptomatic at the same time, and EV-D68 was detected in seven of these patients.

Although the researchers found EV-D68 in the children’s respiratory secretions and in the blood from one case, they did not find it in cerebrospinal fluid. The researchers said this may not be surprising given that other nerve-damaging viruses, like polio, are also extremely difficult to detect in cerebrospinal fluid.

Eighty percent of the children reported having an upper respiratory illness about six days, on average, before their acute flaccid myelitis symptoms began. Slightly more reported having a fever, including all of the cases from the clusters in California and Colorado.

Samples were collected more than a week after the children began showing symptoms of an upper respiratory infection, and this likely made it much harder to find EV-D68. There may also be other reasons to explain why the virus was not found in cerebrospinal fluid in children with neurological symptoms.

“The lack of detectable virus in CSF could also mean that the neurological symptoms are coming from an aberrant immune response to recent EV-D68 infection and not because the virus is directly invading neurons,” said Chiu, senior author on the paper published today (March 30) in The Lancet Infectious Diseases.

This study was supported by grants from the National Institutes of Health, a University of California Discovery Award, an Abbott Viral Discovery Award and the Centers for Disease Control and Prevention Emerging Infections Program.

Other authors include Alexander Greninger, M.D., Ph.D., Samia Naccache, Ph.D., Guixia Yu, B.S., Sneha Somasekar, B.S., Scot Federman, B.A., and Doug Stryke, B.S., of UCSF; Kevin Messacar, M.D., and Samuel Dominguez, M.D., Ph.D., of Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora; Anna Clayton, B.S., M.P.H., Christopher Anderson, B.S., Shigeo Yagi, Ph.D., Sharon Messenger, Ph.D., Debra Wadford, Ph.D., Dongxiang Xia, M.D., Ph.D., and Carol Glaser, D.V.M., M.D., of the California Department of Public Health; Keith Van Haren, M.D., of Lucile Packard Children’s Hospital at Stanford University; and Grace Aldrovandi, M.D., of Children’s Hospital Los Angeles and University of Southern California.

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New genetic method promises to advance gene research, control insect pests


In two years, molecular biologists have witnessed a revolution in genome manipulation.

A rare fruit fly in which the left half has been mutated by MCR (hence the pale color) while the right half remains normal. (Photo by Valentino Gantz, UC San Diego)

By Kim McDonald, UC San Diego

Biologists at UC San Diego have developed a new method for generating mutations in both copies of a gene in a single generation that could rapidly accelerate genetic research on diverse species and provide scientists with a powerful new tool to control insect-borne diseases such as malaria as well as animal and plant pests.

Their achievement was published today (March 19) in an advance online paper in the journal Science. It was accomplished by two biologists at UC San Diego working on the fruit fly Drosophila melanogaster who employed a new genomic technology to change how mutations could spread through a population — a concept long established in plants by the father of modern genetics, Gregor Mendel.

“Mendel conducted classic genetic experiments with peas that revealed the fundamental of inheritance in many organisms including humans,” explains Ethan Bier, a professor of biology at UC San Diego whose graduate student, Valentino Gantz, developed the method.  “According to these simple rules of inheritance, the fertilized egg receives one copy of most genes from our mothers and one from our fathers so that the resulting individual has two copies of each gene.”

One advantage of having two copies of a gene is that if one copy carries a non-functional mutation, then the other “good” copy typically can provide sufficient activity to sustain normal function.  Thus, most mutations resulting in loss of gene function are known as recessive, meaning that an organism must inherit two mutant copies of the gene from its parents before an overt defect is observed, as is the case in humans with muscular dystrophy, cystic fibrosis or Tay Sachs disease.

“Because individuals carrying a single mutant copy of a gene often mate with an individual with two normal copies of gene, defects can be hidden for a generation and then show up in the grandchildren,” Bier adds. “This is how genetics has been understood for over a century in diverse organisms including humans, most animals we are familiar with, and many plants.”

But in the past two years, Bier and other molecular biologists have witnessed a veritable revolution in genome manipulation.

“It is now routine to generate virtually any change in the genome of an organism of choice at will,” he notes. “The technology is based on a bacterial anti-viral defense mechanism known as the Cas9/CRISPR system.”

By employing this development in their experiments with laboratory fruit flies, Gantz and Bier demonstrated that by arranging the standard components of this anti-viral defense system in a novel configuration, a mutation generated on one copy of a chromosome in fruit flies spreads automatically to the other chromosome. The end result, Bier says, is that both copies of a gene could be inactivated “in a single shot.”

The two biologists call their new genetic method the “mutagenic chain reaction,” or MCR.

“MCR is remarkably active in all cells of the body with one result being that such mutations are transmitted to offspring via the germline with 95 percent efficiency,” says Gantz, the first author of the paper. “Thus, nearly all gametes of an MCR individual carry the mutation in contrast to a typical mutant carrier in which only half of the reproductive cells are mutant.”

Bier says “there are several profound consequences of MCR. First, the ability to mutate both copies of a gene in a single generation should greatly accelerate genetic research in diverse species. For example, to generate mutations in two genes at once in an organism is typically time consuming, because it requires two generations, and involved, because it requires genetic testing to identify rare progeny carrying both mutations. Now, one should simply be able to cross individuals harboring two different MCR mutants to each other and all their direct progeny should be mutant for both genes.”

“MCR should also be highly effective for dispersing genetic elements in populations to control insect borne diseases such as malaria, dengue and chikungunya as well as animal and plant pests,” he adds. “For example, in the case of malaria, several groups have created genetic cassettes that when introduced into mosquitoes prevent the malarial parasite from propagating thereby blocking infection. A major challenge in the field, however, has been devising a way to disseminate these gene cassettes throughout mosquito populations. MCR offers an obvious solution to this problem since the incorporation of an anti-malarial gene cassette into an MCR element should result in the rapid spread of the gene cassette through the target population. For example, if one in 100 individuals initially carried the cassette, the cassette should spread to virtually all individuals in as few as 10 generations, which is less than one season for mosquitoes.”

It also may be possible to use MCR to spread genes among cells within an individual using modified viruses to carry the genetic elements, Gantz points out. “Since MCR works by targeting specific DNA sequences, in cases where diseased cells have altered DNA as in HIV-infected individuals or some types of cancer, MCR-based methods should be able to distinguish diseased from healthy cells and then be used to selectively either destroy or modify the diseased cells.”

The two biologists note in their paper that while applications of MCR offer potential solutions to important problems in health and human welfare, it could also pose serious potential risks in the wrong hands.

“Could an accidental release of MCR-bearing organisms into the environment result in their spreading potentially deleterious mutation to the vast majority of individuals in a wild population?” says Bier. “We don’t know and would advocate that scientists examine this possibility before permitting experiments using the new method to be used in open laboratories. It is also possible that MCR technology could be intentionally misused, which should be considered as a risk on par with that associated with nefarious uses of select agents.”

Gantz and Bier showed in their experiments, which were conducted in a biosafety laboratory with a high-level of containment to prevent the accidental release of any deleterious mutant genotypes, that propagation of an MCR mutation in flies is remarkably efficient, with a gene conversion rate of about 95 percent.

As a consequence, the two researchers say stringent safety protocols for handling MCR organisms and the prompt establishment of regulatory guidelines for performing experiments with such organisms are imperative. “Development of methods for reversing MCR spread would also provide a means for mitigating risk,” says Gantz.

Bier concurs with others who have raised serious concerns about strategies to disperse genetic elements in pest populations that one other step needs to be taken by scientists. “In an analogy to the famous Asilomar conference concerns held to address concerns raised at the dawn of recombinant DNA technology in the 1970s,” he says, “perhaps a similar meeting should be convened to discuss how MCR technology should be regulated at both federal and institutional levels to assure that it is employed safely to achieve its full potential to ameliorate the human condition.”

The study was funded by two grants (R01 GM067247 and R56 NS029870) from the National Institutes of Health and a generous gift from Sarah Sandell and Michael Marshall. The UC San Diego Technology Transfer Office has applied for a patent to license the new technology.

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The path to eradicating Ebola


New technology helps UCSF volunteers continue to fight Ebola.

By Kathleen Masterson, UC San Francisco

The worst Ebola outbreak in history is not yet over.

While Ebola no longer dominating headlines and nightly newscasts, global health care workers remain in West Africa fighting the deadly virus and helping communities still reeling from the outbreak. More than 9,700 people have died of the disease since the epidemic emerged in December 2013, according to the World Health Organization.

For many on the frontlines, there’s also a bigger opportunity: leveraging the global outcry to improve health system infrastructure and disease surveillance in countries still trying to recover from decades of civil war.

Ebola response volunteers joined leading researchers at a Feb. 26 UC San Francisco town hall meeting to discuss the current state of the outbreak – and the path forward. The UCSF community also took the time to recognize the courageous work by volunteers who worked on the ground in West Africa, as well as those who ensured we were prepared for potential cases at UCSF Medical Center.

“It’s certainly fitting that Time magazine named Ebola responders as the persons of the year,” said Chancellor Sam Hawgood, M.B.B.S. “They certainly should be hailed as heroes, no question about that. So today I’d like to take a moment to recognize and show appreciation for more than 100 local and global UCSF responders to Ebola.”

Testing new Ebola diagnostic tools

Despite the containment of Ebola in some countries, volunteer responders are still needed in West Africa.

Sierra Leone and Guinea continue to face new Ebola cases and ongoing struggles with the virus, while the Ebola outbreak in Liberia appears to be contained, said George Rutherford, M.D., who serves as the director of the Global Health Sciences Prevention and Public Health Group and co-chair of the Chancellor’s Ebola Task Force.

“As of Feb. 18, 23,350 cases had been reported worldwide,” said Rutherford. “Currently Sierra Leone has substantially more cases than other countries.”

To that end, researchers and clinicians are testing and implementing a new rapid Ebola diagnostic field tool in Sierra Leone.

It’s a simple dipstick that tests a tiny prick of blood from a patient’s finger, giving results within minutes. The tool can be transported to remote clinics across the country, and requires no complex machinery other than refrigeration.

“It’s a game-changer,” said Dan Kelly, M.D. ”It will change the way we approach screening and triage with patients, and not just at Ebola treatment units but through all clinics, as well as potentially at schools and other facilities.”

Initial data suggest this dipstick tool is effective in screening for Ebola.

Kelly and responders investigated the point-of-care diagnostic tool in the field and plan to release this final level of validation testing before clinical use. Then, he will begin to evaluate the clinical outcomes, looking to answer such questions as: Does the result from the rapid diagnostic predict survival? Can its clinical use improve mortality rates?

Kelly has been working with Sierra Leonean medical staff to improve health infrastructure since he co-founded the Wellbody Alliance in 2006 with Mohamed Bailor Barrie, M.B.Ch.B., a Sierra Leonean doctor who is now a global health fellow at Harvard University.

Kelly, who is curently on leave to boost response efforts in Sierra Leone, is one of a dozen UCSF trainees and faculty members to respond to the outbreak in West Africa.

“Given the altruism of our faculty and staff, we have made a conscious decision to facilitate their involvement in providing care to patients in West Africa.” said Rutherford. “UCSF, in contrast to other North American academic medical centers, has been remarkably foresighted about the Ebola outbreak.”

Better diagnostics beyond Ebola

UCSF researchers are also working on diagnostic tools that could detect not only Ebola, but other causes of acute hemorrhagic fever that up until recently were more common than Ebola.

“We need tools in the field to not only diagnose Ebola, but also distinguish it from Lassa, malaria, typhoid and dengue,” said Charles Chiu, M.D., Ph.D., an infectious disease specialist who is working on validating the data from early prototypes of a comprehensive diagnostic test for hemorrhagic fever. Malaria is endemic in West Africa, and Lassa fever causes more than 300,000 cases in West Africa each year.

“These infections can all cause a similar clinical illness, and Ebola hemorrhagic fever actually presents more like flu in the early stages, so it’s critical to have a test that could be rapidly implemented once a person rolls into the clinic.”

Accurately identifying a person’s illness could curb the spread of an epidemic like Ebola, and help get the patient more quickly get the treatment he or she needs.

Beyond individual diagnosis, a test that can simultaneously test for eight different hemorrhagic fever diseases will be an invaluable tool for local, regional and global health surveillance, said Chiu.

“Once these surveillance measures are in place, they will help prevent this outbreak from spreading, because if we can curtail it early on, we can limit the disease to very few people,” said Chiu.

Creating lasting change in global response

Better disease surveillance is indeed a key part of building a stronger health care infrastructure – not just in West Africa, but for our a global community.

The flurry of international attention and the horror of the disease did serve to highlight how woefully unprepared some African countries and global health organizations are to manage an outbreak like this, said Eric Goosby, M.D., the director for Global Health Delivery and Diplomacy in UCSF Global Health Sciences.

“Up until now, strengthening the health system hasn’t been a high priority because it’s not sexy, but now I think it’s at the front of the discussion, and I hope we can keep it there.”

Goosby – former global AIDS coordinator for the Obama administration who recently was appointed the United Nations Special Envoy on Tuberculosis – has been closely involved in ongoing reforms at the World Health Organization, which he said has involved unusually frank discussions of its current efforts and how they can be realistically enhanced. Local and international officials are trying to understand what happened, what didn’t happen, who was in charge and how to put disease reporting mechanisms in place. It’s all led to difficult conversations among the highest levels at WHO and the UN, he said.

“I believe [these discussions] have generated a substantive move to understand the specifics, and to use our findings as opportunity to pivot into real solutions that will be laid in place over next few years,” said Goosby.

“I don’t believe it’s there by any means yet, but I’ve never seen the movement that has occurred before,” he said. “I’m quite optimistic.”

Helping on the homefront

Here are some ways the UCSF community rallied to help in the Ebola response, even without leaving the country.

  • As Ebola cases started being reported in the U.S., more than 100 UCSF Medical Center staff volunteered and went through training to serve in an Ebola Isolation Unit constructed at Mount Zion to handle potential cases. “It was heartwarming, how quick and easy it was to recruit for this position,” said Adrienne Green, M.D., associate chief medical officer at UCSF Medical Center.
  • UCSF created a “vacation bank” where employees could donate vacation time, so Ebola volunteers traveling to West Africa needn’t take unpaid leave. More than 2,000 hours have been donated. In one infectious diseases division, within an hour after an e-mail went out asking people to pitch in, two months’ worth of shifts had been filled.

To learn more about UCSF efforts, watch a replay of the Ebola town hall meeting here.

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Airport screening for viruses can be improved, says UCLA-led study


Current airport screening misses at least half of infected travelers, researchers find.

By Jennifer Mitchell, UCLA

In the past decade, the H1N1 virus and Ebola are just two of the diseases whose spread was spurred by international airline travel. Screening passengers at airports, therefore, could be one key method for slowing the global spread of infectious diseases.

And although a team lead by UCLA researchers has found that airport screening misses at least half of infected travelers, the scientists say that rate could be improved. Their research was published in eLife, a highly regarded open-access online science journal.

The life scientists used a mathematical model to analyze screening for six viruses: the SARS coronavirus, the Ebola virus, the Middle East respiratory syndrome coronavirus, the Marburg virus, Influenza H1N1 and Influenza H7N9.

“We found that for diseases with a long incubation period, such as Marburg and Ebola, taking passengers’ temperature to test for fever is particularly ineffective at the start of an epidemic but does pick up more cases as the epidemic stabilizes,” said Katelyn Gostic, a lead author of the study and a UCLA doctoral student in the laboratory of Professor James Lloyd-Smith. “With diseases such as swine flu, which take a shorter time to incubate, fever screening is the most effective method throughout an epidemic.”

Depending on the circumstances, airport workers conduct screenings before passengers board their flights, when they land at their destinations, or both. The researchers write that although fever screening on arrival has been criticized for being ineffective, it can catch cases that are missed before passengers’ flights depart. Screeners often use infrared non-contact thermometers to help identify sick passengers, but previous studies have shown that the devices identify fevers no more than 70 percent of the time, so the “double-check” of arriving passengers can help catch people who were missed before their departures.

Currently, traveler questionnaires are one of the tools screeners use — asking passengers, for example, whether they have been in contact with an infected individual (in the case of Ebola) or have handled live poultry (for viruses like avian influenza). The researchers write that screeners could more effectively identify sick passengers if those who create those questionnaires understand the risk factors for each disease, which would help them to better tailor the surveys.

The researchers found that no more than 25 percent of passengers answered honestly about whether they had been exposed to influenza during the 2009 pandemic, and that some may have hidden their symptoms by taking medication.

“Anyone who reports honestly puts himself or herself at risk of delay or detainment; this is a terrible incentive for truthful reporting,” Gostic said. “A high number of people use over-the-counter drugs like acetaminophen that conceal fevers and can make their symptoms undetectable, which is likely an overlooked problem.”

Lloyd-Smith, a UCLA associate professor of ecology and evolutionary biology and senior author of the research, said current screening programs can reduce the rate of importing infections, but nowhere close to zero.

“Even under the best-case scenarios we considered, arrival screening missed at least half of infected travelers for all pathogens,” he said. “Traveler screening by these methods is inherently leaky.”

The researchers identified ways to make current screening as effective as possible and highlighted how it can be improved.

“An important gap is that we have little direct data on the efficacy of departure screening,” Lloyd-Smith said. “This is needed to weigh the benefits of different screening policies and areas for investment. For example, in the current Ebola outbreak, how many potential travelers were turned away before boarding airplanes to depart West Africa? Of these, how many were actually Ebola cases? There is broad agreement that departure screening is probably more efficient than arrival screening, but we don’t actually have any examples where we know how well it worked in practice.”

In the paper, the researchers recommend cost-effectiveness studies that allow policy makers to assess the social and economic impact of screening policies at departure and arrival, but note that these studies will require more extensive data on the efficacy of current screening practices. They also recommend studies to quantify how many travelers are using fever-suppressing drugs, and evaluating the possible use of incentives to encourage honest reporting.

Adam Kucharski from the London School of Tropical Hygiene and Medicine was the study’s other co-author. The research was supported by the National Institutes of Health, the National Science Foundation and the Medical Research Council in the U.K.

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Increased risk found for toxoplasmosis


South American strains of parasite can cause infection even in hosts thought to be immune.

By James Leonard, UC Merced

A third of all humans carry the parasite that causes toxoplasmosis — a disease commonly associated with cats, HIV-AIDS patients and pregnant women — with scientists long believing healthy immune systems control the parasite and prevent the disease from emerging. But new research by professor Kirk Jensen of the University of California, Merced, shows the parasite might be more dangerous than previously believed.

In a paper published today (Feb. 24) in mBio — an open-access journal presented by the American Society for Microbiology — Jensen shows that secondary exposure to most parasite strains found in South America can lead to uncontrolled infection and disease, which in humans can cause severe congenital infection or lesions in the retina and brain.

“There are a few strains of the Toxoplasma parasite present in North America and Europe, but in South America, there are many strains,” said Jensen, a professor in the university’s School of Natural Sciences. “We found these South American strains are really good at evading the immune system.”

After an initial infection, the immune system is typically primed and ready to protect against repeat offenses by the same parasite or disease. This is how vaccines protect humans from infectious diseases like measles. However, Jensen said, “There are known cases where pregnant women who were seropositive — and therefore should have been protected from toxoplasmosis — developed congenital infection following travel to South America.”

Toxoplasma is a pathogen that is acquired orally, typically by eating undercooked meat or through interaction with cat feces, such as through garden soil contaminated by stray cats. According to the Centers for Disease Control, more than 60 million people in the U.S. carry the Toxoplasma parasite, but few develop toxoplasmosis because of the immune system’s response.

Pregnant women and those with compromised immune systems, however, are much more prone to toxoplasmosis, which is considered to be a leading cause of death attributed to foodborne illness in the United States. The CDC has targeted toxoplasmosis as a “Neglected Parasitic Infection” requiring public health action.

Jensen said that in a person with a healthy immune system, the single-cell Toxoplasma parasite is blocked from replicating by T-cells. But the more virulent South American parasites can evade T-cells by injecting specialized “antagonizers” into cells. The body begins to create too many active T-cells, which can kill the host by causing excessive inflammation, so it turns off its own immune response. This allows the parasite to further replicate and toxoplasmosis to take hold.

Now that he’s found secondary toxoplasmosis infection is possible, Jensen said the next step is to prevent the immune system from shutting down its response to the parasite — but to do so without putting the infected host in danger. A similar approach has been used to successfully stop the spread of cancer in melanoma patients, he said.

“You’re basically telling the immune system to respond against its will, but you have to do that without going too far,” he said. “Right now, the big thing in the news is cancer immune therapy — telling the immune system to turn itself back on and attack the cancer. Why not try that for Toxoplasma, or for other dangerous pathogens that we cannot vaccinate against or easily treat?”

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Small loop in human prion protein prevents chronic wasting disease


UC San Diego-led finding provides new therapeutic target for prion diseases.

Prion protein aggregates (brown) in the brain of a mouse expressing the human-elk protein.

By Heather Buschman, UC San Diego

Chronic wasting disease (CWD) — an infectious disease caused by prions — affects North American elk and deer, but has not been observed in humans. Using a mouse model that expresses an altered form of the normal human prion protein, researchers at the UC San Diego School of Medicine have determined why the human proteins aren’t corrupted when exposed to the elk prions. Their study, published today (Feb. 23) in the Journal of Clinical Investigation, identifies a small loop in the human prion protein that confers resistance to chronic wasting disease.

“Since the loop has been found to be a key segment in prion protein aggregation, this site could be targeted for the development of new therapeutics designed to block prion conversion,” said Christina Sigurdson, D.V.M., Ph.D., associate professor at UC San Diego and UC Davis and senior author of the study.

Prions aren’t microorganisms like bacteria or viruses; they’re simply protein aggregates. Some prion diseases are caused by an inherited genetic mutation, while others are caused by exposure to infectious prions in food. Acquired prion diseases are triggered when a foreign, misfolded prion protein causes the body’s own natural prion proteins to misfold and aggregate. In addition to chronic wasting disease, examples include scrapie and bovine spongiform encephalopathy (or “mad cow disease”) in animals and variant Creutzfeldt-Jakob disease in humans. In humans, prion diseases can cause a variety of rapidly progressive neurological symptoms, such as difficulty walking and speaking, and dementia. These diseases are 100 percent fatal and there is currently no effective treatment.

“We suspected that a loop in the human prion protein structure may block the elk prions from binding, as the sequences did not appear to be compatible,” Sigurdson said.

To test this hypothesis, Sigurdson and her team developed a transgenic mouse that expresses a prion protein that’s identical to the human version — except for a small loop, which they swapped out for the elk prion sequence. When these mice were exposed to the elk prions, they developed chronic wasting disease.

In contrast, control mice expressing the normal human prion sequence resisted infection when exposed to the same materials — just as humans seem to, even those who consume venison meat.

“This finding suggests that the loop structure is crucial to prion conversion and that sequence compatibility with the host prion protein at this site is required for the transmission of certain prion diseases,” Sigurdson said.

Co-authors of this study include Timothy D. Kurt, Cyrus Bett, Jun Liu, Tom Yang, UC San Diego; Lin Jiang, David Eisenberg, UCLA and Howard Hughes Medical Institute; Natalia Fernández-Borges, CIC bioGUNE, Spain; Terry R. Spraker, Colorado State University, Fort Collins; Joaquín Castilla, CIC bioGUNE and Basque Foundation for Science, Spain; and Qingzhong Kong, Case Western Reserve University.

This research was funded, in part, by the National Institutes of Health (grants NS055116, NS069566, U54AI0359 and AG029430), national grants from Spain and the Morris Animal Foundation.

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UC Davis student diagnosed with meningococcal disease


Student is receiving medical care and treatment at a local hospital.

(Updated Feb. 25: University and Yolo County Public Health officials say the student with meningococcal disease is recovering. The officials added that they had contacted people who had been in close contact with the student, so that they could arrange preventive medication for them. Read more, including the strain of meningococcal bacteria in this case.)

By Andy Fell, UC Davis

A student who attends the University of California, Davis, has been diagnosed with meningococcal disease, a bacterial infection that can cause bloodstream infections and meningitis, the university and public health officials said today (Feb. 23).

The student is receiving medical care and treatment at a local hospital.

UC Davis and Yolo County Public Health teams are investigating the case, providing preventive antibiotics to contacts where indicated, and educating the university community about meningococcal disease. Close contacts of meningococcal cases who are recommended to receive preventive antibiotics include people who were exposed to the ill person’s respiratory and throat secretions through living in close quarters, or kissing or other prolonged close contact.

University and county health officials are identifying people who had close contact with the student and recommending antibiotics to protect them from becoming ill. Officials are not recommending antibiotic prophylaxis for community members or UC Davis students in general. Prophylaxis is recommended for people specifically identified as close contacts of the ill student.

Meningococcal disease signs and symptoms, which are sometimes mistaken for those of flu early in the course of illness, can include:

  • High fever
  • Severe headache
  • Rash
  • Body aches/joint pain
  • Nausea/vomiting
  • Increased sensitivity to light
  • Confusion

Anyone with the signs or symptoms of meningococcal disease should seek medical care immediately. Early treatment of meningococcal disease is critical as the infection can quickly become life threatening.

Students with questions or any of the above symptoms should contact: UC Davis Student Health and Counseling Services’ Advice Nurse Line, (530) 752-2349.

Parents, family members and the general public with questions or concerns should contact: Student Health and Counseling Services’ Directors Office, (530) 752-2333.

Covering coughs, keeping hands clean and being up to date with recommended vaccines, especially flu vaccine this time of year, are actions everyone can take to stay healthy, protect themselves from illness and prevent the spread of infections to others.

Media contacts:
Beth Gabor
Public affairs manager
Yolo County
(530) 666-8042
beth.gabor@yolocounty.org

Andy Fell
UC Davis News Service
(530) 752-4533
ahfell@ucdavis.edu

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Malaria vaccine candidate produced from algae


Cheap, green technique advances efforts toward malaria transmission vaccine in humans.

Algae technique used to produce candidate vaccine that prevents transmission of the malaria parasite from host to mosquito.

By Heather Buschman, UC San Diego

Researchers at the UC San Diego School of Medicine used algae as a mini-factory to produce a malaria parasite protein. The algae-produced protein, paired with an immune-boosting cocktail suitable for use in humans, generated antibodies in mice that nearly eliminated mosquito infection by the malaria parasite. The method, published Feb. 17 by Infection and Immunity, is the newest attempt to develop a vaccine that prevents transmission of the malaria parasite from host to mosquito.

“Most malaria vaccine approaches are aimed at preventing humans from becoming infected when bitten by mosquitos that carry the parasite,” said Joseph M. Vinetz, M.D., professor of medicine and senior author of the study. “Our approach is to prevent transmission of the malaria parasite from infected humans to mosquitoes. This approach is similar to that of the current measles vaccine, which is such a hot topic of discussion these days, because the goal is to generate herd immunity in a population. We think that this approach is key to global malaria elimination, too.”

To do this, Vinetz and team wanted to produce a large quantity of properly folded Pfs25, a protein found on the surface of the malaria parasite’s reproductive cells, which are only present within the mosquito’s gut after it feeds on a malaria-infected blood meal. Since antibodies against Pfs25 can halt the parasite’s lifecycle in the mosquito, they might also block transmission of the parasite to the next host.

However, properly folded Pfs25 that induces transmission-blocking antibodies has been difficult to produce in the lab. To overcome this problem, researchers turned to an algae better known for its ability to produce sustainable biofuels. They introduced the Pfs25 gene into the algae by shooting the DNA into the plant cell’s nucleus. Then, after they let the algae do the work of replicating, building and folding the protein, the team was able to purify enough functional Pfs25 for laboratory testing.

Besides its effectiveness as a protein producer, algae is an advantageous tool for developing vaccines because it’s cheap, easy and environmentally friendly. The only requirement is simple chemical nutrients to feed the algae, which can be grown in plastic bags and easily scaled up to produce large quantities of desired proteins.

Vinetz and collaborators at the Infectious Disease Research Institute in Seattle also tested several new adjuvants, molecules that help stimulate the immune system’s response to Pfs25. The best Pfs25/adjuvant combination elicited a uniquely robust antibody response in mice with high affinity and avidity — antibodies that specifically and strongly reacted with the malaria parasite’s reproductive cells.

Mosquitos were fed malaria parasites in the presence of control serum or immune serum collected from mice vaccinated with algae-produced Pfs25 in the presence of the new adjuvant. Eight days later, the researchers examined the mosquitos’ guts for the presence of the malaria parasite.

The results were dramatic: only one of 24 mosquitos (4.2 percent) that consumed the Pfs25/adjuvant-treated mouse serum was positive for the malaria parasite. That’s compared to the 28 infected mosquitoes out of the 40 in the control group (70 percent).

“We are really excited to see that Pfs25 produced by algae can effectively prevent malaria parasites from developing within the mosquito,” said study co-author Stephen P. Mayfield, Ph.D., professor of biological sciences and director of the California Center for Algae Biotechnology at UC San Diego. “With the low cost of algal production, this may be the only system that can make an economic malaria vaccine. Now we’re looking forward to comparing algae-produced Pfs25 and adjuvant head-to-head against other approaches to malaria vaccine production and administration.”

Malaria is the leading cause of death and disease in many developing countries. In 2012, there were approximately 207 million cases of malaria infection worldwide. Young children and pregnant women are most affected by the disease.

Co-authors of this study also include Kailash P. Patra, Fengwu Li, Sheyenne Baga, UC San Diego; Darrick Carter, Steven G. Reed, Infectious Disease Research Institute; and James A. Gregory, formerly at UC San Diego Division of Biological Sciences, currently at Icahn School of Medicine at Mount Sinai.

This research was funded, in part, by the National Institutes of Health (grants U19AI089681, 1R01AI067727, K24AI068903, D43TW007120 and P30NS047101), U.S. Public Health Service, U.S. Department of Energy, San Diego Foundation, California Energy Commission and Bill and Melinda Gates Foundation.

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UCSF expert appointed UN Special Envoy on Tuberculosis


Drug-resistant TB poses threat to global health security.

Eric Goosby, UC San Francisco

By Laura Kurtzman, UC San Francisco

UC San Francisco’s Eric Goosby, M.D., who led the Obama administration’s efforts on HIV/AIDS, has been appointed to a new position as United Nations Special Envoy on Tuberculosis. He will remain at UCSF while he takes on his new duties with the UN.

Goosby’s appointment comes amid an epidemic of drug-resistant forms of TB that is posing a significant threat to global health security. Every year, nearly 9 million people become ill with TB, which has long been among the world’s top killers, and about 1.5 million die. A third of those with TB also have HIV, and TB is a leading cause of death for HIV-positive people.

New technology can rapidly diagnose drug-resistant strains of TB, even in remote and poorly equipped clinics, so patients do not waste time taking ineffective drugs. But curing these patients requires a long and arduous therapeutic regimen, which is difficult to sustain, especially in the low-income countries where the vast majority of infections are occurring.

“We know how to prevent, diagnose, treat and cure TB, but many programs have not yet been able to implement the effective measures that identify, enter and retain people in care for the time that is needed to give them a cure,” Goosby said.

Goosby, who attended medical school and did his residency and fellowship at UCSF, was ambassador-at-large and global AIDS coordinator from 2009 to 2013 in the Obama administration. He returned to UCSF in 2013 as a professor in the Department of Medicine and in Global Health Sciences, where he is the director for Global Health Delivery and Diplomacy.

“I will engage in international dialogue around direction and resource allocation for TB and HIV/AIDS, two of the largest killers on the planet, which is a core mission of UCSF Global Health Sciences,” he said. “UCSF affords a wonderful platform that combines the basic sciences with clinical and public health knowledge. Faculty members here have been leaders globally for years. I hope to amplify and catalyze more involvement from UCSF faculty.”

As UN envoy, Goosby will encourage countries to adopt and implement the World Health Organization’s global End TB Strategy after 2015, and its international targets for tuberculosis prevention, care and control, while also pursuing the tuberculosis targets outlined in the Millennium Development Goals.

“Eric will be fundamental to our efforts to promote the new WHO global strategy with member states, donors and all stakeholders,” said Dr Hiroki Nakatani, assistant director-general at the WHO. “His profound knowledge of global health challenges, the AIDS epidemic and the fight against TB will be a tremendous asset for our work and will make the difference. WHO is enthusiastic about this appointment.”

He will work closely with the World Health Organization to carry out the ambitious new targets agreed to at last year’s World Health Assembly: to reduce TB deaths by 95 percent and cut new cases by 90 percent by 2035.

In his new role, Goosby expects to focus on both TB and HIV/AIDS, an important driver of the tuberculosis epidemic, especially in Africa, which has 80 percent of the HIV-associated TB patients around the world.

He will focus on identifying and expanding the best TB programs, while improving those already in place. Although the science of how to treat TB is well established, little is known about what interventions work best in the real world.

Michel Sidibé, executive director of UNAIDS, worked with Goosby when he was head of the President’s Emergency Plan for AIDS Relief (PEPFAR) to cut the number of HIV infections among children by almost half in 21 countries. He said Goosby brings a wealth of practical experience to his new role.

“Dr. Goosby’s knowledge and experience working on HIV and TB, together with his dynamic and committed leadership, will further strengthen our collaboration and bring us closer to ending the dual epidemics of HIV and TB,” Sidibé said.

Through interdisciplinary education, service and research programs, Global Health Sciences harnesses UCSF’s scientific strengths to train global health leaders and develop solutions to today’s toughest health challenges. GHS faculty, staff and students are on the cutting edge of research, treatment, public health practice and policy development for HIV/AIDS, malaria, tuberculosis, neglected tropical diseases, immunizations, women’s reproductive and children’s health, and other conditions that have a devastating impact both globally and locally. They work in more than 50 countries and partner with academic centers, international organizations, ministries of health and private industries to improve the health of vulnerable populations.

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Forecasting the flu better


Combination of ‘big’ and traditional data improves power of prediction.

By Inga Kiderra, UC San Diego

Three UC San Diego researchers say they can predict the spread of flu a week into the future with as much accuracy as Google Flu Trends can display levels of infection right now.

The study – appearing in Scientific Reports, an online journal from the publishers of Nature – uses social network analysis and combines the power of Google Flu Trends’ “big data” with traditional flu monitoring data from the U.S. Centers for Disease Control and Prevention (CDC).

“Our innovation,” said corresponding author Michael Davidson, a doctoral student in political science at UC San Diego, “is to construct a network of ties between different U.S. health regions based on information from the CDC. We asked: Which places in years past got the flu at about the same time? That told us which regions of the country have the strongest ties, or connections, and gave us the analytic power to improve Google’s predictions.”

Google Flu Trends (GFT) is very good, Davidson said, at showing where in the U.S. people are searching for information on flu and flu-like symptoms. And these data are valuable because they come in real time, he said, about two weeks ahead of when the CDC can issue its reports. But GFT has also made some infamous errors – errors that probably reflect widespread public concerns about flu more than actual confirmed illness.

By weighting GFT predictions with a social network derived from CDC reports on laboratory-tested cases of flu, the researchers were able to refine and improve GFT’s predictions.

The researchers are optimistic their work will soon be put to public use. “We hope our method will be implemented by epidemiologists and data scientists,” Davidson said, “to better target prevention and treatment efforts, especially during epidemics.”

Davidson’s co-authors are Dotan A. Haim, who is also a political science graduate student at UC San Diego, and Jennifer M. Radin, of the UC San Diego/San Diego State University Joint Doctoral Program in Public Health.

The study was funded in part by the Robert Wood Johnson Foundation and the James S. McDonnell Foundation.

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