TAG: "Infectious disease"

Gel filled with nanosponges cleans up MRSA infections


Nanosponge-hydrogel minimizes growth of skin lesions on mice infected with MRSA.

oxin-absorbing nanoparticles are loaded into a holding gel to make a nanosponge-hydrogel, which can potentially treat local bacterial infections.

By Liezel Labios, UC San Diego

Nanoengineers at UC San Diego developed a gel filled with toxin-absorbing nanosponges that could lead to an effective treatment for skin and wound infections caused by MRSA (methicillin-resistant Staphylococcus aureus), an antibiotic-resistant bacteria. This nanosponge-hydrogel minimized the growth of skin lesions on mice infected with MRSA – without the use of antibiotics. The researchers recently published their findings online in Advanced Materials.

To make the nanosponge-hydrogel, the team mixed nanosponges, which are nanoparticles that absorb dangerous toxins produced by MRSA, E. coli and other antibiotic-resistant bacteria, into a hydrogel, which is a gel made of water and polymers. The hydrogel holds the nanosponges in place so that they can remove toxins at the infected spot.

“We combined the strengths of two different materials – nanosponges and hydrogels – to create a powerful formulation to treat local bacterial infections,” said Liangfang Zhang, nanoengineering professor in the Jacobs School of Engineering at UC San Diego, who led the team. “Nanosponges alone are difficult to use on local tissues because they diffuse away to other parts of the body very quickly. By integrating the nanosponges into a hydrogel, we can retain them at the site of infection.”

Since the nanosponge-hydrogel treatment does not involve antibiotics, the researchers say that it will not likely be affected by existing bacterial antibiotic resistance. Also, because antibiotics are not involved, the treatment will likely not cause bacteria to develop new resistance.

This work is a follow-up to a study that the team presented in Nature Nanotechnology in 2013. The previous study showed that nanosponges absorbed harmful bacterial toxins in the bloodstream and drew them away from their real targets: red blood cells. In this new study, the team reports that removing bacterial toxins could potentially lead to clearing up antibiotic-resistant bacterial infections.

“One way to treat these infections is to remove the toxins, which act as a weapon and a defense shield for the bacteria that produce them,” said Zhang. “We hypothesize that without the toxins, the bacteria become significantly weakened and exposed, allowing the body’s immune system to kill them more easily without the use of drugs.”

Nanosponge-hydrogel treatment

How does the nanosponge-hydrogel treatment work? Each nanosponge is a nanoparticle coated in a red blood cell membrane. This coating disguises the nanosponges as red blood cells, which are the real targets of the harmful toxins produced by MRSA. By masquerading as red blood cells, the nanosponges attract harmful toxins and remove them from the bloodstream. In order for the nanosponges to remove toxins from a specific spot, such as an infected skin wound, a lot of them need to be held at that spot. This is where the hydrogel plays a role; it can hold billions of nanosponges per milliliter in one spot. The hydrogel’s pores are also small enough to keep most of the nanosponges from escaping, but big enough so that toxins can easily get inside and attach to the nanosponges.

The researchers showed that the nanosponge-hydrogel treatment kept down the size of skin lesions caused by MRSA infections. In mice, the skin lesions that were treated with the nanosponge-hydrogel were significantly smaller than those that were left untreated.

“After injecting the nanosponge-hydrogel at the infected spot, we observed that it absorbed the toxins secreted by the bacteria and prevented further damage to the local blood, skin and muscle tissues,” said Zhang.

The team also showed that the hydrogel was effective at holding the nanosponges in place within the body. Two days after the nanosponge-hydrogel was injected underneath the skin of a mouse, nearly 80 percent of the nanosponges were still found at the injection site. When nanosponges were injected without the hydrogel, only 20 percent of them remained at the injection site after two hours. Most of them diffused to the surrounding tissues.

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

Journal reference:

Fei Wang, Weiwei Gao, Soracha Thamphiwatana, Brian T. Luk, Pavimol Angsantikul, Qiangzhe Zhang, Che-Ming J. Hu, Ronnie H. Fang, Jonathan A. Copp, Dissaya Pornpattananangkul, Weiyue Lu and Liangfang Zhang. “Hydrogel Retaining Toxin-Absorbing Nanosponges for Local Treatment of Methicillin-Resistant Staphylococcus aureus Infection.” Advanced Materials 2015. DOI: 10.1002/adma.201501071

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Researchers reverse bacterial resistance to antibiotics


UC Merced, American University professors show how to restore efficacy of antibiotics.

Miriam Barlow, UC Merced

By James Leonard, UC Merced

The rise of antibiotic-resistant bacteria is a growing problem in the United States and the world. New findings by researchers in evolutionary biology and mathematics could help doctors better address the problem in a clinical setting.

Biologist Miriam Barlow of the University of California, Merced, and mathematician Kristina Crona of American University tested and found a way to return bacteria to a pre-resistant state. In research published in the open-access journal PLOS ONE, they show how to rewind the evolution of bacteria and verify treatment options for a family of 15 antibiotics used to fight common infections, including penicillin.

Their work could have major implications for doctors attempting to keep patient infections at bay using “antibiotic cycling,” in which a handful of different antibiotics are used on a rotating basis.

“Doctors don’t take an ordered approach when they rotate antibiotics,” Barlow said. “The doctors would benefit from a system of rotation that is proven. Our goal was to find a precise, ordered schedule of antibiotics that doctors could rely on and know that in the end, resistance will be reversed, and an antibiotic will work.”

Dangers of antibiotic resistance

When bacteria grow powerful enough that antibiotics no longer work, it can be a matter of life and death. Recently, at the Ronald Reagan UCLA Medical Center, two people died and seven were injured when a medical scope used in patient procedures harbored drug-resistant bacteria. In the U.S. annually, more than 2 million people get infections that are resistant to antibiotics and at least 23,000 people die as a result, according to the Centers for Disease Control and Prevention.

Resistance to antibiotics is a natural part of the evolution of bacteria, and unavoidable given the many types of bacteria and the susceptibility of the human host. To compensate for bacterial evolution, a doctor fighting infections in an intensive care unit may reduce, rotate or discontinue different antibiotics to get them to be effective in the short term.

The researchers — from UC Merced, AU and UC Berkeley — have been leading the way to uncover how to reverse resistance in the drug environment. They’ve done so by combining lab work with mathematics and computer technology.

“We have learned so much about the human genome as well as the sequencing of bacteria,” Crona said. “Scientists now have lots and lots of data, but they need to make sense of it. Mathematics helps one to draw interpretations, find patterns and give insight into medical applications.”

Challenging work yields important results

After creating bacteria in a lab, the researchers exposed them to 15 different antibiotics and measured their growth rates. From there, they computed the probability of mutations to return the bacteria to its harmless state using the aptly named “Time Machine” software.

Managing resistance in any drug environment is extremely difficult, because bacteria evolve so quickly, becoming highly resistant after many mutations. To find optimal cycling strategies, the researchers tested up to six drugs in rotation at a time and found optimal plans for reversing the evolution of drug-resistant bacteria.

“This shows antibiotics cycling works. As a medical application, physicians can take a more strategic approach,” Crona said. “Uncovering optimal plans in antibiotics cycling presents a mathematical challenge. Mathematicians will need to create algorithms that can decipher optimal plans for a greater amount of antibiotics and bacteria.”

The researchers hope to next test the treatment paths in a clinical setting, working with doctors to rotate antibiotics to maximize their efficacy.

“This work shows that there is still hope for antibiotics if we use them intelligently,” Barlow said. “More research in this area and more research funding would make it possible to explore the options more comprehensively.”

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Smartphone video microscope automates parasite detection in blood


UC Berkeley’s CellScope technology could help efforts to eradicate filarial diseases.

By Sarah Yang, UC Berkeley

A research team led by UC Berkeley engineers has developed a new smartphone microscope that uses video to automatically detect and quantify infection by parasitic worms in a drop of blood. This next generation of UC Berkeley’s CellScope technology could help revive efforts to eradicate debilitating filarial diseases in Africa by providing critical information to health providers in the field.

“We previously showed that mobile phones can be used for microscopy, but this is the first device that combines the imaging technology with hardware and software automation to create a complete diagnostic solution,” said Daniel Fletcher, an associate chair and professor of bioengineering, whose UC Berkeley lab pioneered the CellScope. “The video CellScope provides accurate, fast results that enable health workers to make potentially life-saving treatment decisions in the field.”

The UC Berkeley engineers teamed up with Dr. Thomas Nutman from the National Institute of Allergy and Infectious Diseases (NIAID), and collaborators from Cameroon and France to develop the device. They conducted a pilot study in Cameroon, where health officials have been battling the parasitic worm diseases onchocerciasis (river blindness) and lymphatic filariasis.

The video CellScope, which uses motion instead of molecular markers or fluorescent stains to detect the movement of worms, was as accurate as conventional screening methods, the researchers found. The results of the pilot study are reported today (May 6) in the journal Science Translational Medicine.

“This research is addressing neglected tropical diseases,” said Fletcher. “It demonstrates what technology can do to help fill a void for populations that are suffering from terrible, but treatable, diseases.”

Battling parasitic worms

River blindness is transmitted through the bite of blackflies and is the second-leading cause of infectious blindness worldwide. Lymphatic filariasis, spread by mosquitoes, leads to elephantiasis, a condition marked by painful, disfiguring swelling. It is the second-leading cause of disability worldwide and, like river blindness, is highly endemic in certain regions in Africa.

The antiparasitic drug ivermectin, or IVM, can be used to treat these diseases, but mass public health campaigns to administer the medication have been stalled because of potentially fatal side effects for patients co-infected with Loa loa, which causes loiasis, or African eye worm. When there are high circulating levels of microscopic Loa loa worms in a patient, treatment with IVM can potentially lead to severe or fatal brain or other neurologic damage.

The standard method of screening for levels of Loa loa involves trained technicians manually counting the worms in a blood smear using conventional laboratory microscopes, making the process impractical for use in field settings and in mass campaigns to administer IVM.

The serious side effects of Loa loa and the difficulty of rapidly quantifying Loa levels in patients before treatment make it too risky to broadly administer IVM, representing a major setback in the efforts to eradicate river blindness and elephantiasis.

Next generation CellScope uses video, automation

For this latest generation of the mobile phone microscope, named CellScope Loa, the researchers paired a smartphone with a 3-D-printed plastic base where the sample of blood is positioned. The base included LED lights, microcontrollers, gears, circuitry and a USB port.

Control of the device is automated through an app the researchers developed for this purpose. With a single touch of the screen by the health care worker, the phone communicates wirelessly via Bluetooth to controllers in the base to process and analyze the sample of blood. Gears move the sample in front of the camera, and an algorithm automatically analyzes the telltale “wriggling” motion of the worms in video captured by the phone. The worm count is then displayed on the screen.

Fletcher said previous field tests revealed that automation helped reduce the rate of human error. The procedure takes about two minutes or less, starting from the time the sample is inserted to the display of the results. Pricking a finger and loading the blood onto the capillary adds another minute to the time.

The short processing time allows health workers to quickly determine on site whether it is safe to administer IVM.

“The availability of a point-of-care test prior to drug treatment is a major advance in the control of these debilitating diseases,” said aquatic ecologist Vincent Resh, a professor in UC Berkeley’s Department of Environmental Science, Policy and Management. “The research offering a phone-based app is ingenious, practical and highly needed.”

Resh, who is not involved in the CellScope project, has worked in West Africa for 15 years on the control of onchocerciasis.

The researchers are now expanding the study of CellScope Loa to about 40,000 people in Cameroon.

Co-lead authors of the study are Michael D’Ambrosio, UC Berkeley research scientist in bioengineering, and Matthew Bakalar, UC Berkeley graduate student in bioengineering. Other study authors included researchers from the University of Yaoundé in Cameroon and the University of Montpellier in France.

The Bill and Melinda Gates Foundation, UC Berkeley Blum Center for Developing Economies, U.S. Agency for International Development and NIAID helped support this work. The NIAID is part of the National Institutes of Health.

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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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