TAG: "Infectious disease"

Scientists engineer antibiotics to catch up in race against drug resistance


Souped-up antibiotics attack cells responsible for making bacteria resistant to new drugs.

We face an urgent global health problem because scientists are not developing new antibiotics as fast as bacteria are developing antibiotic resistance.

But new research from UCLA has made important progress toward solving this problem. An interdisciplinary team of scientists from UCLA’s California NanoSystems Institute has developed a method to re-engineer antibiotics that sharply enhances their activity against certain key bacterial cells, called persisters, that are responsible for making bacteria resistant to new drugs.

Persister cells slow down their metabolism and shut down their mechanisms for taking in molecules, preventing normal antibiotics from getting into them, which is necessary for the drug to kill the bug. After the persister cells survive the initial antibiotic treatment, they pass on their genes as the bacteria reproduce.

Led by Gerard Wong, professor in the UCLA Department of Chemistry and Biochemistry and the Department of Bioengineering, and Andrea Kasko, associate professor of bioengineering, the team has developed a method analogous to taking an ordinary car and adding high-performance parts to make a fast and furious street racer.

“We’re in an unsustainable race with bacteria. They become resistant to our antimicrobials too fast,” Wong said. “It takes upwards of $100 million to develop one antibiotic drug, and bacteria develop resistance to it within two years. It’s a race that we can’t win. This reality brought us to the idea of taking an existing antibiotic and renovating it, giving it a new, complementary antimicrobial ability while preserving its original ability to make a better drug overall.”

The study was published Aug. 18 online in the journal ACS Nano.

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Ionic liquids can aid in speedy wound healing


They can disrupt biofilms with virtually no irritation, inflammation of already damaged tissue.

Ionic liquids have been found to disrupt microbial biofilms, aiding in speedy wound healing with virtually no inflammation and irritation. (Illustration by Peter Allen)

Microbial biofilms are the bane of chronic wound sufferers and wound care specialists around the world. Colonies of various microorganisms that are embedded in a protective matrix, microbial biofilms adhere to a surface — often the skin — and impair the healing process.

Affixed to each other by self-produced secretions of polysaccharides, proteins and other substances, and shielded by these secretions and the outermost layer of skin under which they often form, these microbes are able to resist antibiotics and continue to prey on the tissue beneath. The results are wounds that are slow to heal, or continue to reappear. It’s a circumstance both painful and expensive: In the United States last year, up to $75 billion was spent for the treatment of recurring and resistant wounds.

At UC Santa Barbara, researchers at the campus’s Center for BioEngineering (CBE) and the Department of Chemical Engineering have found that ionic liquids (IL), a known class of materials, can not only disrupt these biofilms, which increases the effectiveness of accompanying antibiotics, they can do so with virtually no irritation and inflammation of the already damaged tissue. Furthermore, their findings indicate that some ionic liquids, even without the use of antibiotics, are often capable of neutralizing pathogens. Their results are published in the Proceedings of the National Academy of the Sciences.

“The challenge was how to find a chemical, or a composition of chemicals, that are toxic to bacteria — they disrupt the biofilm and enhance the transport of antibiotic drugs — but do not kill the healthy mammalian cells or cause inflammation to the skin,” said CBE Director Samir Mitragotri, senior author of the paper, who specializes in targeted drug delivery.

Ionic liquids are essentially salts — pairings of positively charged cations and negatively charged anions — that exist in liquid form under 100 degrees Celsius. These liquids have been known to scientists for over a century and are used in various applications, from solvents to additives to electrolytes.

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Veterinary scientists serving on the Ebola frontline


UC Davis alums working for CDC in Sierra Leone.

Kim Dodd at the entrance to the "hot lab" wearing the associated personal protective equipment.

As Sierra Leone enters a three-day, house-to-house campaign in an effort to slow the spread of Ebola virus, two veterinary scientists working for the Centers for Disease Control and Prevention (CDC) who received their Ph.D. and D.V.M. degrees from the UC Davis School of Veterinary Medicine will stay in the field, on the front lines in battling the largest Ebola outbreak since the deadly virus was identified in 1976.

Kim Dodd, a current UC Davis combined degree student (Ph.D. ‘14, DVM ‘15), joined her mentor and UC Davis alum Brian Bird in Sierra Leone in early September. Bird (Ph.D. ’08, DVM ‘09) serves as a veterinary medical officer in the Viral Special Pathogens Branch of the CDC and is now the lead of the CDC Ebola Field-Laboratory located at an Ebola Treatment Unit in Kenema, Sierra Leone.  This field-laboratory supports the international response to this unprecedented outbreak in partnership with the Sierra Leone Ministry of Health, the World Health Organization (WHO) and other international collaborators. The laboratory serves as a regional reference laboratory to provide rapid Ebola testing.

According to the latest data from the WHO, the current outbreak in West Africa encompasses five countries with more than 5,000 cases identified and 2,630 deaths to date, more people than the last 38 years combined. Veterinary scientists such as Dodd and Bird comprise a critical role in conducting the laboratory testing to identify cases so that rapid tracing of patient-contacts can begin and to reduce the transmission of Ebola within the population.

Bird and the CDC stress the importance of early and rapid testing, as the initial clinical signs of Ebola virus infection can be nonspecific and similar to those seen with malaria, lassa fever, or other tropical diseases. It is therefore critical to rapidly identify positive cases for referral to Ebola treatment centers, and to send negative cases elsewhere for treatment and follow-up, in order to reduce community transmission and control the outbreak.

Professor James MacLachlan, their mentor at UC Davis, says veterinary researchers like Dodd and Bird with the joint skillset of a D.V.M. and Ph.D. are invaluable in dealing with One Health situations like this Ebola outbreak where emerging and zoonotic diseases have such a devastating impact on global health.

“These two remarkable individuals now are on the front line of this exceptionally brutal disease outbreak – what an example for what a veterinary degree can lead to,” he said.

In an email update, Dodd notes that “the impact of the outbreak is devastating with so many families reeling from loss of loved ones, including many young children.”

Yet there are bright moments.

“Today was a good day – a total of 20 patients (survivors) were released to their families after fully recovering and finally testing negative. I spoke to the father of a 6-year-old girl who had been in the treatment center for 21 days. When she walked out, small yet brave in a new shirt two sizes too big for her, he and I both wept.”

While Bird and Dodd’s involvement in the outbreak response highlights the value of veterinary scientists in global public health challenges, it also illustrates the need for more individuals in the public health field with training in veterinary medicine, human medicine, diagnostics, and epidemiology to support international One Health efforts.

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UCLA doctors prepared to treat Ebola


Kits have been assembled that contain special protective gear.

UCLA infectious disease specialists have assembled kits containing special protective gear to be used in the event that a patient infected with Ebola or other infectious diseases arrives at the emergency room for treatment.

Doctors began putting the kits together in July after the Centers for Disease Control issued new guidelines for U.S. hospitals in the face of the unprecedented spread of Ebola in West Africa. Four American aid workers who contracted the disease are now being treated at two U.S. hospitals. More are expected to arrive stateside for treatment. The World Health Organization (WHO) estimates that more than 240 health care workers have become infected by Ebola so far, and more than 120 have died.

Ebola presents special challenges for hospitals because it is transmitted through body fluids, and hospital workers are at high risk of infection from a sick patient, according to Dr. Zachary Rubin, infection disease expert at the UCLA David Geffen School of Medicine.

“Blood, urine, stool, even sweat are infectious to other people and require very special handling,” Rubin said.

The Ebola kit contains full-body protective gear that covers health care workers from head to toe. Each kit holds a fluid-resistant gown, disposable booties that extend to the knee and a full-face shield that protects the health care worker’s eyes, ear, nose and mouth from any kind of splashes of body fluids from the patient.

A total of 50 Ebola kits are now at the ready, 25 at Ronald Reagan UCLA Medical Center, and 25 at UCLA Medical Center, Santa Monica.

“We’re going to keep them in central supply, so that we can use them fairly quickly if we need to,” Rubin said.  “We’re ready for potential patients.”

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Making maps to predict malaria


UCSF, Google Earth Engine fighting infectious disease with cloud computing.

A sample risk map of malaria in Swaziland during the transmission season using data from 2011-13.

UC San Francisco (UCSF) is working to create an online platform that health workers around the world can use to predict where malaria is likely to be transmitted using data on Google Earth Engine.

The goal is to enable resource poor countries to wage more targeted and effective campaigns against the mosquito-borne disease, which kills 600,000 people a year, most of them children.

Faced with a multitude of public health needs, countries often make the mistake of cutting their malaria efforts just when they are close to eliminating the disease, said Hugh Sturrock, Ph.D., M.Sc., an assistant professor of epidemiology and biostatistics and a researcher in the Global Health Group, which is a part of UCSF’s Global Health Sciences.

“This can have disastrous consequences, since malaria can quickly rebound, putting years of expensive control efforts to waste,” he said. “But with these maps, health workers will know exactly where to target their scarce resources. That way, they can keep fighting the disease until it’s eliminated within their borders.”

Google Earth Engine brings together the world’s satellite imagery — trillions of scientific measurements dating back almost 40 years — and makes it available online with tools for scientists, independent researchers and nations to mine this massive warehouse of data to detect changes, map trends and quantify differences on the Earth’s surface.

With the malaria prediction platform, local health workers will be able to upload their own data on where and when malaria cases have been occurring and combine it with real-time satellite data on weather and other environmental conditions within Earth Engine to pinpoint where new cases are most likely to occur. That way, they can spray insecticide, distribute bed nets or give antimalarial drugs just to the people who still need them, instead of blanketing the entire country.

By looking at the relationship between disease occurrence and factors such as rainfall, vegetation and the presence of water in the environment, the maps will also help health workers and scientists study what drives malaria transmission. Google Earth Outreach, which helps nonprofits use Google’s mapping technology, is giving UCSF $100,000 to develop the new platform.

The new tool will be piloted in Swaziland, a country in southern Africa that has limited malaria to a few small pockets across the country through the malaria elimination program it launched in 2008 with help from the Global Health Group. Plans are to make the tool available to health workers in other countries working with the Global Health Group’s Malaria Elimination Initiative. The tool could also be adapted to predict other infectious diseases.

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Researchers assisting in search for Ebola immune response targets


San Diego Supercomputer Center, La Jolla Institute provide rapid online analysis.

The effort to develop therapeutics and a vaccine against the deadly Ebola virus disease (EVD) requires a complex understanding of the microorganism and its relationship within the host, especially the immune response. Adding to the challenge, EVD can be caused by any one of five known species within the genus Ebolavirus (EBOV), in the Filovirus family.

Now, researchers at the La Jolla Institute for Allergy and Immunology (La Jolla Institute) and the San Diego Supercomputer Center (SDSC) at UC San Diego are assisting the scientific community by running high-speed online publications of analysis of EBOV-related epitope data being curated in the Immune Epitope Data Base (IEDB), and predicting epitopes using the IEDB Analysis Resource. Sebastian Maurer-Stroh of Bioinformatics Institute, A*STAR, Singapore is also assisting with analysis of the latest outbreak sequences of Ebola proteins.

“These results are the first installment of a series of analysis, whose ultimate goal is to provide a comprehensive overview of the molecular targets of the immune responses to Ebola virus,” said Julia Ponomarenko, a senior research scientist at SDSC and UCSD PI of IEDB.

The recent Ebola outbreak in West Africa has now reached historic proportions surpassing 1,900 deaths from 3,500 confirmed or probable cases, prompting the World Health Organization (WHO) to declare an international public health emergency, according to recent news reports. Outbreaks of EVD have occurred in Africa in the past; however the current epidemic, caused by Zaire Ebolavirus, has been characterized by its unprecedented breadth and rapid spread.

“Clearly, research related to development of therapeutics and a vaccine against EVD is an urgent need, as well-engineered vaccines don’t exist at this time; our analysis is aimed at assisting the clinical and scientific communities in fine evaluation of laboratory results with the express intent of improving therapeutic targets or new vaccine development,” said Alessandro Sette of the Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, IEDB PI.

As of last month, the IEDB reported, in preliminary analysis, 67 T cell (CD4+ and CD8+) and 35 B cell epitopes (linear and conformational), from viruses within the EBOV and Marburgvirus genera. Within EBOV, data are provided for all known species, including Zaire, Sudan, Reston, Bundibugyo, and Tai Forest Ebolavirus. To date, 29 papers have been published that describe experimental data on the epitopes in the Filoviridae family, with 23 papers focused on the EBOV-related epitope data.

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Diaper detective


Students develop inexpensive, versatile pad to detect medical problems in infants.

A team of UC Riverside Bourns College of Engineering students created an inexpensive pad that can be inserted into diapers to detect dehydration and bacterial infections in infants.

The product, which recently won an award that included a $10,000 prize at a national engineering design contest, operates much like a home pregnancy test or urine test strip. Chemical indicators change color when they come in contact with urine from an infant who is suffering from dehydration or a bacterial infection.

The pad, which is 2.5 inches by 5 inches and called “The Diaper Detective,” is attractive for numerous reasons. It costs 34 cents to make. It doesn’t require electricity, cold storage or an advanced education to interpret. It’s customizable so that other chemical indicators can be added to test for other medical conditions. And it could be adapted to be used in adult diapers.

“We created this to fulfill a need for a versatile, inexpensive, non-invasive method of urine collection in developing countries and elsewhere,” said Veronica Boulos, one of the team members. “The beauty of this is that it solves a huge problem with simplicity.”

Strike against infant mortality

The Diaper Detective addresses the worldwide problem of infant mortality in developing nations. Of the estimated 3.9 million annual neonatal deaths, 98 percent occur in developing countries and could be prevented with access to low cost, point-of-care diagnostics.

In developing countries, the students hope the Diaper Detective will be distributed via relief organizations. In the United States, the students believe the pad would qualify for reimbursement through medical insurance, making it an inexpensive option for low-income users.

The uniqueness of the diaper insert comes from the use of lateral flow channels that guide the user’s urine to the reactive regions where the color change takes place. The lateral flow channels were originally created using Crayola crayons and are now created by paraffin wax and a laser printer.

The students won a third place award at the National Institute of Biomedical Imaging and Engineering Design by Biomedical Undergraduate Teams Challenge. They have also submitted the product to the National Collegiate Inventors and Innovators Alliance BMEStart competition.

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Infants receiving different diets after birth develop distinct immune systems


Study compares breast- and bottle-fed infant monkeys.

Researchers have long known that breast milk is good for babies. This research gives further insight about why that might be so and suggests immunologic effects may persist long after breast feeding has ceased. (Photo by Kathy West, California National Primate Research Center)

Infant rhesus monkeys receiving different diets early in life develop distinct immune systems that persist months after weaning, a study by researchers from UC Davis, the California National Primate Research Center (CNPRC) at UC Davis and UC San Francisco has shown. The study, which compares breast- and bottle-fed infants, appears online today (Sept. 3) in Science Translational Medicine.

While the researchers expected different diets would promote different intestinal bacteria (microbiota), they were surprised at how dramatically these microbes shaped immunologic development. Specifically, breast-fed macaques had more “memory” T cells and T helper 17 (TH17) cells, which are known to fight salmonella and other pathogens.

These differences persisted for months after the macaques had been weaned and placed on identical diets, indicating that variations in early diet may have long-lasting effects.

“We saw two different immune systems develop: one in animals fed mother’s milk and another in those fed formula,” said Dennis Hartigan-O’Connor, a CNPRC scientist in the Infectious Diseases Unit and Reproductive Sciences and Regenerative Medicine Unit, and an assistant professor in the Department of Medical Microbiology and Immunology at UC Davis.

“But what’s most startling is the durability of these differences. Infant microbes could leave a long-lasting imprint on immune function,” he said.

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Malaria’s clinical symptoms fade on repeat infections


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

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

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

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

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

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


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

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

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

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

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

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

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

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

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New vaccine may be stronger weapon against both TB and leprosy


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

Antigen 85B structure

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

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

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

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

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

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Antimalarial drug shipped to Africa


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

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

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

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

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