TAG: "Infectious disease"

Surviving sepsis


UC Santa Barbara scientist receives $3.5M NIH grant to expand his research on sepsis.

The enzyme neuraminidase remodels the surface of platelets and glycoproteins, triggering an inherent protective mechanism that can reverse the coagulation factors that make sepsis lethal. (Photo by Sanford-Burnham Medical Research Institute)

It’s the most common cause of death in American hospitals and among the top five killers worldwide, but sepsis remains largely under the radar in conversations about public health — and in promising treatments.

A biomedical scientist at UC Santa Barbara may have a hand in reversing both those trends, thanks to his novel therapeutic approach and a big new grant from the National Institutes of Health.

Jamey Marth, director of UCSB’s Center for Nanomedicine (CNM) and a professor of the Sanford-Burnham Medical Research Institute, has been awarded $3.5 million from the NIH Heart, Lung and Blood Institute for his continued work to boost survival rates in sepsis.

“This research funding award represents recognition by the NIH and scientific colleagues throughout the nation of the leading research in sepsis going on at CNM focused on understanding and thwarting the pathogenesis of sepsis, a common syndrome that remains one of the most difficult to detect and treat effectively,” said Marth, who is also the Carbon Professor of Biochemistry and Molecular Biology and the Mellichamp Professor of Systems Biology at UCSB. “With this grant, we will be able to more rapidly and more effectively follow up on our earlier discoveries of a completely new approach to the treatment of sepsis that once in the clinic may save millions of lives.”

The new grant supports an ongoing collaboration of UCSB, the Sanford-Burnham Medical Research Institute, the Santa Barbara Cottage Hospital and UC San Diego that is focusing on advancing these discoveries to the point of clinical trials. His team has already shown the method increases, by twofold, sepsis survival rates in models of bacterial infection.

Now, using Cottage’s robust data registry of septic patients, including blood samples from consenting participants, the research will accelerate to further translate the approach for human patients.

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Scientists discover exact receptor for DEET that repels mosquitoes


Discovery could pave the way for better, more affordable insect repellents.

UC Davis biochemist Walter Leal has discovered which receptor on mosquito antennae detects DEET, making it an effective repellant. (Photo by Kathy Keatley Garvey, UC Davis)

DEET has been the gold standard of insect repellents for more than six decades, and now researchers led by a UC Davis scientist have discovered the exact odorant receptor that repels them.

They also have identified a plant defensive compound that might mimic DEET, a discovery that could pave the way for better and more affordable insect repellents. Findings from the study appear today (Oct. 27) in the journal Proceedings of the National Academy of Sciences.

More than 200 million people worldwide use DEET, developed by scientists at the U.S. Department of Agriculture and patented by the U.S. Army in 1946.

“Mosquitoes are considered the most deadly animals on the planet, but unfortunately, not everyone who needs this repellent can afford to use it, and not all who can afford it can use it due to its undesirable properties such as an unpleasant odor,” said lead author professor Walter Leal of the Department of Molecular and Cellular Biology.

“Vector-borne diseases are major health problems for travelers and people living in endemic regions,” Leal said. “Among the most notorious vectors are mosquitoes that transmit the protozoan parasites causing malaria and viruses that cause infections, such as dengue, yellow fever, chikungunya and encephalitis.”

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Scientists trying old weapon against deadly new target


Developed at UC San Diego more than a decade ago, brincidofovir takes on Ebola.

(From left) James Beadle and Karl Hostetler, UC San Diego (Photo by Ryan Parks, UC San Diego)

With the Ebola crisis ongoing, much attention is focused upon finding a drug capable of slowing – if not stopping – the infectious, deadly and terrifying virus.

There is Zmapp, of course, the experimental biopharmaceutical produced by a San Diego-based biotech firm that was used briefly before supplies ran out. There are other anti-Ebola drugs reportedly under development in Oregon, Canada and China.

And there is brincidofovir, a compound with a decidedly unwieldy name that was discovered more than a decade ago by researchers at UC San Diego. Brincidofovir (pronounced brin-SIGH-doh-fo-veer) wasn’t invented to fight Ebola – the scientists were actually looking for a new way to fend off the menace of bioterrorism – but it may represent one of the best chances yet to conquer a virus that has killed more than 4,500 people, almost all in stricken West Africa.

In 1999, Dr. Karl Hostetler, then a professor of medicine in UC San Diego School of Medicine, got a call from officials at the National Institute of Allergy and Infectious Diseases. They posed a question: Could he help create a new drug to protect Americans if bioterrorists unleashed smallpox – the one-time global scourge now restricted to a few high-security labs?

There was already a drug called cidofovir that might serve, but it required an injection. NIAID officials wanted a pill, something safe, stable and broadly effective against not just smallpox, but other highly infectious, deadly viruses that might be deployed as bioweapons.

“There was a lot of talk and fear about such attacks at the time,” recalled Hostetler, now professor emeritus. “It’s still a legitimate concern.”

Hostetler, who studied the lipid molecules necessary to build cell membranes and was working on improved ways to deliver therapeutic drugs inside cells, agreed to help. Funding from NIAID arrived within days.

Over the next few years, he and colleagues created multiple analogs or variations of cidofovir. The first was brincidofovir. In cultured cell tests, the compound proved active against an array of viruses, blocking their ability to replicate.

“With any disease that causes high mortality, the idea isn’t so much to absolutely stop viral replication as to slow it down so that the patient’s immune system can catch up and ultimately eradicate the infection,” Hostetler said.

One of the viruses seemingly impacted by brincidofovir is Ebola, though Hostetler’s focus at the time was elsewhere. Brincidofovir targets double-stranded DNA viruses like herpes, cytomegalovirus, Epstein-Barr, hepatitis and papillomavirus. Ebola is an RNA virus. It replicates differently.

“Brincidofovir is the first broad-spectrum antiviral for DNA viruses. It’s not unprecedented that it might also work against RNA viruses like Ebola, but back then, the greatest interest was in DNA viruses,” he said.

Unable to arouse outside interest and investment in brincidofovir, Hostetler founded Chimerix in Durham, N.C. to further develop the drug – both for smallpox and for other diseases. These efforts have progressed measurably. Phase 3 trials under the Food and Drug Administration’s (FDA) animal rule are planned next year for a smallpox treatment. Phase three human trials are underway for brincidofovir as a therapy for cytomegalovirus and adenovirus – common viruses that can cause fever, diarrhea, conjunctivitis and bladder infections, but in persons with weakened or suppressed immune systems are life-threatening.

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UCSF-based team awarded $8M agreement with CDC


Team includes investigators from UC Berkeley, UC Davis, UC San Diego.

A UC San Francisco-based team has been awarded a multimillion-dollar, five-year cooperative agreement with the U.S. Centers for Disease Control and Prevention (CDC) to conduct economic modeling of disease prevention in five areas: HIV, hepatitis, STI (sexually transmitted infections), TB (tuberculosis) and school health. The team, led by James G. Kahn, M.D., M.P.H., and Paul Volberding, M.D., both faculty in Global Health Sciences, is a multi-institution consortium, with 39 investigators across UCSF; Stanford University; UC Berkeley, UC Davis, UC San Diego; the San Francisco Department of Public Health, Health Strategies International, and PATH. It will be based at the UCSF Philip R. Lee Institute for Health Policy Studies.

The consortium was awarded $1.6 million for the first year and $8 million over the full project period. Called CAPE (Consortium for the Assessment of Prevention Economics), it will conduct economic analyses including costing, cost-effectiveness analysis, cost-benefit analysis, resource allocation, and return on investment.

“We are looking at five different health areas, using a range of economic methods – this breadth is very unusual for an economics project,” said Kahn. “We are also excited about collaborating with colleagues in the Bay Area and throughout California.”

The project advances the UCSF Global Health Sciences vision for research that crosses and links disease areas, and that integrates economics with basic and applied science. While CAPE’s geographic focus is the United States, modeling methods and tools can be adapted to global settings, using local data on population and disease characteristics.

CAPE is the largest award arising from the UCSF Global Health Economic Consortium, established in 2013.

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UC Irvine disaster medicine experts examine Ebola preparations


Article describes principles for diagnosing, treating Ebola patients while ensuring staff safety.

Kristi Koenig, UC Irvine

When the World Health Organization announced in early August that the Ebola outbreak in West Africa was an international health emergency, Dr. Kristi L Koenig began anticipating the “what ifs.”

Her response: “Ebola Virus Disease: Essential Public Health Principles for Clinicians,” an article which describes the basic principles for diagnosing and treating Ebola patients while ensuring staff safety. Written in collaboration with colleagues Dr. Cassondra Majestic and Dr. Michael J. Burns, the article was published Sept. 19 in the Western Journal of Emergency Medicine.

“I just had the feeling that Ebola was going to become a major topic of public discussion, similar to the situation with the H1N1 virus in 2009,” Koenig said. “I wrote the article to increase awareness that there are basic health principles that are valid for every infectious disease.”

An internationally recognized expert, Koenig is director of the UC Irvine Center for Disaster Medical Sciences, professor of emergency medicine, director of public health preparedness at the University of California, Irvine, and an attending physician in the emergency department at UC Irvine Medical Center in Orange.

“We are always prepared, especially in managing all kinds of infectious diseases,” Koenig said. “Orange County is one of the most popular travel destinations in the world, and UC Irvine Medical Center is the major trauma center in the county.”

Like other hospitals throughout the nation, UC Irvine Medical Center follows the Centers for Disease Control and Prevention isolation and infection control recommendations for safely treating potential patients with the Ebola virus. Preparation efforts included assembling kits containing personal protective equipment for staff, warning signs for isolation units, and information on patient precautions, transportation and placement.

At UC Irvine, training for handling health emergencies is part of the routine.

“We prepare for hazards of all types on a regular basis,” Koenig said. “We conduct exercises for handling various viruses, such as the Middle East Respiratory Syndrome and also practice drills for medical response to a natural disaster such as an earthquake.”

Read more about UC Irvine Medical Center’s Ebola virus preparation.

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Slime-producing molecules help spread disease from cats to sea otters


Gelatinous polymers act to provide environment conducive to transmit infectious diseases.

The spread of diseases from land animals to sea otters and other marine mammals is aided and abetted by gelatinous, sticky polymers produced by seaweed, reports a research team headed by a UC Davis veterinary infectious disease expert.

These large, complex molecules form slimy biofilms and bind water-borne organic matter into larger particles, in which disease-causing micro-organisms can become embedded and introduced to the marine food chain, the researchers discovered.

Using the parasite Toxoplasma gondii as a model, they showed how these sticky polymers increase the chance that disease-causing organisms would be picked up by marine snails, which graze on kelp and are among the common foods of some endangered sea otters.

Findings from the new study will be published Oct. 8 in the journal Proceedings of the Royal Society B.

“Discovering the role that these invisible polymers play in disease transmission in the ocean is a tremendous step forward in helping us better understand and mitigate the impacts of coastal water pollution on the health of wildlife and humans,” said lead author Karen Shapiro, a research scientist in the School of Veterinary Medicine.

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Ebola genome browser now online


UC Santa Cruz Genomics Institute releases bioinformatic tool to assist vaccine efforts.

Jim Kent, UC Santa Cruz

The UC Santa Cruz Genomics Institute late Tuesday (Sept. 30) released a new Ebola genome browser to assist global efforts to develop a vaccine and antiserum to help stop the spread of the Ebola virus.

The team, led by UC Santa Cruz researcher Jim Kent, worked around the clock for the past week, communicating with international partners to gather and present the most current data. The Ebola virus browser aligns five strains of Ebola with two strains of the related Marburg virus. Within these strains, Kent and other members of the UC Santa Cruz Genome Browser team have aligned 148 individual viral genomes, including 102 from the current West Africa outbreak.

UC Santa Cruz has established the UCSC Ebola Genome Portal, with links to the new Ebola genome browser as well as links to all the relevant scientific literature on the virus.

“Ebola has been one of my biggest fears ever since I learned about it in my first microbiology class in 1997,” said Kent, who 14 years ago created the first working draft of the human genome.  “We need a heroic worldwide effort to contain Ebola. Making an informatics resource like the genome browser for Ebola researchers is the least we could do.”

Scientists around the world can access the open-source browser to compare genetic changes in the virus genome and areas where it remains the same. The browser allows scientists and researchers from drug companies, other universities, and governments to study the virus and its genomic changes as they seek a solution to halt the epidemic.

The release of the new Ebola genome browser comes as the U.S. Centers for Disease Control and Prevention Tuesday confirmed the first case of Ebola in the United States.

The Ebola browser was started shortly after a phone conversation between Kent and his sister, an epidemiologist at the CDC, who spoke of how she and her staff were consumed with Ebola research in the face of the escalating crisis. UC Santa Cruz professor Phil Berman, an HIV specialist, had also asked Kent for help with his efforts in developing a vaccine for Ebola.

Kent asked his supervisor, UC Santa Cruz bioinformatics researcher David Haussler, if he could divert his team to Ebola work.  Haussler replied with an enthusiastic affirmative, and they pulled together a team of UC Santa Cruz bioinformatics scientists that, within a week, was able to create a fully functional Ebola genome browser.

“The incredible speed with which this group was able to assemble all the genetic information about Ebola and make it available to the world shows what a great team Jim Kent has assembled,” Haussler said.

In June 2000, Kent and Haussler released the first working draft of the human genome sequence on the Web. Two months later, Kent developed the UCSC Genome Browser, which has become an essential resource to biomedical science.

In a similar marshaling of forces in the face of a worldwide threat 11 years ago, UC Santa Cruz researchers created a SARS virus browser.

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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, other infectious diseases, if needed


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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