TAG: "Infectious disease"

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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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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Malaria vaccine candidate produced from algae


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

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

By Heather Buschman, UC San Diego

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

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

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

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

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

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

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

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

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

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

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

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

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UCSF expert appointed UN Special Envoy on Tuberculosis


Drug-resistant TB poses threat to global health security.

Eric Goosby, UC San Francisco

By Laura Kurtzman, UC San Francisco

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Forecasting the flu better


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

By Inga Kiderra, UC San Diego

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

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

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

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

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

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

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

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

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Scientists ID important mechanism involved in production of mosquito eggs


Research could lead to innovative strategies for controlling mosquito populations.

Alexander Raikhel, UC Riverside (Photo by Lonnie Duka)

By Iqbal Pittalwala, UC Riverside

Diseases transmitted by mosquitoes have contributed to the death and suffering of millions throughout human history, earning the mosquito the title as the world’s most dangerous animal. Even today, several devastating mosquito-borne diseases (such as malaria, dengue fever and West Nile virus) continue to rage.

The urgent need to better control mosquito numbers and interfere with disease transmission has guided much mosquito research in laboratories worldwide. Female mosquitoes rely on a blood-meal as a source of nutrients required for reproduction.  The thinking is that if the mechanisms that govern mosquitoes’ egg production are better understood, novel approaches to controlling the reproduction and population of mosquitoes can be devised.

Now a team of scientists at UC Riverside has made a research breakthrough in understanding, at the molecular level, one such mechanism related to the mosquito reproductive process.  This mechanism includes small regulatory RNA molecules known as microRNAs or miRNAs.

The researchers report in this week’s issue of the Proceedings of the National Academy of Sciences that they have identified microRNA-8 (miR-8) as an essential regulator of mosquito reproductive events. They note that its depletion in the female mosquito results in severe defects related to egg development and deposition.

Using newly established genetic tools in mosquito biology and doing analysis that identifies microRNA targets, they were able to show that miR-8 plays an essential role in the female mosquito “fat body” (fatty tissue analogous to the mammalian liver) by regulating a molecule, called “swim,” that miR-8 directly targets.  High levels of this molecule are detrimental to egg development.

“To our knowledge, this is the first time a mosquito miRNA has been investigated in this specific manner,” said Alexander Raikhel, a distinguished professor of entomology, who has received wide acclaim for his research in the areas of insect reproductive biology. “In the lab, female transgenic mosquitoes with deficiency in miR-8 displayed severely compromised ovary development and reduced egg-laying.”

While the researchers focused in this study on only Aedes aegypti, the mosquito that spreads dengue and yellow fever, their research results can be applied also to other disease-spreading mosquitoes.

“Our work provides insight into the importance of miRNAs in adult mosquito development and how these small regulatory molecules have potential to serve as novel control approach to regulate mosquito numbers,” Raikhel said.

He explained that what his lab had set out to do was introduce birth control in mosquitoes.

“We were looking to find a way to disrupt the host-seeking behavior of mosquitoes by interrupting their egg development,” he said.  “With egg development halted, the population of mosquitoes would eventually collapse.”

At UC Riverside, Raikhel’s lab specializes in understanding the molecular basis of events in the mosquito reproduction cycle linked to a blood meal and pathogen transmission. His research focuses, too, on how pathogens of major human diseases, transmitted by mosquitoes, interact with their mosquito hosts.  A member of the National Academy of Sciences, he occupies the Mir S. Mulla Chair in Entomology at UCR, as well as the University of California President’s Chair.

To date, no effective vaccines for malaria, dengue fever or West Nile virus exist. This lack of vaccines, along with increasing pesticide resistance in mosquitoes, adds to the urgency of exploring alternative strategies for mosquito control.

Nearly 2.5 billion people are at risk for contracting dengue fever.  Each year, there are 100 million cases of dengue in the world.  Yellow fever results in 30,000 deaths per year; about 200,000 cases are reported each year. Malaria alone causes over a million deaths annually. Dengue fever is emerging across the globe at an alarming rate; more than three billion people are now at risk of contracting this serious and debilitating viral disease. West Nile virus has invaded and spread throughout North America in just one decade; thousands in the United States are afflicted with this mosquito-borne virus every year.

Raikhel was joined in the research by Keira J. Lucas, the research paper’s first author and a fifth-year Ph.D. graduate student in the Graduate Program in Genetics, Genomics and Bioinformatics; Sourav Roy, Jisu Ha, Amanda L. Gervaise and Vladimir A. Kokoza.  Ha is a fourth-year Ph.D. student in the Graduate Program in Genetics, Genomics and Bioinformatics.

The research was supported by a grant to Raikhel from the National Institutes of Health.

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Common human protein linked to adverse parasitic worm infections


UC Riverside-led research could lead to new therapies for parasitic worm infections.

Hookworms infect the lung and cause severe inflammation. This image shows immunofluorescent staining of infected mouse lung tissue for worm antigen (green), worm and macrophage bound lectin (red) and cell nuclei (blue). (Credit: Nair Lab, UC Riverside)

By Kathy Barton, UC Riverside

Worm infections represent a major global public health problem, leading to a variety of debilitating diseases and conditions, such as anemia, elephantiasis, growth retardation and dysentery. Several drugs are available to treat worm infections, but reinfection is high especially in developing countries.

Now, scientists at UC Riverside and colleagues around the world have made a discovery, reported in this month’s issue of PLOS Pathogens, that could lead to more effective diagnostic and treatment strategies for worm infections and their symptoms. The researchers found that resistin, an immune protein commonly found in human serum, instigates an inappropriate inflammatory response to worm infections, impairing the clearance of the worm.

“Targeting this inflammatory pathway with drugs or antibodies could be a new therapeutic strategy to treat worm infections and the associated pathology,” said Meera Nair, an assistant professor of biomedical sciences in the UC Riverside School of Medicine, whose laboratory made the discovery.  “Additionally, our data point to the diagnostic potential for resistin as a new biomarker for impaired immune responses to worms.”

Jessica Jang, the lead author of the research paper and a third-year UCR graduate student in microbiology, explained that resistin regulates the recruitment of innate immune cells called monocytes to the site of infection to produce inflammatory cytokines (small proteins that are important in cell signaling).

“Future work in my Ph.D. research will focus on further investigating the activation of monocytes so we can clinically exploit this immune pathway,” she said.

Parasitic worms, known scientifically as helminths, include filarial worms and hookworms. They cause diseases such as elephantiasis, which produces extreme swelling of extremities, and necatoriasis, which causes abdominal pain, diarrhea and weight loss. The infections are often associated with life-long morbidity, including malnutrition, growth retardation and organ failure.

In many developing countries where parasitic worms are prevalent due to substandard sanitation facilities, infections in humans are common, as are reinfections. Some infected patients develop immunity, but others remain susceptible to infections when they are re-exposed or develop chronic infections. Currently, no vaccine is available against human worm pathogens.

The research directed by Nair’s lab combined mouse studies with human data to demonstrate that resistin is actually detrimental, causing excessive inflammation that impedes the body’s ability to clear parasitic worms.

In the animal studies, mice containing the gene expressing human resistin and infected with a parasitic worm similar to the human hookworm experienced excessive inflammation, leading to increased weight loss and other symptoms. Clinical samples from two groups of individuals from the south Pacific island of Mauke and from Ecuador – one group infected with filarial worms causing lymphatic filariasis and a second group infected with intestinal roundworms Ascaris – revealed increased levels of resistin in the infected individuals compared to those who were uninfected or immune.

A better understanding of human resistin may also reveal new knowledge about obesity and diabetes. Resistin has been mapped to the pathway of immune-mediated inflammation that promotes diabetes and other obesity-related disorders and Nair hopes to combine her lab’s basic science expertise with the developing clinical research enterprise in the UCR medical school as a future avenue to research new diagnostic or treatment strategies.

Collaborating in the study were scientists from: the Malaghan Institute of Medical Research in New Zealand; Pontificia Universidad Católica del Ecuador in Quito, Ecuador; St. George’s University of London; the Laboratory of Parasitic Diseases at the National Institutes of Health; and the Perelman School of Medicine at the University of Pennsylvania.

Funding for the research at UCR was provided by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the Division of Biomedical Sciences (UCR School of Medicine) and a UCR Academic Senate Regents Faculty Fellowship.

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Study rules out spiders as common cause of bacterial infections in humans


Spiders shouldn’t be scapegoated for bacterial infections, UC Riverside spider expert advises.

By Iqbal Pittalwala, UC Riverside

Can spiders be carriers of human pathogens?  Can they provoke an infection through a break in the skin?

A team of scientists, led by an entomologist at the University of California, Riverside, has data-mined the history of publications on spider envenomations to conclude that the evidence for spider-vectored infection is scanty.  Further, the researchers note that the mere presence of bacteria on spider fangs or mouthparts does not establish spiders as vectors for these bacteria.

Study results appear as a letter to the editor in the January 2015 issue of Toxicon.

“Although spider bite may be an attractive and tenable causative agent of a bacterial infection, the data show this is highly improbable,” said Richard S. Vetter, the lead author of the study and a former staff research associate in the UC Riverside Department of Entomology, now retired. “Any implied causative association between skin infections and spider bites should be considered suspect.  The medical community should not scapegoat spiders for bacterial infections. When examining reports of thousands of spider bites of many species worldwide, we found almost no mention of infection associated with the arachnid-inflicted injury.”

Vetter explained that an important advancement in spider bite diagnosis in recent years is the realization that bacterial infections have been commonly misattributed as spider envenomation by both physicians and patients.

“‘Spider bite’ is used as a default diagnosis despite lack of supporting evidence,” he said. “In a study published three years ago, of 182 Southern Californian patients presenting with complaint of spider bite, less than 4 percent had spider envenomations, while about 86 percent had skin infections.”

He mentioned that the only credible report of spider bite leading to infection that his research team is aware of is an episode involving an Australian golden silk spider, a very large orbweaver.

“It resulted in colonization by a bacterium rarely found in humans,” he said.  “The bite led to a pus-filled lesion that persisted more than two months.”

Vetter’s advice to people concerned with skin infections is that both the medical community and the general public should stop blaming spiders as the cause of bacterial infections.

“This medical platitude is not supported by the history of spider bite data and could lead to misdiagnosed patients who then have an overzealous reaction that could, in turn, lead to the unwarranted development of arachnophobia in bite victims, possibly then requiring psychological desensitization to spiders or excessive use of pesticides in living spaces,” he said.

Vetter was joined in the study by David L. Swanson, Mayo Clinic, Scottsdale, Ariz.; and Scott A. Weinstein and Julian White at the Women’s and Children’s Hospital, North Adelaide, Australia.

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A sense for biosensors


UC Irvine’s Weian Zhao has created a device that improves detection of bacterial, viral invaders in blood samples.

The Integrated Comprehensive Droplet Digital Detection system invented by Weian Zhao of UC Irvine converts blood samples directly into billions of very small droplets. (Photo by Steve Zylius, UC Irvine)

By Tom Vasich, UC Irvine

As a doctoral student at McMaster University in Hamilton, Ontario, Weian Zhao took part in a Canada-wide research effort to develop bioactive paper that would detect, capture and deactivate waterborne and airborne pathogens.

As part of this project, he helped invent gold nanoparticle-coated paper that could detect common pathogens, such as E. coli, but ultimately, the product didn’t meet his exacting standards of diagnostic speed and sensitivity. With a freshly minted Ph.D. in chemistry, Zhao moved on to a joint postdoctoral fellowship at both the Massachusetts Institute of Technology and Harvard, where he dove into stem cell research, his biosensor work seemingly left north of the border.

But the challenge of creating a technology that could rapidly and selectively identify bacterial and viral invaders in blood samples nagged at the young scientist, even as he joined UC Irvine in 2011 as an assistant professor of pharmaceutical sciences with state-of-the-art lab space in the Sue & Bill Gross Stem Cell Research Center.

And then he met Enrico Gratton. In his Laboratory for Fluorescence Dynamics, the UCI biomedical engineer and colleagues have been developing imaging tools for biomedical applications. Among them is a three-dimensional particle counter that tags low-concentration fluorescent particles in large volumes of solution within several minutes, which drew Zhao’s attention. He knew he was back in the biosensor game.

Employing this particle counter, Zhao created a bloodstream infection test that speeds up diagnosis times with unprecedented accuracy – allowing physicians to treat patients with potentially deadly ailments more promptly and effectively.

Zhao says that the Integrated Comprehensive Droplet Digital Detection system can, in as little as 90 minutes, detect bacteria in milliliters of blood with single-cell sensitivity; no cell culture is needed. He published his latest results in the November issue of Nature Communications.

“We are extremely excited about this technology because it addresses a long-standing unmet medical need in the field,” says Zhao, who also holds a faculty appointment in biomedical engineering. “As a platform technology, it may have many applications in detecting extremely low-abundance biomarkers in other areas, such as cancers, HIV and, most notably, Ebola.”

Bloodstream infections are a major cause of illness and death. In particular, infections associated with antimicrobial-resistant pathogens are a growing health problem in the U.S. and worldwide. According to the Centers for Disease Control & Prevention, more than 2 million people a year globally get antibiotic-resistant blood infections, with about 23,000 deaths. The high mortality rate for blood infections is due, in part, to the inability to rapidly diagnose and treat patients in the early stages.

Recent molecular diagnosis methods, including polymerase chain reaction, can reduce the assay time to hours but are often not sensitive enough to detect bacteria that occur at low concentrations in blood, as is common in patients with incipient blood infections.

The Integrated Comprehensive Droplet Digital Detection technology differs from other diagnostic techniques in that it converts blood samples directly into billions of very small droplets. Fluorescent DNA sensor solution infused into the droplets detects those with bacterial markers, lighting them up with an intense fluorescent signal. Zhao says that separating the samples into so many small drops minimizes the interference of other components in blood, making it possible to directly identify target bacteria without the purification typically required in conventional assays.

“The IC 3D instrument is designed to read a large volume in each measurement, to speed up diagnosis,” Gratton says. “Importantly, using this technique, we can detect a positive hit from hundreds of millions of measurement samples with very high confidence.”

But invention was only the first step. Zhao wants to commercialize IC 3D. At UCI, faculty researchers with an entrepreneurial bent can work with the Institute for Innovation, an interdisciplinary and campuswide center focused on integrating research, entrepreneurship and technology to create real-world applications that benefit the public and drive the economy. The Office of Technology Alliances, part of the institute, helped Zhao patent-protect the IC 3D technology and establish a spin-off company, Velox Biosystems, to test and manufacture a commercial IC 3D device.

Currently, Zhao is focusing on applying IC 3D to cancer treatments – an extension of the research he’s been advancing since joining UCI.

Zhao has been developing stem cell messengers that selectively migrate to cancer sites to deliver tumor-fighting drugs or probes for contrast-enhanced medical imaging. This could, potentially, enable the identification of cancer micro-metastases at their early stages and increase the effectiveness of chemotherapeutic treatments for metastatic cancer while mitigating the symptoms associated with systemic chemotherapy.

For this work, Zhao was included in the MIT Technology Review’s 2012 list of the world’s top innovators under the age of 35, and this year he earned a prestigious National Institutes of Health Director’s New Innovator Award to further his efforts to create stem cell-based detection methods and treatments for cancer.

He’s also collaborating with Dr. Jason Zell, an assistant professor of medicine and co-leader of the Colon Cancer Disease-Oriented Team at UCI’s Chao Family Comprehensive Cancer Center, to use IC 3D to identify biomarkers in colon cancers. This could enable oncologists to gauge the effectiveness of treatment during the cancer’s early stages more accurately than with current methods, which Zell says are not reliable.

Zhao is now seeking business partners to accelerate Velox Biosystems’ growth and hopes to conduct clinical studies of IC 3D’s utility in patient diagnosis and treatment.

“That’s what’s so important about this project,” he says. “We’ve created a multi-platform tool that has the potential to work with a variety of infections and diseases. I’m very excited about its future.”

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Typhoid Mary, not Typhoid Mouse


Lack of enzyme explains why typhoid fever is a human-specific disease.

By Heather Buschman, UC San Diego

The bacterium Salmonella Typhi causes typhoid fever in humans, but leaves other mammals unaffected.  Researchers at UC San Diego and Yale University schools of medicine now offer one explanation — CMAH, an enzyme that humans lack. Without this enzyme, a toxin deployed by the bacteria is much better able to bind and enter human cells, making us sick. The study is published in today’s (Dec. 4) issue of Cell.

In most mammals (including our closest evolutionary cousins, the great apes), the CMAH enzyme reconfigures the sugar molecules found on these animals’ cell surfaces into a form that the typhoid toxin cannot bind. Humans don’t produce CMAH, meaning our cell surface sugars are left unchanged — and as this study shows, in a state just right for typhoid toxin attachment.

“We started this project looking at something completely different in relation to cancer, but serendipity instead helped us solve the mystery of what the typhoid toxin binds,” said co-senior author Ajit Varki, M.D., Distinguished Professor in the departments of medicine and cellular and molecular medicine at UC San Diego. “That’s the beauty of basic research — though we didn’t set out with the intent, these findings may now spur the development of new therapies for typhoid fever.” Varki co-directed the study with Jorge E. Galán, Ph.D., D.V.M., professor and department chair at Yale University School of Medicine.

All mammals decorate their cell surfaces with a type of sialic acid sugar called Neu5Ac. In most mammals, the enzyme CMAH coverts Neu5Ac to Neu5Gc, a subtle but important distinction involving a single oxygen atom. Varki, Galán and their teams are the first to discover that typhoid toxin binding is exquisitely specific for Neu5Ac (the human type). The toxin damages cells expressing Neu5Ac sugars on their surface, but not those with Neu5Gc (the non-human type). In fact, when the researchers added Neu5Gc to cultured human cells, they became resistant to typhoid toxin. The findings were confirmed in a mouse model.

“We have previously shown that typhoid toxin can cause typhoid fever in experimental animals and that to intoxicate cells, the toxin must bind specific surface glycoproteins. The discovery that a single oxygen atom could make such a difference in toxin binding is remarkable and has implications for the design of potential toxin inhibitors,” said Galán.

Typhoid is typically transmitted through food or water contaminated by infected people. While hand washing and other sanitary measures have minimized occurrences of typhoid fever in the U.S.,  roughly 21 million cases of typhoid fever and 200,000 deaths occur worldwide each year, according to the Centers for Disease Control and Prevention.

Co-authors include Lingquan Deng, Nissi Varki, Yuko Naito-Matsui, UC San Diego School of Medicine; Jeongmin Song, Xiang Gao, Yale University School of Medicine; Jiawei Wang, Tsinghua University; Hai Yu, Xi Chen, University of California, Davis.

This research was funded, in part, by the National Cancer Institute (grant CA38701) and the National Institute of Allergy and Infectious Diseases (grant AI079022), both part of the U.S. National Institutes of Health.

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