Case Western Reserve University School of Medicine announced last week it will receive funding through the Achieving Healthy Growth program within the Grand Challenges in Global Health initiative. This initiative was launched by the Bill & Melinda Gates Foundation to overcome persistent bottlenecks preventing the creation of new and better health solutions for the developing world.
Charles H. King, professor of international health and epidemiology and biostatistics will pursue a research project titled, "Enhancing Infant Immunity: Effect of Early Maternal Treatment for Parasitic Infections."
"Children in developing countries do not always respond appropriately to life-saving vaccines," King said, "and although several factors may be responsible for this poor vaccination response, chronic parasitic infections appear to play a significant role. We aim to determine how the effects of maternal parasite infections are linked to reduced vaccine efficacy and whether prenatal anti-parasite treatment can reverse this effect."
The goal of the Healthy Growth grant program is to discover the causes of faltering growth during the first 1,000 days of life and to identify effective and affordable interventions to promote healthy growth.
King's project is one of seven grants.
"Safeguarding the health of young children is one of the world's most urgent priorities and a core focus of our work," said Chris Wilson, director of Discovery & Translational Sciences at the Bill & Melinda Gates Foundation. "We hope the suite of grants announced today will give us a deeper understanding of the reasons underlying stunted growth in children in the developing world and how this can be predicted to guide new approaches to improve the health and development of these children."
Parasitic infections are a group of debilitating chronic diseases affecting millions of people worldwide. They greatly impact early childhood development, lead to life-threatening disease and interfere with children's ability to respond to life-saving vaccines. Case Western Reserve's research program will determine how parasitic infections in pregnant mothers affect the developing fetal immune system, how this interference is mediated and whether earlier prenatal parasitic treatment can reverse the trend. These studies are crucial to facilitate current global vaccination programs, future vaccine trials and ongoing parasite treatment and control programs.
The program relies on the considerable resources and expertise at Case Western Reserve, Children's Hospital Oakland Research Institute, and the Division of Vector Borne and Neglected Diseases of the Kenyan Ministry of Public Health and Sanitation. The initiative is based on the group's more than 28 years of collaborative studies in the underserved coast of Kenya, where multiple parasitic infections are endemic.
King is an infectious disease specialist, epidemiologist and senior member of the Center for Global Health and Diseases at Case Western Reserve, and the Schistosomiasis Consortium for Operational Research and Evaluation at the University of Georgia. Since 1984, he has been active on parasite control and immunology research in Kenya, and has recently focused on modeling and implementation of advanced programs for schistosomiasis control and elimination. His current research focuses on identifying human and environmental ecological drivers of vector-borne parasite transmission, and the design of more effective, integrated programs for parasite control.
National Science Foundation: People in developing countries who don't have access to clean water or good sanitation facilities can be exposed to infected snails that serve as intermediaries between disease-causing worms and humans. The worms carry schistosomiasis, the second most socioeconomically devastating disease after malaria. "Current guidelines focus on suppressing the disease's effects by limiting the infection during childhood," said Charles King, professor of international health. "But that may not be enough to cure it or to prevent re-infection, leaving children still at risk for stunted growth and anemia."
Scientists at Case Western Reserve University and the Cleveland Clinic Lerner Research Institute have discovered that the parasite that causes the most common form of malaria has the same genetic variations-even when the organisms are separated across continents.
The discovery raises concerns that mutations that resist existing medications could spread worldwide, making global eradication efforts even more difficult.
The researchers, including Cleveland-based David Serre and Peter Zimmermna, Didier Menard (Institut Pasteur-Cambodia) and Arsene Ratsimbasoa (Madagascar National Malaria Control Program), are the first to sequence the genome of the parasite Plasmodium vivax, taken from patients at coverage needed to verify genome-wide DNA sequence variation. The genome contains all of the organism's inheritable information.
The ability to sequence is crucial to understanding the hard-to-study parasite, which annually causes up to 250 million cases of malaria and places an economic burden-mostly on the poor-in excess of $1.4 billion, by some estimates.
The researchers reported their findings in the Sept. 6 issue of the online journal PLOS Neglected Tropical Diseases.
At first, the scientists were surprised to find little genetic variation specific to different locations among the samples, which came from humans in Madagascar and Cambodia and South America.
How can parasites, which are transmitted by mosquitoes, share genome-wide variations on three continents?
"The parasite's life cycle enables P. vivax to be a microbial globe-trotter," said Peter Zimmerman, professor of international health, genetics and biology in the Center for Global Health and Diseases at Case Western Reserve University School of Medicine.
In parts of the world where Plasmodium vivax malaria is endemic, the primary infection gets into the red blood cells and makes people sick, he explained. When they feel better, people resume their normal activities and travel.
But a portion of the infectious form can remain in the liver, where it may lay dormant for months or a year then re-emerge in the blood when that person is in a different place.
"In that new place, local mosquitoes bite, become infected, and start spreading the P. vivax parasite and its genome in locations that can be a long distance away from where the original human infection occurred," Zimmerman, a senior author of the new study, said.
This ability for worldwide travel raises concerns among the researchers. There is no vaccine and there is only one drug that kills the parasite in the liver.
"If drug resistance arises, with modern travel, how long would it be before the resistance is spread over the world?" Zimmerman said. "This data suggests it could quickly become a big problem."
Learning how Plasmodium vivax lives and causes maleria has been challenging because the parasite dies when removed from its host. With improvements in sequencing techniques and reductions in costs, David Serre, Assistant Professor at the Genomic Medicine Institute, Cleveland Clinic Lerner Institute, and Zimmerman decided to try to see if the parasite's genome could be sequenced and what it might tell.
"Our work provides the first report on genome-wide variation of this malaria parasite and provides the malaraia research community with more than 80,000 genetic markers that can now be used for trait mapping or population monitoring," Serre said. "This is a critical step to understand the biology of this parasite that cannot be studied in the laboratory yet affects millions of people each year."
Serre and Ernest R. Chan, a post-doctoral research fellow at the Genomic Medicine Institute, sequened the genomes of parasites in blood samples taken from two P. vivax malaria patients in Madagascar and three in Cambodia, after first removing the white blood cells. For comparison, they sequenced P. vivax from a monkey that had been infected with a human strain of the parasite found in South America. The results showed the six samples shared alternative forms of the same gene, called alleles.
Sequencing parasite strains straight from humans is a big step forward, Serre said. Most researchers have been studing human strains of P.vivax propagated through monkeys. This method is not as reliable as using human samples, because it introduces variability and is limited to only about a dozen strains that have been adapted to monkeys. Far more strains have been found in humans.
The 80,000 genetic markers identified can now be used to search for links to drug-resistant malaria, a growing problem in Southeast Asisa; and to study possible new treatments for P.vivax malaria.
Zimmerman and Serre are seeking grants to expand their work sequencing more samples from more locations.
The researchers will use the data to perform genetic evolution studies in order to learn where the parasite originated, how it spreads, and how different strains are geographically distributed.
The team will also study evolving P. vivax infection mechanisms. For example, in a classic example of natural selection, African persons do not develop P. vivax malaria, but the disease is prevalent in Madagascar. Serre and Zimmerman believe specific mutations in Malagasy P. vivax strains make the parasite able to infect individuals previously thought to be resistant.
"These studies will help advance the understanding of P. vivax biology and how the parasite successfully evades malaria eliminatoin efforts worldwide," Serre said.
Chan, Serre, Zimmerman, Menard and Ratsimbasoa worked with Saorin Kim, Pheaktra Chim, Catherine Do and Benoit Witkowski of the Unite d'Epidemiologie Moleculaire, Institut Pasteur du Cambodge, Phnom Penh, Cambodia; and Peter H. David and Odile Mercereau-Puijalon of Unite d'Immunologie Moleculaire des Parasites, Institut Pasteur, Paris, France.
Sample collections and field laboratory works were supported in Madagascar by a Natixis Banques Grant, and in Cambodia by the Global Fund Grant Malaria Programme Round 9 (CAM-S10-G14-M). This work was funded by a Cleveland CTSC Pilot award to DS and a NIAID award to PAZ (R21 AI093922). DM was supported by the French Ministry of Foreign Affairs during this work and CD by a grant from Fondation Pierre Ledoux - Jeunesse Internationale (2010-2011).
LiveScience: Researchers at the Centers for Disease Control and Prevention found that one in 15 people in a remote region of Peru were protected from rabies because vampire bats expose them to the virus. "The new news here is that in areas in the world where rabies is endemic and there aren't vaccinations, there may be some resistance," said James Kazura, professor of international health.
The Fogarty International Center of the National Institutes of Health has recently awarded $1.25 million to scientists at Case Western Reserve University's School of Medicine and the Center for Global Health and Diseases to renew an educational program in infectious disease research training with collaborating institutions in Papua New Guinea.
This program, co-directed by Peter Zimmerman, professor of international health, biology and genetics, and Peter Siba, director, Papua New Guinea Institute of Medical Research (PNGIMR), extends a 29-year history of productive ID research collaborations between CWRU and PNGIMR initiated by James Kazura and former PNGIMR Director Michael Alpers. CWRU collaborators on this renewed Fogarty Training grant include Christopher Cullis, chairman of the Department of Biology, and Scott Frank, director of the Masters of Public Health Program. The program adds expertise in entomology through collaboration with Edward Walker and Ernest Delfosse, chairman of the Department of Entomology at Michigan State University. Renewal of this training program was announced at PNG's National Medical Research Symposium in early September.
The School of Medicine and College of Arts and Sciences, as well as MSU's Department of Entomology, have contributed significant institutional support to this ID Training Program.
Phase I of the Program (2005-2010) supported one-year undergraduate honors thesis projects on infectious disease research including mosquito resistance to insecticides, malnutrition, drug resistant tuberculosis and a range of studies focused on malaria. During this time 23 students finished their Bachelor of Science Honors thesis projects; 5 completed or are nearing completion of Masters of Medical Science requirements. Results of the students' research have been published in the Malaria Journal, the American Journal of Tropical Medicine and Hygiene and Clinical Infectious Diseases. Many of these students have received awards to present their ID research findings at international scientific meetings and scholarships to continue their graduate education in Europe, Australia, Japan and the United States.
Three of these students received Fulbright International Scholarships to pursue master's degrees in the United States: two at CWRU and one at Michigan State University. These students provided the inspiration for the renewal proposal submitted in November 2010. In Phase II of this ID Research Training Program (2011-2016) students will receive two years of support to pursue graduate degrees in biology or public health at CWRU or in entomology at MSU.
PNG students who are part of the first in-take cohort include Krufinta Bun and Barne Willie at CWRU and John Keven at MSU.
New funding from the National Institute of Health's Fogarty International Center and the National Institute of Nursing Research will support three post-doctoral trainees in anthropology, epidemiology and nursing from Case Western Reserve University. Over the next year, the trainees will undertake behavioral science research in Papua New Guinea to study self management of potential drug treatments for lymphatic filariasis.
As part of the training, they will collaborate on a trial of potential drugs to destroy the lymphatic filariasis parasite that causes blockages in the lymphatic system.
James Kazura and Christopher King from the Center for Global Health and Disease at Case Western Reserve School of Medicine direct the drug study. The principal investigators on the new, one-year $228,000 grant are Elizabeth Madigan, professor at the Frances Payne Bolton School of Nursing; Janet McGrath in the Department of Anthropology in the College of Arts and Sciences; and Daniel Tisch in the Department of Epidemiology and Biostatistics in the School of Medicine.
The post-doc trainees represent three schools participating in the Global Health Framework project at Case Western Reserve University's Center for Global Health and Disease.
Started in 2007, the Framework is a collaboration to design interdisciplinary courses, provide mentored international opportunities and support a certificate program in global health.
The funds were made possible through federal stimulus money to jumpstart the economy and provide salaries and living abroad expenses.
Lymphatic filariasis causes a form of elephantiasis or gross enlargement of limbs and body parts, Madigan said. Afflicted individuals suffer from stigma and limited job and social opportunities.
Because this disease is not transmitted in the United States, sending trainees to places where the disease is endemic to learn from local science experts and see the disease's impact in the broader context of the community is important, Tisch said.
The university has been working in Papua New Guinea since 1983 and has long-standing research projects in the country, making it an ideal setting to train post-doc students in global health issues.
"The post-doctoral students will each have unique and valuable skills from their respective disciplines to contribute to the implementation of the drug trial," Tisch said.
"This is an unusual opportunity to fund post-docs fellows for overseas research," Madigan said, explaining funds usually are made available to support foreign students coming into the country.
"The opportunity to work in a cross-disciplinary team to address a serious health issue in underserved populations is exciting and prepares the trainees for careers in global health in their respective disciplines," McGrath said, noting that the post-doctoral project is an important new expansion of the Global Health Framework project.
A mutation on the surface of human red blood cells provides protection against malaria caused by the parasite Plasmodium vivax, research led by Case Western Reserve University School of Medicine shows. The minute change, at a single position of red blood cell surface protein called the Duffy blood-group antigen, has been known for years. But the researchers found this mutation makes it harder for the parasite to lock onto the red cell surface and gain entry. No entry, no infection.
The research is now published in the advanced online edition of the Proceedings of the National Academy of Sciences. "The findings has practical implications as medical researchers continue attempts to develop vaccine for vivax malaria," said Christopher King, a professor of international health, medicine and pathology at the Center for Global Health and Diseases at Case Western Reserve University School of Medicine, and lead author.
The protective aspect of the mutation was discovered in campus labs and confirmed through a population study in the Amazon region of Brazil.
Malaria is caused by four different parasites, the majority of cases in Asia and the Americas are caused by P. vivax.
"Plasmodium vivax carries a Duffy binding protein that binds to the Duffy antigen on the surface of the red cell- a critical step to invading the cell," King explained. "Both parasite and human proteins appear to be needed for the parasite to invade the cell."
King's lab had been studying the parasite's protein as a target for a vaccine. He teamed with Peter A. Zimmerman, a professor of international health, genetics and biology, also at the Center for Global Health and Diseases. Zimmerman's lab was studying the mutation in the DNA sequence of Duffy blood group gene.
While investigating the binding process, they found that Duffy binding protein interaction with red blood cells varied between samples.
They performed the genetic tests for the single-point mutation. Antigens with the mutation are called Duffy 'A' and those without, Duffy 'B.'
They found the parasite bound to red blood cells expressing Duffy 'B' about twice as often as the parasite bound to cells expressing Duffy 'A.'
The researchers then wanted to see if the finding translated to real life.
They collaborated with Marcelo U. Ferreira, an investigator at the Department of Parasitology, Institute of Biomedical Sciences, University of Sao Paulo, to analyze data from 400 individuals tracked for malaria infections for more than a year in northwest Brazil.
In northwestern Brazil, where a mixture of Duffy 'A' and 'B' variants are inherited, the researchers found that people expressing the Duffy 'B' variant experience P. vivax malaria more often than those who expressed the Duffy 'A' variant.
"Therefore, stronger binding to Duffy 'B' leads to greater success at red cell invasion and more vivax malaria," Zimmerman said. "Seen from the other side of this relationship, weaker binding to Duffy 'A' appears to reduce red cell invasion and is therefore protective against vivax malaria."
The analysis showed that those with the Duffy 'A'/Duffy 'A' genotype had a 29 percent reduced risk of vivax malaria. Those who had the Duffy 'A'/Duffy 'B-negative' (a variant that has no antigen) genotype, had an 80 percent reduced risk. Reduced risk was not associated with an increase in antibodies in either case.
Those with Duffy 'B'/Duffy 'B' or Duffy 'B'/Duffy 'B-negative' genotypes had an increased risk of 220 to 270 percent for vivax malaria.
A vaccine's effectiveness therefore may depend on whether a recipient carries one or two copies of the Duffy 'A' or 'B' mutation in his DNA, King said.
"The Duffy 'B' variant is ancestral to Duffy 'A.' We know this because all non-human primates carry the Duffy 'B' variant," Zimmerman said. "So a case can be made for the Duffy 'A' variant arising as protection frm vivax malaria."
In a further analysis, the researchers found no association with the Duffy 'A' variant and Plasmodium falciparum, the parasite that causes the majority of infections in sub-Saharan Africa and the cause of 66 cases among the 400 individuals studied.
The National Institute of Allergy and Infectious Diseases has recently named Case Western Reserve University the lead institution of an International Center of Excellence for Malaria Research. The $7.9M seven-year grant will be lead by principal investigator James Kazura, MD, Director of the Center for Global Health and Diseases, and will work to eliminate Malaria worldwide.
The prestigious center is one of ten new malaria research centers around the world. James Kazura, MD, Professor of International Health and Medicine at Case Western Reserve University will serve as the principal investigator of a project titled "Research to Control and Eliminate Malaria in SE Asia and SW Pacific."
Click here to learn more about the project in the article in Medicus, the bi-annual magazine published by the CWRU School of Medicine.
Arlene Dent, M.D. Ph.D. received a two-year Thrasher New Researcher Award for her research proposal: "Ultrasound detection of abnormal placental blood flow as an early marker of placental malaria". The research will be conducted in Msambweni District Hospital in Kenya with Chris King, M.D.,Ph.D. as the mentor. Per their website , " The Thrasher Research Fund seeks to foster an environment of creativity and discovery aimed at finding solutions to children's health problems. The Fund awards grants for research that offers substantial promise for meaningful advances in prevention and treatment of children's diseases, particularly research that offers broad-based applications. "
The Center for Global Health and Diseases to lead broad international initiative to promote infectious disease education in Papua New Guinea
The Fogarty International Center of the National Institutes of Health has just awarded a training grant to scientists at Case Western Reserve University's School of Medicine, Center for Global Health and Diseases to lead an educational program in infectious disease (ID) research training.
This five-year program will be conducted in Papua New Guinea (PNG), a developing country located in the equatorial region of the South Pacific. The work will be done in collaboration with the PNG Institute of Medical Research and the University of PNG
This program, lead by Dr. Peter Zimmerman, extends a 23-year history of productive ID research collaboration with the PNG Institute of Medical Research initiated by Dr. James Kazura. Collaborators of the Fogarty grant include Dr. Cynthia Beall (Case, Department of Anthropology) and ID research experts from Australia and Switzerland. The program will be launched at PNG's National Medical Research Symposium in September of 2005, and will seek to fund short-term projects and Bachelors Honors and Masters level certificates for 75 Papua New Guinean students.
In PNG, malaria and pneumonia are the leading causes of illness and mortality. These infectious diseases are responsible for at least 30% of hospital admissions, and contribute to mortality rates in children under 5 years of age that are 18-24 times higher than those observed in the United States and Australia (UNICEF 2003 statistics; www.unicef.org).
The people of PNG represent extensive cultural and ethnic diversity. With over 850 spoken languages, this presents unique challenges to communication about infection, disease and health care.
To provide educational experiences most relevant to PNG's public health challenges, this ID research training program will emphasize the importance in-country educational experiences. Research training will introduce students to the complicated ID milieu where illness may include multiple pathogens and non-specific symptoms conceal the complexity of infections. Laboratory and field experiences will emphasize the importance of developing diagnostic tools and strategies that are practical for PNG. Clinical field-based experience will emphasize the importance of effective communication, accurate diagnosis and improved specificity of treatment for the most significant infectious pathogens in PNG.