Seattle BioMed, Yecuris Corporation, Oregon Health and Science University and The Rockefeller University report findings in the Journal of Clinical Investigation
Researchers from Seattle Biomedical Research Institute (Seattle BioMed), Yecuris Corporation, Oregon Health and Science University and The Rockefeller University have developed a human liver-chimeric mouse model to study the liver stage of the human malaria parasite Plasmodium falciparum. This parasite causes the most lethal human malaria infections, killing upwards of 800,000 people per year. The researchers involved in the study have shown, for the first time, that human malaria liver stage development in the humanized mouse is complete and leads to a blood stage infection that can be maintained in blood culture. The research is published online in the Journal of Clinical Investigation (JCI), a premier scientific journal that highlights groundbreaking research on the clinical aspects of disease. Study photos from the research were selected to appear in “Scientific Show Stoppers” on the JCI blog.
“This is going to fundamentally change the way we can study human malaria parasites in the laboratory,” said Stefan Kappe, senior author of the study, principal investigator, full professor and director of the Malaria Program at Seattle BioMed.
The malaria parasite life cycle begins in humans when a female mosquito carrying the malaria parasite, bites an unsuspecting individual. As she bites, the mosquito deposits infectious malaria sporozoites at the bite site. Sporozoites make their way to the liver and invade an individual liver cell, the hepatocyte. Over the next week, the liver stage parasite replicates within the hepatocyte and ultimately releases tens of thousands of malaria merozoites into the blood stream. Merozoites infect red blood cells and the blood stages are responsible for all clinical symptoms of the disease that ultimately, can lead to death. The liver stage is ‘clinically silent’ and is impossible to study in humans – and unlike the blood stage of the disease, the liver stage cannot be effectively cultured in the laboratory setting. Yet, the liver stage is a tantalizing target for drugs and vaccines because killing the liver stage parasite will prevent blood stage disease and further malaria transmission.
Researchers from the Kappe lab have worked in close collaboration with the Yecuris Corporation to develop a humanized mouse model to study human malaria liver stage development. The mouse in question, known as the FRG huHep mouse, has a humanized liver, containing human hepatocytes. The Seattle team infected the mouse with Plasmodium falciparum sporozoites and showed that the sporozoites travelled to the liver and infected human hepatocytes. The liver stage parasites then grew over the next seven days and finally released merozoites into the blood stream of the mouse – just as would happen in the liver of a human. When the FRG huHep mouse was also carrying human red blood cells, the merozoites released at the end of liver stage development infected these red blood cells causing blood stage malaria. The malaria blood stages could then be cultured in the lab. The transition of human malaria liver stages to a culturable blood stage has never been accomplished before in the laboratory using a small animal model. “This breakthrough will allow us to test the efficacy of drugs that target the liver stage parasites and the effect of attenuation on liver stage development”, Kappe explained. Additionally, since the FRG huHep mouse supports the liver stage to blood stage transition, it raises the possibility of using the mouse to carry out genetic crosses of Plasmodium falciparum strains. This has only ever been achieved in chimpanzees and on only three occasions. “Being able to perform genetic crosses in a small animal model of human malaria will help us understand drug resistance in Plasmodium falciparum and speed up the process of finding new drugs to target the malaria parasite,” said Kappe, “which will help in malaria eradication efforts”.
"This image shows a section of a mature Plasmodium falciparum liver stage parasite in the liver of the human liver-chimeric FRG huHep mouse. Individual merozoites are surrounded by a plasma membrane (red), and contain a single nucleus (blue) and a single apicoplast (green)."
"This image shows a maturing Plasmodium falciparum liver stage parasite in the liver of the human liver-chimeric FRG huHep mouse. Membranes of the developing merozoites are shown in red, DNA in blue and the human hepatocytes within the liver-chimeric FRG huHep mouse are shown in green."
The FRG huHep mouse was developed by nationally accomplished stem cell researcher and co-author of the paper, Marcus Grompe, M.D., in the Papé Family Pediatric Research Institute, a research arm of Oregon Health & Science University Doernbecher Children’s Hospital. In 2007 the technology was licensed to the Yecuris Corporation a biotechnology company that produces the model on a commercial scale.
Investigators who contributed to this work include: Stefan H. Kappe, Ashley M. Vaughan, Sebastian A. Mikolajczak, Alexis Kaushansky, Nelly Camargo, Seattle Biomedical Research Institute; Elizabeth M. Wilson, John Bial, Yecuris Corporation; Markus Grompe, Papé Family Pediatric Research Institute, Oregon Stem Cell Center, Oregon Healthy & Science University, Doernbecher Children’s Hospital; and Alexander Ploss, Center for the Study of Hepatitis C, The Rockefeller University.
The study was funded by grants awarded to Stefan H. Kappe from the Bill and Melinda Gates Foundation (OPP1016829) and the Department of Defense (W81XWH‐11‐2‐0184).
ABOUT SEATTLE BIOMEDICAL RESEARCH INSTITUTE:
Seattle BioMed is the largest independent, non-profit organization in the U.S. focused solely on infectious disease research. Our research is the foundation for new drugs, vaccines and diagnostics that benefit those who need our help most: the 14 million who will otherwise die each year from infectious diseases, including malaria, HIV/AIDS and tuberculosis. Founded in 1976, Seattle BioMed has nearly 400 staff members. By partnering with key collaborators around the globe, we ensure that our discoveries will save lives sooner. For more information, visit www.seattlebiomed.org.
ABOUT YECURIS CORPORATION
Portland, Oregon-based Yecuris Corporation was formed in April 2007 to commercialize transgenic mouse technology that was developed in the lab of Dr. Markus Grompe at the Oregon Health & Science University. The FAH(null) / RAG2(null) / IL2RG(null) (FRG huHep) mice were originally developed to explore pathways for Hereditary Tyrosinemia Type 1 (HT1), an often fatal pediatric disease. Based in part on support from the Grompe lab and the Yecuris™ mouse, medications have been developed to aid in the treatment of this disease.
Oregon Health & Science University is the state’s only health and research university. As Portland's largest employer, OHSU's size contributes to its ability to provide many services and community support activities not found anywhere else in the state. OHSU serves patients from every corner of the state and is a conduit for learning for more than 4,000 students and trainees. OHSU is the source of more than 200 community outreach programs that bring health and education services to each county in the state.
ABOUT THE ROCKEFELLER UNIVERSITY
The Rockefeller University is a world-renowned center for research and graduate education in the biomedical sciences, chemistry, bioinformatics and physics. The university’s 73 laboratories conduct both clinical and basic research and study a diverse range of biological and biomedical problems with the mission of improving the understanding of life for the benefit of humanity.
Throughout Rockefeller’s history, 24 of its scientists have won Nobel Prizes, 21 have won Lasker Awards and 20 have garnered the National Medal of Science, the highest science award given by the United States.
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