A novel human liver-chimeric mouse model developed at Oregon Health & Science University and Yecuris Corporation has made possible a research breakthrough at Seattle Biomedical Research Institute that will greatly accelerate studies of the most lethal forms of human malaria.
This image shows a maturing Plasmodium falciparum liver stage parasite in the liver of the human liver-chimeric FRGTM KO. Membranes of the developing merozoites are shown in red, DNA in blue, and the human hepatocytes within the liver-chimeric FRGTM KO mouse are shown in green.
Credit: Seattle Biomedical Research Institute
The study findings are published online in the Journal of Clinical Investigation. Study photos were selected to appear in "Scientific Show Stoppers" on the JCI blog.
Plasmodium falciparum, one of two human-specific malaria parasites, is a global health crisis, causing more than 216 million new infections annually and resulting in an estimated 655,000 deaths, according to the World Health Organization.
Sporozoites, the infectious form of the parasite, are spread to people through the bites of infected mosquitos and multiply in the human liver during the initial stages of infection. There, they undergo liver stage development, culminating in the formation and release of tens of thousands of merozoites, the parasitic phase of development that infects red blood cells.
Until now, there have been few data on human malaria liver stage biology due to the lack of a viable small animal model and because liver stage P. falciparum does not grow well in a dish. Consequently, most research and therapeutics to date have targeted the human blood stage of P. falciparum's development because it replicates well in culture.
The liver-to-blood stage of P. falciparum is the focus of this research because the parasite is virtually harmless, causing no disease symptoms, prior to its transition to the blood stage.
In this study, researchers at Seattle Biomedical Research Institute, Yecuris Corporation, Oregon Health & Science University and The Rockefeller University have demonstrated that a complete liver-to-blood stage infection of P. falciparum is possible using a unique immunocompromised mouse model engrafted with human liver-chimeric cells.
The mouse model, termed the FRGTM KO mouse, was developed by paper co-author and internationally accomplished stem cell researcher Markus 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 Yecuris Corporation, a biotechnology company that now produces the model and human hepatocytes on a commercial scale. As a result of this work, the FRGTM KO mouse now will be used to study new drug interventions, parasite attenuation and innate immune responses to P. falciparum liver stage infection.The scientists also report that through the infection of the FRGTM KO mouse model, they were able to observe a previously unknown expression of proteins in liver stage development in humans that may be exploited for intervention. Equally important, they say, the FRGTM KO mouse could well provide unique opportunities for the study of another severe form of human malaria, Plasmodium vivax.
Grompe founded Yecuris Corporation in 2007 and is a shareholder. John Bial, who joined Yecuris in 2009, is president and chief executive officer.
"The extensive collaborative relationships and risk-taking involved in planning and executing this research is a testament to the tireless dedication of these teams to solving one of the globe's oldest killers. It also highlights how private and public funding can come together effectively to address critical challenges in global health," said Bial.
"This first demonstration of the newly developed dual humanized FRGTM KO system is a good introduction to the kinds of translational medicine benefits that we can expect to see from these technologies. We anticipate that the next frontier for these systems will be as platforms for human vaccine development and validation, which may very likely first be tested in the area of malaria," Bial explained.
Investigators who contributed to this work include: Stefan Kappe, Ashley Vaughan, Sebastian Mikolajczak, Alexis Kaushansky, Nelly Camargo, Seattle Biomedical Research Institute; Elizabeth Wilson, John Bial, Yecuris Corporation; Markus Grompe, Papé Family Pediatric Research Institute, Oregon Stem Cell Center, Oregon Health & Science University, Doernbecher Children's Hospital; and Alexander Ploss, Center for the Study of Hepatitis C, The Rockefeller University.
Today's JCI study, "Complete Plasmodium falciparum liver stage development in liver-chimeric mice," was funded by grants to the Seattle Biomedical Research Institute from the Bill and Melinda Gates Foundation and the Department of Defense.
The Oregon Health & Science University research leading to the development of the FRGTM KO mouse was funded by the National Institutes of Health and The Oregon Opportunity fund.ABOUT OHSU
Tamara Hargens-Bradley | EurekAlert!
Meadows beat out shrubs when it comes to storing carbon
23.11.2017 | Norwegian University of Science and Technology
Migrating Cells: Folds in the cell membrane supply material for necessary blebs
23.11.2017 | Westfälische Wilhelms-Universität Münster
Heat from the friction of rocks caused by tidal forces could be the “engine” for the hydrothermal activity on Saturn's moon Enceladus. This presupposes that...
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
23.11.2017 | Information Technology
23.11.2017 | Physics and Astronomy
23.11.2017 | Life Sciences