According to the World Health Organization 2010 World Malaria Report, malaria, a mosquito-borne disease, affects 225 million people annually, and 781,000 of those infected die each year. Even so, an effective vaccine has yet to be developed. For scientists looking for a solution, the most significant barrier is the complexity of dealing with a parasite that develops in two stages in the human host: the liver stage and the blood stage.Noah Butler and Nathan Schmidt, postdoctoral fellows in microbiology at The University of Iowa, have helped discover a potential vaccination approach to fight malaria during both stages of the infective parasite’s life cycle in the host.
In a study published online June 15 in the journal Cell Host & Microbe, the scientists, using mouse models, showed that exposure to malarial parasites genetically engineered to stop developing very late during liver-stage development in the mammalian host elicits an immune response that combats the parasite during its liver stage and subsequent critical blood stage. When parasites enter the red blood cells, the host develops clinical malaria, which is associated with severe fever, chills, and anemia, or even unconsciousness or death if left untreated.“The conclusion of the study is that if you immunize with an attenuated malaria parasite that undergoes most of its liver-stage differentiation in the host, but then arrests very late during its developmental life cycle, you’re exposing the host to even more parasite antigens that serve as protective targets of immune cells,” says Butler, a co-lead study author with Schmidt. “This enhanced immunogenicity underlies the superior protective efficacy of late-liver-stage arresting parasite vaccination.”
An attenuated malaria parasite infects the host, but is unable to replicate or cause disease.
John Harty, a UI professor of microbiology and pathology and faculty member in the immunology interdisciplinary graduate program, is the senior study author and the mentor for Butler and Schmidt.
“The successful completion of this complex but potentially paradigm-shifting study was only made possible by the outstanding intellectual and experimental collaborative interactions between Drs. Butler and Schmidt,” Harty says. “As a mentor, it is a real pleasure for me to interact with such creative young scientists and see their efforts come to fruition.”
A radiation-attenuated vaccination approach, which is currently undergoing clinical trials, has been the most successful at stopping these parasites from differentiating into the blood stage. But Butler and Schmidt feel this radiation strategy leaves too much to chance compared with a genetically attenuated approach and doesn’t provide protection at the blood stage of infection.
“When you’re attenuating malaria parasites with radiation, it’s a random accumulation of mutations, whereas this genetically attenuated approach can pinpoint exactly what that mutation is and predict every time what the outcome is going to be for that parasite,” Schmidt says.
The researchers used two versions of genetically attenuated parasites (GAP)—one that arrests very early after it infects the host’s liver, and one that arrests much later during this liver stage.
They determined that late-liver-stage arresting GAP provided the mice superior protection against liver-stage infection when compared with early-liver-stage GAP and irradiated parasites.
“If you can have your own immune system deal with the infection, that is much better than using chemicals to control mosquitoes or drugs to eliminate the parasite after infection because both the mosquitoes and the parasites become resistant to these agents,” Schmidt says. “Also, if the parasite doesn’t stop at the liver stage, it goes into the second stage of the life cycle, the blood stage.
“Importantly, the blood stage is associated with all the health problems. What’s nice is that with this vaccination approach you stop the infection early on before showing signs of being sick.”
Butler says this genetic approach is at the first stage of clinical trials.
This research was published one month before Schmidt completed his postdoctoral appointment in Harty’s lab. This fall, Schmidt will join the microbiology faculty at the University of Tennessee.
He heads to Tennessee having learned a great deal from Harty.
“Members of the lab get direct feedback from an internationally recognized scientist, and I don’t think that’s necessarily true in a lot of really big labs with well-known principal investigators,” Schmidt says. “John takes our success very seriously. He really cares about our progression as postdocs, and that shows through in his response to mentoring.”
Butler will continue in the Harty lab this fall. He appreciates the wide range of responsibilities postdocs have in the lab.
“Postdocs in the Harty lab are well positioned for success as independent scientists,” Butler says. “In addition to the intellectual freedom to develop our own independent projects, we are heavily involved in mentoring graduate students, the peer review process, and grant writing, so our training is wide-ranging and focused on more than just becoming good experimentalists.”