Researchers at MIT revealed that they have developed a new system through which liver tissue can be grown to support the liver stage of the life cycle of the two most common variants of malaria causing parasite; Plasmodium falciparum and Plasmodium vivax.
This system could be used to test drugs and vaccines against both species, says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science at MIT.
Bhatia is the senior author of a paper describing the liver-tissue system in the July 17 issue of the journal Cell Host & Microbe
. The paper's lead author is Sandra March, a research scientist in Bhatia's lab, and scientists from the Broad Institute, Sanaria Inc. and the University of Lisbon also contributed to the research.
The malaria life cycle has several stages. Once the parasite infects a human victim, through a mosquito bite, it takes up residence in the liver. The parasite spends about a week in the liver, producing tens of thousands of copies that eventually burst free to infect blood cells. After this initial infection, P. vivax
can lurk for weeks, months or even years, reactivating to cause another malaria bout.
So far, researchers have been able to grow P. falciparum
in human blood and, to a certain extent, in its liver stages, but they have not been able to reliably grow P. vivax
in either stage. P. falciparum
has the highest malaria mortality rate, but P. vivax
can cause debilitating, long-term infections. To eradicate malaria, drugs and vaccines that target both species will probably be needed, Bhatia says.
Bhatia — who is also a senior associate member of the Broad Institute and a member of MIT's Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science — has previously created micropatterned surfaces on which liver tissue can be grown, surrounded by supportive cells. These engineered cells survive for up to six weeks and mimic most of the functions of liver cells in the body, including drug metabolism and production of liver proteins.
Using unique, frozen samples of P. falciparum
obtained in collaboration with Stephen L. Hoffman and his team at Sanaria, the researchers infected healthy liver cells and observed the development of liver-stage parasites using an automated imaging system designed in collaboration with Anne Carpenter's group at the Broad Institute. This system allows them to quickly evaluate not only how much infection has occurred, but also the effects of potential drugs. They can also measure how weakened forms of the parasites, which could be used as vaccines, perform in the liver.
To test the system's usefulness, the researchers studied a P. falciparum
vaccine that is now in clinical trials. For a weakened, or attenuated, parasite to succeed as a vaccine, it must infect the liver and progress enough to raise an immune response, but then arrest and not reach the blood stage. The researchers showed that the vaccine now in trials does follow that trajectory.
The new system could also be used for larger-scale drug studies than previously possible, Bhatia says. Researchers now use liver cancer cells grown in the lab to study P. falciparum
infection, but those cells have deficient drug metabolism and keep growing instead of providing a quiet home for the parasite to persist.
Seeking P. vivax
Obtaining enough P. vivax
samples to test the system took several years, but the team eventually acquired samples, flown in from Thailand, India and South America. Using these samples, they were able to grow P. vivax
in liver tissue and show that it produces small persistent parasites that appear to be dormant forms called hypnozoites.
"We don't want to call them hypnozoites yet, because nobody has a gold-standard marker for them, but we have persistent small forms that live for three weeks. So we are optimistic and doing more to wake them up again. Reactivation would be the ultimate confirmation," Bhatia says.
The researchers are now working on confirming that the P. vivax
they grew in the liver tissue really did create hypnozoites. Once this is confirmed, they plan to start testing some candidate drugs, now in development, against P. vivax