With close to 50% of the world’s population living in endemic areas and it being one of the leading causes of death in children under the age of 5, malaria is a scourge that humans have endured since before they could walk fully upright. Moreover, the rate of resistance to current drug therapies is growing exponentially and scientists are always on the hunt for novel targets that have the potential to not only treat symptoms of infected patients, but also to block the transmission from the host to the mosquito vector.
Now, researchers from the Harvard T.H. Chan School of Public Health have discovered what they believe will become an indispensable new target for the development of antimalarial drug therapies. The scientists found that a malaria protein called calcineurin is essential for parasite invasion into red blood cells.
“Our study has great biological and medical significance, particularly in light of the huge disease burden of malaria,” explained senior author Manoj Duraisingh, Ph.D., professor of Immunology and Infectious Diseases at the T.H. Chan School of Public Health. “As drug resistance is a major problem for malaria control and eradication, it is critical that that we continue to develop new antimalarials that act against previously unexploited targets in the parasite to keep priming the drug pipeline.”
The findings from this study were published recently in Cell Host Microbe through an article entitled “Parasite Calcineurin Regulates Host Cell Recognition and Attachment by Apicomplexans.”
Using a mixture of reverse genetic and chemical genetic approaches the investigators were able to provide evidence for the function and essentiality of calcineurin and its associated signaling pathway for the parasite invasion mechanism. The Harvard team found that the protein enables the malaria parasites to recognize and attach to the surface of red blood cells—a necessary process not only for invasion, but an essential element to the overall survival of the parasite.
Interestingly, the researchers found that the inhibition of calcineurin rendered the parasites non-infective to red blood cells. Furthermore, studies from another group publishing in the same issue of the journal, showed that calcineurin inhibition was effective at different stages of the parasite life cycle, implicating the protein as a potential target for blocking malaria transmission.
Since there is much genetic conservation among parasites in the Apicomplexa phylum, the Harvard group worked closely with a team from Boston College to determine if calcineurin had a similar effect on the parasite, Toxoplasma gondii. Not surprisingly, this pathway seems to be conserved, as it prevented cellular attachment in this parasite species as well—opening up the potential that calcineurin could target other parasitic diseases in addition to malaria.
“Our study shows that the ability of malaria parasites to engage red blood cells is driven by an ancient mechanism for cellular attachment,” stated Aditya Paul, Ph.D., postdoctoral researcher in Dr. Duraisingh's laboratory and lead author on the current study. “In addition to a possible drug target, calcineurin underlies a very basic aspect of parasite biology.”