Key molecular signal allows malarial parasites to target human red blood cells

Northwestern University researchers have identified a key molecular "signal" that allows malarial parasites to release virulence proteins inside human red blood cells.

The investigators, led by Kasturi Haldar and N. Luisa Hiller, also found that the process by which the malarial parasite remodels red blood cells is far more complex than scientists previously had realized.

Haldar is Charles E. and Emma H. Morrison Professor in Pathology and professor of microbiology-immunology and Hiller a sixth-year student in the Integrated Graduate Program in the Life Sciences at Northwestern University Feinberg School of Medicine.

Other key researchers on this study were Souvik Bhattacharjee; Christiaan van Ooij; Konstantinos Liolios; Travis Harrison; and Carlos Estrano.

Findings from the Northwestern study were published in the Dec. 10 issue of the journal Science.

Malaria is a blood-borne illness transmitted by mosquitoes. Forty percent of the world's population lives at risk for infection, and between 200 and 300 million people are afflicted each year, particularly in underdeveloped and impoverished tropical and sub-Saharan countries.

Plasmodium faciparum is the most virulent form of the four human malarial parasite species, killing over 1 million children each year, and is responsible for 25 percent of infant mortality in Africa, according to the World Health Organization.

Following invasion of human red blood cells – the "blood stage" of malaria – P. falciparum exports proteins that modify the properties of the host red blood cell membrane, are required for parasite survival and are responsible for fatal pathologies such as cerebral – or "brain" – malaria as well as placental malaria.

It is during the "blood stage" of malaria when symptoms of malaria occur. These symptoms include fever and flu-like symptoms, such as chills, headache, muscle aches and fatigue, as well as complex disease pathologies of cerebral malaria (leading to coma), metabolic acidosis and anemia. Immunity is slow to develop, and left untreated, malaria may be fatal, taking its greatest toll in children and pregnant women.

How the malaria parasite targets proteins to the host red blood cell was essentially unknown. Using cutting-edge bioinformatic techniques combined with functional studies, the researchers identified a "signal" on exported parasite proteins that is required for their secretion into the host.

This signal is present on more than 320 proteins, which represents approximately 6 percent of total proteins encoded in the P. falciparum genome, indicating that modification of this export signal not only established a major host-targeting pathway but also enabled the recognition of a wide range of proteins (a "secretome") that present high-value candidate effectors of disease and infection.

Results revealed the power of functional informatics to lead scientists from the tip of the iceberg (five to 10 parasite proteins exported to the erythrocyte) to the global complexity of infection (where the parasite is exporting dozens of proteins).

Remarkably, 91 of the secretome proteins share few or no similarities with known cellular proteins, emphasizing novel and complex ways in which the malarial parasite establishes infection in human red blood cells.

These proteins represent a vastly expanded pool of major candidate targets to block blood stage infection as well as complex disease pathologies associated with acute and severe malaria.