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New understanding of parasite biology might help stop malaria transmission

Date of news: 16 March 2018

Researchers at the Swiss Tropical and Public Health Institute and Radboud University made an important step toward deeper understanding of how malaria blood stage parasites turn the switch to become transmissible to other humans. This knowledge is fundamental for future research aiming to interrupt malaria transmission. The results are published on Friday 16 March 2018 in Science.

Malaria parasites multiply asexually in the human bloodstream, thereby causing chronic infection and all the complications associated with this devastating disease. During each round of multiplication, a small proportion of parasites develop into non-dividing gametocytes instead. Gametocytes are infectious to mosquitoes and are therefore the catalyst for transmitting malaria to other humans. Understanding how malaria parasites control the switch to gametocyte production is central to support the development of therapeutic interventions that could block malaria transmission.

Giemsa Färbung von p. falciparum Gametocyten in humanen roten Blutzellen_3_photo Eva Hitz_Swiss TPH

FOTO: Gametocytes in human red bood cells

The gametocyte stage poses a major obstacle to malaria elimination and eradication efforts. Hundreds of millions of people in malaria-endemic countries have gametocytes circulating in their blood, many of whom do not develop malaria symptoms, and hence, do not receive drug treatment. In addition, gametocytes are not effectively killed by most of the currently available antimalarial drugs.

How malaria parasites turn the switch

Whether a parasite continues to multiply or develops into a gametocyte is controlled by a molecular switch. It was recently demonstrated that this switch responds to a lipid molecule present in human blood: lysophosphatidylcholine (LPC). Under high LPC concentrations, parasites multiply, consuming LPC to build new membranes. When LPC concentrations drop, as they do during acute infections, parasites convert into gametocytes to secure their transmission to the next human host.

Researchers have now identified a parasite protein (GDV1) that plays a crucial role in activating the gametocyte conversion switch. “GDV1 basically ignites a process that reprograms gene expression in the parasite such that gametocyte development occurs”, said Till Voss, Head of the Malaria Gene Regulation Unit at Swiss TPH.

The molecular function of GDV1 was, until now, unknown. “We show that GDV1 interferes with the silencing of key regualtory protein (AP2-G) and hence enables multiplying parasites to turn into gametocytes”, explains Richard Bartfai, researcher at Radboud University.

“Fundamental knowledge and a new tool for future research”

Drugs and vaccines that target gametocytes are urgently needed to reach the declared aim of eliminating and eradicating malaria. “Although our study does not offer immediate solutions for novel therapies, it sheds new light on the mechanisms responsible for the production of gametocytes,” said Till Voss. “If we can block this mechanism or eliminate gametocytes altogether, we might get an important step closer to interrupting malaria transmission.”

The new knowledge also allows scientists to produce high quantities of gametocytes in the laboratory. “Research on gametocytes is hampered by the fact that they usually only arise in very small numbers. We are now able to engineer genetically-modified parasites that deliver enormous quantities of gametocytes. These will be useful for drug screening”, says Richard Bartfai.

Publication

Michael Filarsky, Sabine A. Fraschka, Igor Niederwieser, Nicolas M. B. Brancucci, Eilidh Carrington, Elvira Carrió, Suzette Moes, Paul Jenoe, Richárd Bártfai, Till S. Voss. GDV1 induces sexual commitment of malaria parasites by antagonizing HP1-dependent gene silencing. Science. DOI: 10.1126/science.aan6042

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