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Physical aspects of blood stage malaria
Malaria is one of the most common infectious diseases, affects 300 million people each year, causes nearly 1 million deaths, primarily children. Its elimination is hampered by the lack of an effective vaccine, and the recurrent evolution of parasites resistant to frontline drugs. In the blood stage of malaria, one parasite (P. falciparum merozoite) invades a red blood cell (RBC), then grows by repeated clonal divisions over about 48 hours, subverting the normal metabolism of the RBC: digesting haemoglobin, the merozoites release toxic heme groups. The parasites crystallise the heme into hemozoin. The metabolism of haemoglobin, and the formation of hemozoin crystals, are specific to this family of parasites and essential to their survival, hence these have been the targets for most malaria drugs up to now; current research is turning the focus also on invasion.
From typically a single infection, a merozoite multiplies over rounds of replication, with up to 20 parasites egressing into the bloodstream each generation. Here, the merozoites have a very short time (about a minute) to adhere and invade a new host cell, and start a new round of clonal growth. This process, repeated over weeks, leads to high fractions of infected RBC and huge numbers of parasites. This is at the root of most human symptoms (e.g. anaemia and haemorrhage) and mortality.
Over time, five PhD students worked on malaria in my lab: Alex Crick, Yen Chun Lin, Viola Introini, Kate Webber and Emma Kals. Viola has continued as an academic in this field and now is group leader in Erlanghen. A research project (EPSRC, funded 2018-2019) allowed us to develop low-cost microscopes in house, with similar optical specification to high end commercial units. This is essential to increase throughput and enable us to test a variety of conditions, on the human genotype side, on the parasite side, and drugs.
The blood stage of malaria can be replicated in the laboratory as a cell culture. In the last decade we have pushed the frontier of direct imaging and micromanipulation to provide single-cell information, which can be crucial, beyond from bulk methods, to disentangle the origin of population behaviours. Live single cell imaging is providing a new class of information which we and others refer to as "invasion phenotypes". Our most recent work has been with J.Rayner (CIMR). Our actual malaria lab, and the mass of help needed for starting up in this area, all came from malaria biologists Teresa Tiffert and Virgilio Lew.
As an example of surprising insights gained using biophysical techniques, we have found strong evidence of the role of RBC tension in regulating the probability of a successful parasite invasion. [S. Kariuki, et al., Nature 585, 579-583 2020].
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