Media Release: Flexi is sexy for malaria parasite

11 April 2016

Human red blood cells have remarkable abilities, allowing them to bend, extend and ‘squeeze’ through capillaries as they circulate through the blood stream. Their durability and flexibility is due to a meshwork of spring-like proteins that assemble under the red blood cell surface. In work published today in PNAS, a team lead by biologists from the University of Melbourne’s Bio21 Institute, in collaboration with teams from the US and Singapore, have shown that the malaria parasite Plasmodium falciparum, is a master renovator of the red blood cells that it inhabits.

A cross-disciplinary team, involving biologists, mathematicians and engineers from top level institutions in the USA, Singapore and Australia has discovered how the sexual stage of the malaria parasite (Plasmodium falciparum) subverts its host red blood cell (RBC) in order to increase its chances of reproduction. It can expand and stiffen the mesh of “springs” to make the whole cell rigid, enabling it to hide in niches away from the circulation. Then 10 days later the sexually mature parasite further modifies the red blood cell meshwork making it flexible, allowing it to reenter the body’s circulation where it can be transmitted from human host to human host when a mosquito bites. These findings could provide targets for drugs that stop transmission of this deadly disease.

During circulation in the body, red blood cells squeeze through narrow slits in the spleen, which are only one quarter of red blood cell's size. The red blood cell membrane exhibits remarkable flexibility that enables it to pass this “squeeze test”. It can undergo dramatic deformation and then pop back to the original shape. If any red blood cell fails the “squeeze test” – which happens as the cell ages – it is removed from the circulation and destroyed.

The sexual stage of the malaria parasite develops inside red blood cells. As it develops the parasite changes its own shape and manipulates its host red blood cell membrane - first adopting a rigid form that can hide in niches away from the circulation. When the parasite is ready for transmission to another human, its reverses these changes, becoming flexible enough to survive in the circulation, where it can be picked up by a mosquito.

To work out exactly how this happens it was necessary to put together a cross-disciplinary team. The biologists prepared malaria parasites at different stages of sexual development in the laboratory and used exciting new imaging techniques – Super-Resolution Optical Microscopy and Atomic Force Microscopy - to study the membrane structure in exquisite detail. This revealed changes in the organization of a meshwork of tiny spring-like proteins in the red blood cell membrane.

The team then turned to engineering colleagues to try to understand how these molecular changes would affect the biomechanical properties of the cell. Engineers use sophisticated computer models to design functional products, such as airplane tyres. In this case they developed a mathematical model that explains how subtle changes to the molecular structure of the RBC membrane can change its flexibility. The work revealed that changing the tension on the spring-like proteins in the red blood cell membrane is sufficient to make the membrane rigid or flexible.

This approach highlights the value of physical and biological scientists working together. And it is pointing to new therapeutic approaches. For example drugs that block the parasite-induced rearrangements of the red blood cell membrane would be promising candidates as malaria transmission-blocking agents.

Malaria expert at the Bio21 Institute, University of Melbourne, Dr Matthew Dixon is available for comment.

Dr Matthew Dixon | 0422 387 286 | matthew.dixon [at] unimelb.edu.au

Publication: Dearnley, M.K., Trang, C.T.T., Zhang, Y.,  Looker, O., Huang, C., Klonis, N., Yeoman, J., Kenny, S., Arora, M., Osborne, J., Chandramohanadas, R., Zhang, S., Dixon, M.W.A. and Tilley, L. (2016) Host cell remodelling in sexual blood stages of the malaria parasite, Plasmodium falciparum. Proceedings of the National Academy of Sciences, USA (publication Apr 11, 2016)