British scientists have successfully cultivated red blood cell lines that can be genetically manipulated for use in research into malaria.
Research into the mechanisms of malaria infection has been hampered by the fact that mature red blood cells lose their nucleus during development, and therefore have no DNA. This means that experiments where genes are removed from red blood cells and the effects on parasite invasion are studied cannot be carried out.
However, a cell line developed in Bristol and provides unlimited numbers of erythroblast-like cells, which do have a nucleus. These cells are also able to produce reticulocytes (early red blood cells) without nuclei.
In this study, the researchers have confirmed that these new cells can be infected by the Plasmodium falciparum parasite, one of the causative agents of malaria. The parasites continue to develop normally inside the reticulocytes.
The research has been carried out by scientists from the University of Bristol and Imperial College London, and the results reported in the journal Nature Communications.
To demonstrate the ability to conduct genetic experiment on these cells, the team carried out an initial study of the basigin protein, thought to be critical to susceptibility to the malaria parasite. They used CRISPR-Cas9 to edit the genome of immature cells to knockout the BSG gene for basigin, and so remove the protein. The reticulocytes generated were completely resistant to invasion, but reintroduction of the gene restored the parasites’ ability to invade – demonstrating the importance of basigin to P. falciparum infection.
Lead author Dr Tim Satchwell, from Bristol, said: “The ability to alter protein expression in the red blood cell and study the effect that these changes have on parasite invasion or development is hugely exciting.
“This system has opened up many new potential avenues of research that should allow us to better understand the mechanism by which the malaria parasite is able to successfully invade the red blood cell, and the specific roles that host cell proteins play in this process.”
Dr Ashley Toye, one of the senior authors of the study and Director of the NIHR blood and transplant research unit, said: “This work has shown that it is now possible to manipulate the red blood cell surface to better understand the process of malaria invasion. It also shows that our reticulocytes produced from the cell line are recognised by the parasite just the same as reticulocytes produced in the body.
“This is important as it provides further evidence that the cells are manufactured correctly in the laboratory.”
Source: Satchwell, T.J., Wright, K.E., Haydn-Smith, K.L., Sánchez-Román Terán, F., Moura, P.L., Hawksworth, J., Frayne, J., Toye, A.M., Baum, J. (2019) “Genetic manipulation of cell line derived reticulocytes enables dissection of host malaria invasion requirements”, Nature Communications, available from doi: 10.1038/s41467-019-11790-w
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