We are a group of researchers fascinated by the tricks that parasites use as they interact with their human hosts. We understand in molecular detail the interactions that parasite surface molecules make during events such as host cell invasion or nutrient acquisition. We study how they hide from the immune system and how they manipulate human immunity. We use these insights to guide the design of improved therapeutic agents, including vaccines and monoclonal antibodies.
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Revealing how PfRH5, from the malaria parasite Plasmodium falciparum, can be inhibited by human antibodies
Showing how RIFINs from the surface of malaria-infected erythrocytes activate inhibitory receptors on our immune cells.
Parasitic organisms, such as those that cause malaria, sleeping sickness and amoebic dysentery have evolved with humans for as long as we have existed. As a result, they have many tricks which allow them to evade our defences and to replicate with our bodies, often resulting in our sickness and death. The Higgins lab study at a molecular level many aspects of how parasites interact with their human hosts and use this insight to design improved therapeutics.
One of our major themes is to understand how the parasites that cause malaria get inside our red blood cells. These parasites can only replicate within our cells. Therefore, if we can prevent the process of erythrocyte invasion, we can stop the symptoms and transmission of malaria. We have particularly focused on structurally characterising a protein complex, containing five components, which is essential for erythrocyte invasion. We showed how the PfRH5 parasite surface protein binds to the human receptor, basigin. We have revealed the structure of the PfRH5-PfCyRPA-PfRIPR parasite complex, essential for invasion. We revealed how human antibodies that target PfRH5 can block invasion (Figure 1) and we use this information to design improved vaccine components.
We are also interested in the mechanisms that parasites use to manipulate our immune systems. Different branches of our immune response, including antibodies, the complement system and cellular immunity exist to destroy pathogens, such as parasites. These ancient parasites have therefore evolved many mechanisms which they can used to suppress immune responses. Here our studies include revealing how the RIFIN proteins from the malaria parasite signal to immune cells to reduce their activation (Figure 2) and how trypanosomes inactivate complement. We hope that learning the tricks of parasites will show us how to regulate the activity of our immune systems.
Matt is the EPA Professor of Structural Biology, a post jointly held between the Department of Biochemistry, The Kavli Institute for NanoScience Research and the Dunn School. His research group is based in the Dorothy Crowfoot Hodgkin Building.
2023
Structural basis for DARC binding in reticulocyte invasion by Plasmodium vivax.
Moskovitz, R., Pholcharee, T., DonVito, S.M., Guloglu, B., Lowe, E., Mohring, F., Moon, R.W. & Higgins, M.K.
Nature Communications – 14(1):3637
2022
Structure of the malaria vaccine candidate Pfs48/45 and its recognition by transmission blocking antibodies
Ko, K.-T., Lennartz, F., Mekhaiel, D., Guloglu, B., Marini, A., Dueker, D.J., Long, C.A., Jore, M.M., Miura, K., Biswas, S. and Higgins, M.K.
Nature Communications – 13(1):5603.
2020
Structural basis for RIFIN-mediated activation of LILRB1 in malaria
Harrison, T.E., Mørch, A.M., Felce, J.H., Sakoguchi, A., Reid, A.J., Arase, H., Dustin, M.L. and Higgins, M.K.
Nature – 587(7833):309-312.
2020
Structure of the Inhibited State of the Sec Translocon
Gérard, S.F., Hall, B.S., Zaki, A.M., Corfield, K.A., Mayerhofer, P.U., Costa, C., Whelligan, D.K., Biggin, P.C., Simmonds, R.E. and Higgins, M.K.
Molecular Cell – 79(3):406-415.e7.
2019
Human Antibodies that Slow Erythrocyte Invasion Potentiate Malaria-Neutralizing Antibodies
Alanine, D.G.W…..Higgins, M.K.* & Draper, S.J.*.
Cell – 178(1):216-228.e21.
2017
One-step design of a stable variant of the malaria invasion protein RH5 for use as a vaccine immunogen
Campeotto, I., Goldenzweig, A., Davey, J., Barfod, L., Marshall, J.M., Silk, S.E., Wright, K.E., Draper, S.J., Higgins, M.K.* & Fleishman, S.J.*
Proc Natl Acad Sci USA – 114(5):998-1002.
2015
Structural conservation despite huge sequence diversity allows EPCR binding by the PfEMP1 family implicated in severe childhood malaria
Lau, C.K.Y, Turner, L., Jespersen, J.S., Lowe, E.D., Petersen, B., Wang, C.W., Petersen, J.E.V., Lusingu, J., Theander, T.G., Lavstsen, T. and Higgins, M.K.
Cell Host Microbe – 17(1):118-29.
2014
Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies
Wright K.E., Hjerrild K.A., Bartlett J., Douglas A.D., Jin J., Brown R.E., Illingworth J.J., Ashfield R., Clemmensen S.B., de Jongh W.A., Draper S.J. & Higgins M.K.
Nature – 515(7527):427-30.