How do neutralising antibodies prevent erythrocyte invasion in malaria?

The interaction between the Plasmodium falciparum invasion receptor PfRH5 and human basigin is essential to allow this malaria parasite to get inside human erythrocytes and forms the target of the most promising blood stage malaria vaccines. Indeed, antibodies which bind to PfRH5 can neutralise parasite invasion and immunisation with PfRH5 can protect Aotus monkeys from parasite challenge.

Nevertheless, there are many mysteries surrounding the PfRH5-basigin interaction. First, we do not understand why the interaction is essential for erythrocyte invasion. What is the molecular mechanism underling its essential role? Second, the most effective invasion-inhibitory neutralising antibodies that target PfRH5 do not directly block PfRH5-basigin binding. How do they neutralise? These are the questions which Abhishek set out to answer.

Clues came when it was shown that, in many cell types, basigin is an obligate subunit of the monocarboxylate transporter, MCT1 or the plasma membrane calcium pump, PMCA. We therefore asked whether this is also the case in human erythrocytes and whether this affects PfRH5 binding and basigin function. Abhishek started by showing that the majority, and possibly all, basigin present in erythrocytes is bound to either MCT1 or PMCA and that these protein complexes bind tightly to PfRH5.

As one of the consequences of the PfRH5-basigin interaction is a change in calcium concentration at the parasite-erythrocyte interface, we wondered whether binding of PfRH5 to basigin-PMCA might alter PMCA-mediated calcium extrusion. However, this turned out to not be the case.

The good news was that studying basigin in complex with PMCA or MCT1 allowed us to reveal how neutralising antibodies work. While the best growth-inhibitory antibodies targeting PfRH5 do not prevent it from binding to free basigin, they do stop it from binding to the basigin-PMCA and basigin-MCT1 complexes, showing that they operate through a steric blocking mechanism. Future studies will investigate how we design vaccine immunogens which specifically induce the production of these effective most antibodies.

Jamwal, A., Constantin, C., Henrich, S., Bildl, W., Faklerrr, B., Draper, S.J., Schulte, U., Higgins, M.K. (2022) Erythrocyte invasion-neutralising antibodies prevent Plasmodium falciparum RH5 from binding to basigin-containing membrane protein complexes. eLife 12 e83681