Successful Plasmodium falciparum merozoite invasion requires the activation of red blood cell (RBC) signalling pathways. The binding of parasite ligand reticulocyte binding protein homologue 5 (RH5) to its host receptor Basigin is essential for merozoite invasion and triggers a Ca2+ influx in RBCs. Here we observed that RH5-bound RBCs form a multimeric protein complex containing Basigin, CD44 and β2-adrenergic receptor (β2AR), suggesting that RH5-Basigin interaction is functionally associated with the host cAMP signalling pathway. Interestingly, we detected a characteristic rise in cAMP levels in the RBC upon RH5-Basigin interaction, which can be blocked by G protein and cAMP-synthesising adenylyl cyclase (AC) inhibitors. Furthermore, we demonstrated that RBC L-type Ca2+ channel inhibitor and cAMP signalling inhibitors are able to block merozoite invasion. Checkerboard invasion inhibition assay containing different combinations of signalling inhibitors also exhibited a drastic amplification of inhibition levels, indicating that these signalling proteins are functioning in a common signalling cascade to activate the L-type Ca2+ channels. Taken together, this study provides new insights into the role of a host cAMP-Ca2+ signalling pathway during merozoite invasion and sheds new light on antimalarial therapeutic strategies to tackle the high infection rate and growing threat of drug resistant parasites.Key PointsA pre-existing Basigin-associated membrane protein complex undergoes increased protein assembly upon RH5 binding on the RBC surface.Plasmodium falciparum merozoite exploits host cAMP signalling to initiate Ca2+ influx in the RBC.
I would like to express my heartfelt gratitude to my supervisor, Professor Peter Preiser, for providing me with this opportunity and for sharing his decade-long experience and knowledge on the field of malaria research. His guidance has helped me immensely throughout the project.I would like to express my sincere appreciation to the invasion group members Dr Annie Gao and Dr Prem Prakash. Their research insights have assisted me greatly in my experiments and made my time in the laboratory a fulfilling and enjoyable experience. Special thanks to Annie for being such an amazing colleague not only for research but also for accompanying me to be well caffeinated and blessed with beer, gin, sake, umeshu and instant noodles.I would also like to thank the past and present members/associates of Preiser's lab. You have all been a brilliant group of lab mates and above all, a role model to aspiring researchers and students. I am truly grateful for all the help I have received from everyone. Furthermore, I would like to thank the Ministry of Education for my scholarship. Also, I would like to show my appreciation to our collaborators Associate Professor Li Hoi Yeung, Professor
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.