Search

Abstract Malaria-causing Plasmodium parasites first replicate as liver stages (LS), which then seed symptomatic blood stage (BS) infection. Emerging evidence suggests that these stages impact each other via perturbation of host responses, and this influences the outcome of natural infection. We sought to understand whether the parasite stage interplay would affect live-attenuated whole parasite vaccination, since the efficacy of whole parasite vaccines strongly correlates with their extend of development in the liver. We thus investigated the impact of BS infection on LS development of genetically attenuated and wildtype parasites in female rodent malaria models and observed that for both, LS infection suffered severe suppression during concurrent BS infection. Strikingly and in contrast to previously published studies, we find that the BS-induced iron-regulating hormone hepcidin is not mediating suppression of LS development. Instead, we demonstrate that BS-induced host interferons are the main mediators of LS developmental suppression. The type of interferon involved depended on the BS-causing parasite species. Our study provides important mechanistic insights into the BS-mediated suppression of LS development. This has direct implications for understanding the outcomes of live-attenuated Plasmodium parasite vaccination in malaria-endemic areas and might impact the epidemiology of natural malaria infection.

Abstract Following their inoculation by the bite of an infected Anopheles mosquito, the malaria parasite sporozoite forms travel from the bite site in the skin into the bloodstream, which transports them to the liver. The thrombospondin-related anonymous protein (TRAP) is a type 1 transmembrane protein that is released from secretory organelles and relocalized on the sporozoite plasma membrane. TRAP is required for sporozoite motility and host infection, and its extracellular portion contains adhesive domains that are predicted to engage host receptors. Here, we identified the human platelet-derived growth factor receptor β (hPDGFRβ) as one such protein receptor. Deletion constructs showed that the von Willebrand factor type A and thrombospondin repeat domains of TRAP are both required for optimal binding to hPDGFRβ-expressing cells. We also demonstrate that this interaction is conserved in the human-infective parasite Plasmodium vivax, but not the rodent-infective parasite Plasmodium yoelii. We observed expression of hPDGFRβ mainly in cells associated with the vasculature suggesting that TRAP:hPDGFRβ interaction may play a role in the recognition of blood vessels by invading sporozoites.