Red blood cell BCL-xL is required for Plasmodium falciparum survival: insights into host-directed malaria therapies

ABSTRACT: The development of antimalarial drug resistance is an ongoing problem threatening progress towards malaria elimination, and antimalarial treatments are urgently needed for drug-resistant malaria infections. Host-directed therapies (HDT) represent an attractive strategy for the devel-opment of new antimalarials with untapped targets and low propensity for resistance. In addi-tion, drug repurposing in the context of HDT can lead to a substantial decrease in the time and resources required to develop novel antimalarials. Host BCL-XL is a major target in anti-cancer therapy and is essential for the development of numerous intracellular pathogens. We hypothe-sised that red blood cell BCL-XL is essential for Plasmodium development and tested this hypoth-esis by using six BCL-XL inhibitors, including one FDA-approved compound. All BCL-xL inhibitors tested impaired proliferation of P. falciparum 3D7 parasites in vitro at low parasite inhibitory concentrations. Western blot analysis and immunofluorescence microscopy assays revealed that host BCL-xL is transferred from the host red blood cells (RBCs) to the parasite upon infection. Further, immunoprecipitation of BCL-XL coupled with mass spectrometry analysis identified that BCL-XL forms unique molecular complexes with human μ-calpain in uninfected RBCs, and with human SHOC2 in infected RBCs. These results open exciting perspectives for the development of host-directed antimalarial therapies and drug repurposing efforts.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human) Plasmodium Falciparum 365.1

TISSUE(S): Blood Cell, Blood

DISEASE(S): Plasmodium Falciparum Malaria

SUBMITTER: Ghizal Siddiqui  

LAB HEAD: Teresa Carvalho

PROVIDER: PXD032276 | Pride | 2022-05-19

REPOSITORIES: Pride