Characterization of the erythrocyte GTPase Rac1 in relation to Plasmodium falciparum invasion

Abstract

Malaria is still a devastating disease with 228 million cases globally and 405,000 lethal outcomes in 2018, mainly in children under five years of age. The threat of emerging malaria strains resistant to currently available drugs has made the search for novel drug targets compelling. The process by which Plasmodium falciparum parasites invade the host cell has been widely studied, but only a few erythrocyte proteins involved in this process have been identified so far. The erythrocyte protein Rac1 is a GTPase that plays an important role in host cell invasion by many intracellular pathogens. Here we show that Rac1 is recruited in proximity to the site of parasite entry during P. falciparum invasion process and that subsequently localizes to the parasitophorous vacuole membrane. We also suggest that this GTPase may be involved in erythrocyte invasion by P. falciparum, by testing the effect of specific Rac1 inhibitory compounds. Finally, we suggest a secondary role of the erythrocyte GTPase also in parasite intracellular development. We here characterize a new erythrocyte protein potentially involved in P. falciparum invasion of the host cell and propose the human GTPase Rac1 as a novel and promising antimalarial drug target.

In Vitro Antimalarial Activity of Inhibitors of the Human GTPase Rac1

“… a Data are the means ± standard deviations from at least 3 independent experiments in duplicate. b Data for EHT1864 and 1A116 were reported previously ( 17 ). …”

“…We previously showed that Rac1 is the only Rac GTPase present in mature erythrocytes ( 17 ). ML141 and Aza-1 also inhibit the closely related Rho GTPase CDC42 ( 22 , 31 ).…”

“…Interestingly, Rac1 was shown to play an important role in infection by many intracellular pathogens ( 8 – 15 ), including Toxoplasma gondii , which belongs to the same phylum as Plasmodium parasites ( 16 ). Recently, we investigated the possible involvement of Rac1 also in Plasmodium infection of RBCs ( 17 ). We showed that Rac1 is recruited in proximity to the site of parasite entry during the invasion process and that it subsequently localizes to the parasitophorous vacuole membrane, the membrane surrounding the parasite during its whole intraerythrocytic life.…”

“…We showed that Rac1 is recruited in proximity to the site of parasite entry during the invasion process and that it subsequently localizes to the parasitophorous vacuole membrane, the membrane surrounding the parasite during its whole intraerythrocytic life. By using two specific Rac1-inhibitory compounds, EHT1864 and 1A116, we demonstrated that the GTPase plays a role both in the invasion process and in parasite intracellular development ( 17 ).…”

Structural organization of erythrocyte membrane microdomains and their relation with malaria susceptibility

“…Interestingly, we found that erythrocyte DRM proteome includes the majority of proteins known to play a role in P. falciparum invasion: Semaphorin-7A 19 , protein G subunit alpha-s 20 , the blood group CD55 8 , Glycophorin A, and C 21 , Basigin receptor (BSG) 22 , the ATP-binding cassette sub-family B member 6 (ABCB6) 23 , and the Ras-related C3 botulinum toxin substrate 1 (Rac1) 24 .…”