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.
Malaria accounts for millions of cases and thousands of deaths every year. In the absence of an effective vaccine, drugs are still the most important tool in the fight against the disease. Plasmodium parasites developed resistance for all the classes of known antimalarial drugs. Thus, the search for antimalarial drugs with novel mechanisms of action is compelling. The human GTPase Rac1 plays a role in parasite invasion of the host cell in many intracellular pathogens. Also in Plasmodium falciparum , it was suggested an involvement of Rac1 both during the invasion process and parasite intracellular development. Aim of this work is to test a panel of Rac1 inhibitors as potential antimalarial drugs. Fourteen commercially available or newly synthesized inhibitors of Rac1 were tested for antimalarial activity. Among these, EHop-016 was the most effective against P. falciparum in vitro, with nanomolar IC 50 (138.8 ± 16.0 nM on the chloroquine-sensitive D10 strain and 321.5 ± 28.5 nM on the chloroquine-resistant W2 strain), and Selectivity Index of 37.8. EHop-016 did not inhibit parasite invasion of red blood cells but affected parasite growth inside them. Among the tested Rac1 inhibitors, EHop-016 showed a promising activity that raises attention on this class of molecules as potential antimalarials and deserves further investigation.
The Apicomplexa are obligate intracellular parasites responsible for several important human diseases. These protozoan organisms have evolved several strategies to modify the host cell environment to create a favorable niche for their survival. The host cytoskeleton is widely manipulated during all phases of apicomplexan intracellular infection. Moreover, the localization and organization of host organelles are altered in order to scavenge nutrients from the host. Small GTPases are a class of proteins widely involved in intracellular pathways governing different processes, from cytoskeletal and organelle organization to gene transcription and intracellular trafficking. These proteins are already known to be involved in infection by several intracellular pathogens, including viruses, bacteria and protozoan parasites. In this review, we recapitulate the mechanisms by which apicomplexan parasites manipulate the host cell during infection, focusing on the role of host small GTPases. We also discuss the possibility of considering small GTPases as potential targets for the development of novel host-targeted therapies against apicomplexan infections.
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