Abstract
The malaria parasite Plasmodium obligatorily infects and replicates inside hepatocytes surrounded by a parasitophorous vacuole membrane (PVM), which is decorated by the host-cell derived autophagy protein LC3. We have previously shown that the parasite-derived, PVM-resident protein UIS3 sequesters LC3 to avoid parasite elimination by autophagy from hepatocytes. Here we show that a small molecule capable of disrupting this interaction triggers parasite elimination in a host cell autophagy-dependent manner. Molecular docking analysis of more than 20 million compounds combined with a phenotypic screen identified one molecule, C4 (4-{[4-(4-{5-[3-(trifluoromethyl) phenyl]-1,2,4-oxadiazol-3-yl}benzyl)piperazino]carbonyl}benzonitrile), capable of impairing infection. Using biophysical assays, we established that this impairment is due to the ability of C4 to disrupt UIS3–LC3 interaction, thus inhibiting the parasite’s ability to evade the host autophagy response. C4 impacts infection in autophagy-sufficient cells without harming the normal autophagy pathway of the host cell. This study, by revealing the disruption of a critical host–parasite interaction without affecting the host’s normal function, uncovers an efficient anti-malarial strategy to prevent this deadly disease.
Highlights
The malaria parasite Plasmodium obligatorily infects and replicates inside hepatocytes surrounded by a parasitophorous vacuole membrane (PVM), which is decorated by the host-cell derived autophagy protein LC3
LC3 towards the tubulovesicular network (TVN) in later stages of intrahepatic development to avoid elimination by the host cells[15], we have shown that Plasmodium’s PVM-resident protein UIS3 (Upregulated in infective sporozoites 3) interacts with LC3 from very early stages of infection and thereby prevents parasite elimination from the cells by the host autophagy machinery[11]
Having found that P. berghei and P. falciparum UIS3 binds to mouse and human LC3 and protecting the parasite from elimination by host cell autophagy[11], we hypothesise that disruption of this interaction by a small molecule would lead to parasite elimination and impaired infection
Summary
The malaria parasite Plasmodium obligatorily infects and replicates inside hepatocytes surrounded by a parasitophorous vacuole membrane (PVM), which is decorated by the host-cell derived autophagy protein LC3. We show that a small molecule capable of disrupting this interaction triggers parasite elimination in a host cell autophagy-dependent manner. Upon initiation of canonical autophagy, a double membrane autophagosome forms around the cellular materials that need to be degraded. Initially demonstrated as a response to cellular stress, autophagy is a well-established host defence mechanism that can substantially hinder the virulence of the intracellular pathogens[2]. Intracellular organisms have evolved various sophisticated strategies to manipulate this host cell pathway to their advantage or escape their recognition and capture by the autophagy machinery, preventing pathogen elimination from the host cell[3,4,5]
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