Malaria parasite liver stages render host hepatocytes susceptible to mitochondria-initiated apoptosis.
Intracellular eukaryotic parasites and their host cells constitute complex, coevolved cellular interaction systems that frequently cause disease. Among them, Plasmodium parasites cause a significant health burden in humans, killing up to one million people annually. To succeed in the mammalian host after transmission by mosquitoes, Plasmodium parasites must complete intracellular replication within hepatocytes and then release new infectious forms into the blood. Using Plasmodium yoelii rodent malaria parasites, we show that some liver stage (LS)-infected hepatocytes undergo apoptosis without external triggers, but the majority of infected cells do not, and can also resist Fas-mediated apoptosis. In contrast, apoptosis is dramatically increased in hepatocytes infected with attenuated parasites. Furthermore, we find that blocking total or mitochondria-initiated host cell apoptosis increases LS parasite burden in mice, suggesting that an anti-apoptotic host environment fosters parasite survival. Strikingly, although LS infection confers strong resistance to extrinsic host hepatocyte apoptosis, infected hepatocytes lose their ability to resist apoptosis when anti-apoptotic mitochondrial proteins are inhibited. This is demonstrated by our finding that B-cell lymphoma 2 family inhibitors preferentially induce apoptosis in LS-infected hepatocytes and significantly reduce LS parasite burden in mice. Thus, targeting critical points of susceptibility in the LS-infected host cell might provide new avenues for malaria prophylaxis.
Seattle Biomedical Research Institute, Seattle, WA 98109, USA. alexis.kaushansky@seattlebiomed.org
A
A
Kaushansky
P G
PG
Metzger
A N
AN
Douglass
S A
SA
Mikolajczak
V
V
Lakshmanan
H S
HS
Kain
S Hi
SH
Kappe
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes / Q000469:parasitology* / Q000473:pathology; D007211:Indoles; D008288:Malaria / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D059208:Parasite Load; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction
D007211:Indoles; D011758:Pyrroles; C520962:obatoclax