077 Type I immunity induces a senescence-like growth arrest in malaria parasites

Abstract

Type I immunity kills and contains plasmodium species in mammalians. However, malaria tends to recur, showing that the natural type I immune response strongly reduces the pathogens but fails to eradicate them. Analyzing the effect of type I immunity on plasmodium-infected hepatocytes, we confirmed that indeed IFN (interferon)-γ strongly reduces parasite number. Surprisingly, we also found that IFN-γ induces in addition a senescence-like growth arrest in the remaining plasmodium parasites. One day of treatment with IFN-γ caused a stable growth-arrest over 14 days in surviving Plasmodium (P.) falciparum liver stages. IFN-γ induced small non-proliferating plasmodium forms in human, monkey and mouse hepatocytes. Atovaquone treatment killed the large majority of the remaining parasites confirming that these small forms are alive. In vitro data showed that mammalian p21 can interact with parasite cyclin-dependent kinases (CDK) PFMRK, PFPK5 and PFPK6. Inhibition of these CDKs with Artemisinin severely impairs the growth of P.falciparum, without killing the parasites. Therefore, we asked whether IFN-γ and plasmodium parasites induce p21 in mammalian hepatocytes and whether mammalian p21 can arrest P.falciparum in vivo. Liver-infection with plasmodium parasites leads to an interferon-response and induced p21 but not p16 protein levels inside primary hepatocytes. The p21 protein was further enhanced by treatment with IFN-γ and tumor necrosis factor. Most importantly, p210/0 hepatocytes had a major defect in containing malaria parasites in vitro. In consequence, infection of p210/0 mice had a major defect in controlling the onset and the extent parasitemia. Hence, type I immunity did not only kill malaria parasites but induced a p21-dependent senescence-like growth arrest in the remaining plasmodium stages. This IFN-γ induced senescence-like growth arrest significantly contributed to the containment of the disease.