Plasmepsin 4-deficient Plasmodium berghei are virulence attenuated and induce protective immunity against experimental malaria

Roberta Spaccapelo, Chris J. Janse, Sara Caterbi, Blandine Franke-Fayard, J. Alfredo Bonilla, Luke M. Syphard, Manlio Di Cristina, Tania Dottorini, Andrea Savarino, Antonio Cassone, Francesco Bistoni, Andrew P. Waters, John B. Dame, Andrea Crisanti

Research output: Journal PublicationArticlepeer-review

95 Citations (Scopus)


Plasmodium parasites lacking plasmepsin 4 (PM4), an aspartic protease that functions in the lysosomal compartment and contributes to hemoglobin digestion, have only a modest decrease in the asexual blood-stage growth rate; however, PM4 deficiency in the rodent malaria parasite Plasmodium berghei results in significantly less virulence than that for the parental parasite. P. berghei △pm4 parasites failed to induce experimental cerebral malaria (ECM) in ECM-susceptible mice, and ECM-resistant mice were able to clear infections. Furthermore, after a single infection, all convalescent mice were protected against subsequent parasite challenge for at least 1 year. Realtime in vivo parasite imaging and splenectomy experiments demonstrated that protective immunity acted through antibody-mediated parasite clearance in the spleen. This work demonstrates, for the first time, that a single Plasmodium gene disruption can generate virulence-attenuated parasites that do not induce cerebral complications and, moreover, are able to stimulate strong protective immunity against subsequent challenge with wild-type parasites. Parasite blood-stage attenuation should help identify protective immune responses against malaria, unravel parasite-derived factors involved in malarial pathologies, such as cerebral malaria, and potentially pave the way for blood-stage whole organism vaccines.

Original languageEnglish
Pages (from-to)205-217
Number of pages13
JournalAmerican Journal of Pathology
Issue number1
Publication statusPublished - Jan 2010
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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