Deletion of the rodent malaria ortholog for falcipain-1 highlights differences between hepatic and blood stage merozoites

Christine S. Hopp, Brandy L. Bennett, Satish Mishra, Christine Lehmann, Kirsten K. Hanson, Jing Wen Lin, Kimberly Rousseau, Filomena A. Carvalho, Wouter A. van der Linden, Nuno C. Santos, Matthew Bogyo, Shahid M. Khan, Volker Heussler, Photini Sinnis

Research output: Contribution to journalArticle

Abstract

Proteases have been implicated in a variety of developmental processes during the malaria parasite lifecycle. In particular, invasion and egress of the parasite from the infected hepatocyte and erythrocyte, critically depend on protease activity. Although falcipain-1 was the first cysteine protease to be characterized in P. falciparum, its role in the lifecycle of the parasite has been the subject of some controversy. While an inhibitor of falcipain-1 blocked erythrocyte invasion by merozoites, two independent studies showed that falcipain-1 disruption did not affect growth of blood stage parasites. To shed light on the role of this protease over the entire Plasmodium lifecycle, we disrupted berghepain-1, its ortholog in the rodent parasite P. berghei. We found that this mutant parasite displays a pronounced delay in blood stage infection after inoculation of sporozoites. Experiments designed to pinpoint the defect of berghepain-1 knockout parasites found that it was not due to alterations in gliding motility, hepatocyte invasion or liver stage development and that injection of berghepain-1 knockout merosomes replicated the phenotype of delayed blood stage growth after sporozoite inoculation. We identified an additional role for berghepain-1 in preparing blood stage merozoites for infection of erythrocytes and observed that berghepain-1 knockout parasites exhibit a reticulocyte restriction, suggesting that berghepain-1 activity broadens the erythrocyte repertoire of the parasite. The lack of berghepain-1 expression resulted in a greater reduction in erythrocyte infectivity in hepatocyte-derived merozoites than it did in erythrocyte-derived merozoites. These observations indicate a role for berghepain-1 in processing ligands important for merozoite infectivity and provide evidence supporting the notion that hepatic and erythrocytic merozoites, though structurally similar, are not identical.

Original languageEnglish (US)
Article numbere1006586
JournalPLoS Pathogens
Volume13
Issue number9
DOIs
StatePublished - Sep 1 2017

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Merozoites
Malaria
Rodentia
Parasites
Liver
Erythrocytes
Hepatocytes
Sporozoites
Peptide Hydrolases
falcipain
Plasmodium
Cysteine Proteases
Reticulocytes
Growth
Infection
Ligands
Phenotype
Injections

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Deletion of the rodent malaria ortholog for falcipain-1 highlights differences between hepatic and blood stage merozoites. / Hopp, Christine S.; Bennett, Brandy L.; Mishra, Satish; Lehmann, Christine; Hanson, Kirsten K.; Lin, Jing Wen; Rousseau, Kimberly; Carvalho, Filomena A.; van der Linden, Wouter A.; Santos, Nuno C.; Bogyo, Matthew; Khan, Shahid M.; Heussler, Volker; Sinnis, Photini.

In: PLoS Pathogens, Vol. 13, No. 9, e1006586, 01.09.2017.

Research output: Contribution to journalArticle

Hopp, CS, Bennett, BL, Mishra, S, Lehmann, C, Hanson, KK, Lin, JW, Rousseau, K, Carvalho, FA, van der Linden, WA, Santos, NC, Bogyo, M, Khan, SM, Heussler, V & Sinnis, P 2017, 'Deletion of the rodent malaria ortholog for falcipain-1 highlights differences between hepatic and blood stage merozoites', PLoS Pathogens, vol. 13, no. 9, e1006586. https://doi.org/10.1371/journal.ppat.1006586
Hopp, Christine S. ; Bennett, Brandy L. ; Mishra, Satish ; Lehmann, Christine ; Hanson, Kirsten K. ; Lin, Jing Wen ; Rousseau, Kimberly ; Carvalho, Filomena A. ; van der Linden, Wouter A. ; Santos, Nuno C. ; Bogyo, Matthew ; Khan, Shahid M. ; Heussler, Volker ; Sinnis, Photini. / Deletion of the rodent malaria ortholog for falcipain-1 highlights differences between hepatic and blood stage merozoites. In: PLoS Pathogens. 2017 ; Vol. 13, No. 9.
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