Identification of an AP2-family protein that is critical for malaria liver stage development

PLoS One. 2012;7(11):e47557. doi: 10.1371/journal.pone.0047557. Epub 2012 Nov 7.

Abstract

Liver-stage malaria parasites are a promising target for drugs and vaccines against malaria infection. However, little is currently known about gene regulation in this stage. In this study, we used the rodent malaria parasite Plasmodium berghei and showed that an AP2-family transcription factor, designated AP2-L, plays a critical role in the liver-stage development of the parasite. AP2-L-depleted parasites proliferated normally in blood and in mosquitoes. However, the ability of these parasites to infect the liver was approximately 10,000 times lower than that of wild-type parasites. In vitro assays showed that the sporozoites of these parasites invaded hepatocytes normally but that their development stopped in the middle of the liver schizont stage. Expression profiling using transgenic P. berghei showed that fluorescent protein-tagged AP2-L increased rapidly during the liver schizont stage but suddenly disappeared with the formation of the mature liver schizont. DNA microarray analysis showed that the expression of several genes, including those of parasitophorous vacuole membrane proteins, was significantly decreased in the early liver stage of AP2-L-depleted parasites. Investigation of the targets of this transcription factor should greatly promote the exploration of liver-stage antigens and the elucidation of the mechanisms of hepatocyte infection by malaria parasites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anopheles / parasitology
  • Cell Nucleus / metabolism
  • Female
  • Gene Expression
  • Gene Expression Regulation
  • Gene Knockout Techniques
  • Hep G2 Cells
  • Hepatocytes / parasitology
  • Host-Parasite Interactions
  • Humans
  • Liver / parasitology*
  • Liver / pathology
  • Malaria / parasitology*
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Annotation
  • Molecular Sequence Data
  • Plasmodium berghei / genetics
  • Plasmodium berghei / metabolism
  • Plasmodium berghei / physiology*
  • Protein Transport
  • Protozoan Proteins / genetics*
  • Protozoan Proteins / metabolism
  • Rats
  • Salivary Glands / parasitology
  • Schizonts / metabolism
  • Schizonts / physiology
  • Sporozoites / metabolism
  • Sporozoites / physiology
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Trophozoites / metabolism
  • Trophozoites / physiology

Substances

  • Protozoan Proteins
  • Transcription Factors

Grant support

This work was supported by the Ministry of Education, Science, Culture, and Sports of Japan (grant 21022019). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.