Abstract
The protozoan parasite Plasmodium, causative agent of malaria, initially invades and develops in hepatocytes where it resides in a parasitophorous vacuole (PV). A single invaded parasite develops into thousands of daughter parasites. Survival of the host cell is crucial for successful completion of liver stage development. Nuclear factor erythroid-derived 2-related factor 2 (NRF2) is a transcription factor known to induce transcription of cytoprotective genes when activated. Here we show that NRF2 is activated in Plasmodium berghei-infected hepatocytes. We observed that this NRF2 activation depends on PV membrane resident p62 recruiting KEAP1, the negative regulator of NRF2. Disrupting the NRF2 gene results in reduced parasite survival, indicating that NRF2 signaling is an important event for parasite development in hepatocytes. Together, our observations uncovered a novel mechanism of how Plasmodium parasites ensure host cell survival during liver stage development.
Highlights
Malaria is caused by the protozoan parasite Plasmodium, which is transmitted by Anopheles mosquitoes
While we were not able to detect a significant phenotype in parasites developing in primary hepatocytes isolated from Nrf2-/- mice (Fig. S3 B&C), we found that parasite survival in HuH7 Nuclear factor erythroid-derived 2-related factor 2 (NRF2)-/cells was reduced to less than 40% compared to parasites infecting WT cells (Figure 5(a))
In this paper we provide evidence for the prosurvival transcription factor NRF2 to be involved in survival of Plasmodium parasites during liver stage development
Summary
Malaria is caused by the protozoan parasite Plasmodium, which is transmitted by Anopheles mosquitoes. There, Plasmodium actively invades hepatocytes by invaginating the host cell plasma membrane leading to the formation of a parasitophorous vacuole (PV) in which the parasite resides throughout liver stage development [3]. Nuclear factor erythroid 2-related factor 2 (NRF2), a member of the Cap’n’Collar (CNC) family of basic leucine zipper transcription factors, mediates intrinsic resistance to oxidative stress and controls the adaptive responses to various environmental stressors It binds to a cis-acting enhancer with a core nucleotide sequence of 5′RTGACNNNGC-3′ that is known as the antioxidant response element (ARE) to control the basic and inducible. Several NRF2 target genes have recently been shown by single cell mRNA seq analysis to be upregulated upon P. berghei infection of hepatocytes [13] Another transcriptome study in P. vivax-infected hepatocytes identified NRF2 regulated expression as a pathway supporting parasite persistence suggesting an important and conserved function of this host cell transcription factor [14]. We provide first evidence of the NRF2-signaling pathway contributing to Plasmodium survival during its liver stage development
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