Plasmodium berghei-Mediated NRF2 Activation in Infected Hepatocytes Enhances Parasite Survival

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.

Single-cell RNA profiling of Plasmodium vivax-infected hepatocytes reveals parasite- and host- specific transcriptomic signatures and therapeutic targets

“…Persistence of hypnozoites is contingent on the longevity of the hepatocyte in which it resides. The increased expression of genes associated with antioxidant stress ( Scarpulla, 2002 ) is consistent with the hypothesis that hypnozoite infection induces changes in the hepatocyte to promote cell survival, in which NRF2 could be playing a regulatory role ( Bindschedler et al., 2022 ). One host gene upregulated in infected hepatocytes validated by IFA, AKR1B10 , is regulated by NRF2, which activates protective pathways in response to oxidative stress ( Tebay et al., 2015 ).…”

LC3B labeling of the parasitophorous vacuole membrane of Plasmodium berghei liver stage parasites depends on the V‐ATPase and ATG16L1

“…Both negative and positive effects have been correlated with LC3B localization to the PVM (Prado et al., 2015; Real et al., 2018; Thieleke‐Matos et al., 2016; Wacker et al., 2017). A strong and prolonged LC3B labeling of the PVM has been shown to result in parasite elimination, but LC3B is also known to attract signaling molecules like p62, which can be beneficial for parasite survival (Bindschedler et al., 2022; Prado et al., 2015; Schmuckli‐Maurer et al., 2017). The answer might be that the level of LC3B localization at the PVM at a given time makes the difference.…”

“…We previously published that parasite survival is positively supported by host cell signaling initiated by LC3B localization at the PVM. Through recruitment of p62 to the PVM by LC3B, the KEAP1‐NRF2 pro‐survival pathway is activated (Bindschedler et al., 2022). Interestingly, in the absence of the transcription factor NRF2, parasite survival is decreased to a similar extent as in SopF‐expressing cells suggesting a link between non‐canonical LC3B lipidation and NRF2 signaling.…”

Machine learning for predicting Plasmodium liver stage development in vitro using microscopy imaging

“…In this study, we delve into the liver stage development of the P. berghei parasite and examine the host-parasite interactions using HeLa cells. HeLa cells, derived from a human cervical cancer cell line [37] ], have been extensively utilized for P. berghei infections, as demonstrated in our recent publications [38] , [39] , [40] . This research is primarily focused on in vitro analysis and does not extend to in vivo applications.…”