Liver stage malaria infection is controlled by host regulators of lipid peroxidation

Abstract

The facets of host control during Plasmodium liver infection remain largely unknown. We find that the SLC7a11-GPX4 pathway, which has been associated with the production of reactive oxygen species, lipid peroxidation, and a form of cell death called ferroptosis, plays a critical role in control of Plasmodium liver stage infection. Specifically, blocking GPX4 or SLC7a11 dramatically reduces Plasmodium liver stage parasite infection. In contrast, blocking negative regulators of this pathway, NOX1 and TFR1, leads to an increase in liver stage infection. We have shown previously that increased levels of P53 reduces Plasmodium LS burden in an apoptosis-independent manner. Here, we demonstrate that increased P53 is unable to control parasite burden during NOX1 or TFR1 knockdown, or in the presence of ROS scavenging or when lipid peroxidation is blocked. Additionally, SLC7a11 inhibitors Erastin and Sorafenib reduce infection. Thus, blocking the host SLC7a11-GPX4 pathway serves to selectively elevate lipid peroxides in infected cells, which localize within the parasite and lead to the elimination of liver stage parasites.

Unraveling Cell Death Pathways during Malaria Infection: What Do We Know So Far?

“…Paradoxically, a large amount of iron provides the supply for Plasmodium development in both liver and blood stages [ 246 , 254 ]. In this sense, a recent work developed by Kain and colleagues [ 166 ] showed that blocking of the SLC7A11-GPX4 pathway in P. yoelii -infected hepatocytes directs these cells to lipid peroxidation and death via ferroptosis; the same occurs when cells are treated with Erastin and Sorofenib, pharmacological inhibitors of SLC7A11 ( Figure 6 D). In contrast, pharmacological induction of p53 was not able to lead to ferroptosis under NOX1 or TFR1 blockage [ 166 ].…”

“…Unlike apoptosis and autophagy, necrosis is lytic cell death, which is traditionally described as a form of ACD (accidental necrosis, AN) [ 51 ]. However, regulated forms of necrosis (regulated necrosis, RN) have recently emerged, of which only pyroptosis, ferroptosis, and NETosis have been well-described in malaria so far [ 48 , 166 , 167 ]. AN and RN share some morphological characteristics, including cell swelling and the loss of membrane cellular integrity accompanied by the release of DAMPs to the extracellular environment, with immunological repercussions [ 52 ].…”

Ferroptosis: molecular mechanisms and health implications

“…185 Conversely, induced ferroptosis may be beneficial in the treatment of certain liver diseases, such as liver fibrosis or parasite infections of Plasmodium at the liver stage. 72,186 The heterozygous knockout of GPX4 in intestinal epithelial cells increases the inflammatory bowel disease (IBD) in mice caused by a PUFA-rich Western diet (containing 10% fish oil with omega-3 and omega-6 PUFAs). 59 The inhibition of ferroptosis by liproxstatin-1 and rosiglitazone (an ACSL4 inhibitor) also reduces intestinal I/R injury.…”

A genome-wide CRISPR-Cas9 screen identifies CENPJ as a host regulator of altered microtubule organization during Plasmodium liver infection

“…Recently, it was demonstrated that targeting host aquaporin 3 leads to the elimination of P. vivax hypnozoites from field isolates (Posfai et al, 2020), suggesting that host targeted interventions may provide an opportunity to tackle even the Achilles heel of malaria control efforts. Another host factor known to be critical for stages infection, the tumor suppressor p53 (Kain et al, 2020;Kaushansky et al, 2013), has been associated with lower severity of infection in Malian children (Tran et al, 2019). Additionally, it was recently demonstrated that host targeted interventions can induce at least partial immunity to subsequent challenge (Ebert et al, 2020).…”