A Profound Membrane Reorganization Defines Susceptibility of Plasmodium falciparum Infected Red Blood Cells to Lysis by Granulysin and Perforin

Abstract

Malaria remains one of the most serious health problems in developing countries. The causative agent of malaria, Plasmodium spp., have a complex life cycle involving multiple developmental stages as well as different morphological, biochemical and metabolic requirements. We recently found that γδ T cells control parasite growth using pore-forming proteins to deliver their cytotoxic proteases, the granzymes, into blood residing parasites. Here, we follow up on the molecular mechanisms of parasite growth inhibition by human pore-forming proteins. We confirm that Plasmodium falciparum infection efficiently depletes the red blood cells of cholesterol, which renders the parasite surrounding membranes susceptible to lysis by prokaryotic membrane disrupting proteins, such as lymphocytic granulysin or the human cathelicidin LL-37. Interestingly, not the cholesterol depletion but rather the simultaneous exposure of phosphatidylserine, a negatively charged phospholipid, triggers resistance of late stage parasitized red blood cells towards the eukaryotic pore forming protein perforin. Overall, by revealing the molecular events we establish here a pathogen-host interaction that involves host cell membrane remodeling that defines the susceptibility towards cytolytic molecules.

Escaping Death: How Cancer Cells and Infected Cells Resist Cell-Mediated Cytotoxicity

“…Treatment of cancer cells with radiotherapy or cell cycle inhibitors did not affect perforin binding or membrane repair responses, suggesting that the mechanism of resistance was impaired pore formation, similar to the observed effects of phosphatidylserine in synthetic lipid membranes ( 68 , 73 , 74 ). Increased surface phosphatidylserine on malaria-infected erythrocytes also correlated with reduced susceptibility to perforin and reduced lysis by γδ T cells ( 84 ). The extent to which phosphatidylserine externalisation affects the elimination of target cells in vivo is unclear, and hard to establish.…”

The role of cholesterol in invasion and growth of malaria parasites

“…The plasma membrane of P. falciparum-infected erythrocytes contains less cholesterol compared to uninfected erythrocytes (Maguire and Sherman, 1990;Jackson et al, 2007;Orjih et al, 2008;Hernańdez-Castañeda et al, 2021). This finding is corroborated by the diminished susceptibility of infected erythrocytes to pore-forming hemolysins and saponin, whose activity is cholesterol-dependent (Jackson et al, 2007;Orjih et al, 2008;Hernańdez-Castañeda et al, 2021). On the other hand, plasma membranes of murine erthrocytes seemingly do not have such a reduced cholesterol content when infected with rodent Plasmodium species (Wunderlich et al, 1991).…”

Erythrocytes as Messengers for Information and Energy Exchange between Cells

“…Infected erythrocytes also produce microvesicles that can be transferred to endothelial cells, astrocytes, and microglia [171]. Plasmodium causes profound changes in the erythrocyte plasma membrane, which can become almost devoid of cholesterol and display phosphatidylserine [172]. Absence of cholesterol makes the plasma membrane susceptible to pore formation by granulysin, a pore-forming peptide produced by cytotoxic cells like gamma-delta T cells.…”