Deciphering host lysosome-mediated elimination of Plasmodium berghei liver stage parasites

Abstract

Liver stage Plasmodium parasites reside in a parasitophorous vacuole (PV) that associates with lysosomes. It has previously been shown that these organelles can have beneficial as well as harmful effects on the parasite. Yet it is not clear how the association of lysosomes with the parasite is controlled and how interactions with these organelles lead to the antagonistic outcomes. In this study we used advanced imaging techniques to characterize lysosomal interactions with the PV. In host cells harboring successfully developing parasites we observed that these interaction events reach an equilibrium at the PV membrane (PVM). In a population of arrested parasites, this equilibrium appeared to shift towards a strongly increased lysosomal fusion with the PVM witnessed by strong PVM labeling with the lysosomal marker protein LAMP1. This was followed by acidification of the PV and elimination of the parasite. To systematically investigate elimination of arrested parasites, we generated transgenic parasites that express the photosensitizer KillerRed, which leads to parasite killing after activation. Our work provides insights in cellular details of intracellular killing and lysosomal elimination of Plasmodium parasites independent of cells of the immune system.

Hijacking of the host cell Golgi byPlasmodiumliver stage parasites

“…Engaged in a more temporal relation with the PVM and its dynamic TVN extension are host cell vesicles of the endo-lysosomal component of the autophagy pathway. This carefully controlled association guarantees optimal nutrient acquisition and prevents simultaneously the elimination of parasite (Agop-Nersesian et al, 2018, 2017; Grützke et al, 2014; Niklaus et al, 2019; Petersen et al, 2017; Prado et al, 2015; Real et al, 2018; Thieleke-Matos et al, 2016; Wacker et al, 2017). With the hcGolgi, however, parasites build a persistent relationship.…”

“…Hepatocyte infections are clinically silent, nevertheless, development of the parasite within the liver is extremely efficient, reportedly, one of the fastest growth rates among eukaryotic organisms (reviewed in (Prudencio et al, 2006)). To accomplish its extensive replication, the parasite depends not only on de novo synthesis of essential metabolites, but also on scavenging and storage of host-derived nutrients (Bano et al, 2007; Inácio et al, 2015; Itoe et al, 2014; Meis et al, 1984; Niklaus et al, 2019; Petersen et al, 2017; Sá E Cunha et al, 2017; Zuzarte-Luís et al, 2017).…”

The tubovesicular network inPlasmodium vivaxliver-stage hypnozoites and schizonts associates with host aquaporin 3

“…The precise composition of this membrane remains unknown, but several studies have revealed it changes minutes to hours after liver invasion when parasite proteins, including up-regulated in infective sporozoites gene 4 (UIS4), are translocated to the PVM (Kaushansky and Kappe, 2015;Mueller et al, 2005;Prado et al, 2015;Sá E Cunha et al, 2017;Schnider et al, 2018). While fewer host proteins are known to associate with the PVM after invasion, examples of protein recruitment crucial for host defense and parasite development have been reported (Grützke et al, 2014;LaMonte et al, 2019;Niklaus et al, 2019;Posfai et al, 2020Posfai et al, , 2018Prado et al, 2015;Raphemot et al, 2019;Thieleke-Matos et al, 2016;Wacker et al, 2017). In particular, we have demonstrated that the host water and solute channel aquaporin 3 (AQP3) is upregulated after P. berghei infection of liver cells, is critical for parasite development, and associates with the PVM (Posfai et al, 2018).…”

“…A key component of the host-parasite interactions in the Plasmodium liver stage is the physical alteration of the PVM. Several elegant studies have shown that the PVM can extend into the host hepatocyte with a highly dynamic membranous system, the tubovesicular network (TVN) (Agop-Nersesian et al, 2018Grützke et al, 2014;Niklaus et al, 2019). In the P. berghei liver-stage, this system consists of elongated membrane clusters, tubules, and vesicles that move to and from the PVM (Grützke et al, 2014).…”

Plasmodium Secretion Induces Hepatocyte Lysosome Exocytosis and Promotes Parasite Entry

“…Many intracellular pathogens target and subvert these trafficking events for their own benefit (Alix et al., 2011, Asrat et al., 2014). Previous work has demonstrated that the Plasmodium liver stage PV membrane co-localizes with late endosomes (Petersen et al., 2017), lysosomes (Lopes da Silva et al., 2012, Niklaus et al., 2019, Prado et al., 2015, Risco-Castillo et al., 2015), and autophagic vesicles (Prado et al., 2015, Real et al., 2018, Wacker et al., 2017). Although these studies have suggested that the vesicle association is gradually lost over the course of liver stage infection (Niklaus et al., 2019, Prado et al., 2015, Risco-Castillo et al., 2015), when this association is initiated during Plasmodium life cycle progression remains unknown, and none of these studies have evaluated infection prior to 3 h post-entry.…”