Extracellular vesicles carrying lactate dehydrogenase induce suicide in increased population density of Plasmodium falciparum in vitro

Abstract

Even with access to sufficient nutrients and atmosphere, Plasmodium falciparum can barely be cultured at maximum growth capacity in vitro conditions. Because of this behavior, it has been suggested that P. falciparum has self-regulatory mechanisms in response to density stress. Only recently has this process begun to be acknowledged and characteristics of a programmed cell death been assigned to the parasite at high parasitaemia in vitro cultures. In searching for death signals within the parasite community, we have found that extracellular vesicles (EVs) of P. falciparum from high parasitaemia cultures are able to induce programmed cell death processes in the population. A comparative proteomic analysis of EVs from low (EVL) and high (EVH) parasitaemia cultures was conducted, pointing to lactate dehydrogenase from P. falciparum (PfLDH) as the only parasite protein overexpressed in the later. Although the major function of P. falciparum lactate dehydrogenase (PfLDH) is the conversion of pyruvate to lactate, a key process in the production of energy in most living organisms, we investigated its possible role in the mechanism of parasite density control by intercellular signaling, given that PfLDH had already been listed as a component of extracellular vesicles of P. falciparum. In this study we present evidence of the EV-associated PfLDH regulation of parasite population by inducing apoptosis in highly parasitized cultures.

Extracellular Vesicles Could Carry an Evolutionary Footprint in Interkingdom Communication

“…Remarkably, EVs can also induce apoptosis during stress and normal development conditions by carrying Fas and TRAIL to different target cells (Janiszewski et al, 2004;Stenqvist et al, 2013). Recently, our group reported that parasite-derived EVs carrying lactate dehydrogenase can induce PCD in in vitro cultures of P. falciparum during high parasitaemia levels, showing that parasites can likely sense each other and release EVs to regulate the parasite population (Correa et al, 2019). If apoptosis induction involves the pathogen communicating with its kind through EVs, as the evidence suggests, this would represent an important evolutionary force in the adaptation of parasitism to specialized niches in the host.…”

“…Based on this behavior, it had been suggested that P. falciparum uses mechanisms of self-regulation in response to density stress (Mutai and Waitumbi, 2010), and these mechanisms might depend on EVs mediated apoptosis. For instance, recent studies have observed programmed cell death in highly parasitized in vitro cultures of Plasmodium, and another study that has identified molecules involved in the signaling of death (Totino et al, 2014;Engelbrecht and Coetzer, 2016;Chou et al, 2017;Correa et al, 2019).…”

“…The composition of EVs has been previously described as "hybrid" (Mantel et al, 2013;Correa et al, 2019) due to the presence of host and parasite proteins. We expect that the composition of EVs can be distinctively associated with its source system (e.g., host, parasite, or vector), suggesting a potential role in information transfer.…”

The characterization of extracellular vesicles-derived microRNAs in Thai malaria patients

“…Exosome-like vesicles have played a role in gametocytogenesis, which is crucial for malaria transmission, and these small membrane-bound vesicles could transfer drug-resistance markers to drug-sensitive parasites [25]. Additionally, EVs which cargo P. falciparum lactate dehydrogenase (PfLDH) could control parasite density in vitro [26]. One study also showed that EVs enriched with the parasite's genomic DNA, released from infected red blood cells could be internalized by monocytes and elicited an innate immune response [27].…”

The characterization of extracellular vesicles-derived microRNAs in Thai malaria patients

“…Exosome-like vesicles have played a role in gametocytogenesis which is crucial for malaria transmission, and these small membrane-bound vesicles could transfer drug-resistance markers to drug-sensitive parasites [28]. Additionally, EVs which cargo P.falciparum lactate dehydrogenase (PfLDH) could control parasite density in vitro [29]. One study also showed that EVs enriched with the parasite's genomic DNA, released from infected red blood cells could be internalized by monocytes and elicited an innate immune response [30].…”