Plasmodium falciparum , but not P. vivax , can induce erythrocytic apoptosis

Abstract

Background: Apoptosis can occur in red blood cells (RBC) and seems to be involved in hematologic disorders related to many diseases. In malaria it is known that parasitized RBC (pRBC) is involved in the development of anemia and thrombosis; however, non-parasitized RBC (nRBC) apoptosis could amplify these malaria-associated hematologic events. In fact, in experimental malaria, increased levels of apoptosis were observed in nRBC during lethal Plasmodium yoelii 17XL infection, but in human malaria erythrocytic apoptosis has never been studied. The present study was performed to investigate if nRBC apoptosis also occurs in P. vivax and P. falciparum infections. Findings: Apoptosis of nRBC was evaluated in blood samples of P. vivax malaria patients and clinically healthly individuals living in Manaus, Brazil, both ex vivo and after incubation of RBC for 24 h. Additionally, the capacity of plasma from P. vivax or P. falciparum patients was tested for induction of in vitro apoptosis of normal RBC from a clinically healthy individual living in a non-endemic malaria region. Apoptosis was detected by flow cytometry using annexin V staining. In contrast to experimental malaria that significantly increased the levels of apoptotic nRBC both ex-vivo and after 24 h of incubation, no significant alteration on apoptotic nRBC rates was detected in P. vivax infected patients when compared with non-infected control individuals. Similar results were observed when plasma of these P. vivax patients was incubated with normal RBC. Conversely, plasma from P. falciparum-infected subjects induced significant apoptosis of these cells. Conclusions: Apoptosis of normal RBC can be induced by plasma from individuals with P. falciparum (but not with P. vivax) malaria. This finding could reflect the existence of erythrocytic apoptosis during infection that could contribute to the pathogenesis of hematological and vascular complications associated with falciparum malaria.

Manipulating Eryptosis of Human Red Blood Cells: A Novel Antimalarial Strategy?

“…In a study using a rodent malaria model, increased numbers of eryptotic uRBCs have been observed in mice 6–7 days post-infection with P. yoelii (Totino et al, 2013 ). Similarly, incubation of human RBCs with serum from patients infected with P. falciparum leads to increased PS exposure and decreased cell size of uRBCs (Totino et al, 2014 ), suggesting that P. falciparum is able to induce cell death of non-infected erythrocytes. Interestingly, this has not been observed in the case of P. vivax infections, so one cannot exclude that the proinflammatory response common in P. falciparum infections, but not in P. vivax infections, could be at least partially responsible for this observation (Totino et al, 2014 ).…”

“…Similarly, incubation of human RBCs with serum from patients infected with P. falciparum leads to increased PS exposure and decreased cell size of uRBCs (Totino et al, 2014 ), suggesting that P. falciparum is able to induce cell death of non-infected erythrocytes. Interestingly, this has not been observed in the case of P. vivax infections, so one cannot exclude that the proinflammatory response common in P. falciparum infections, but not in P. vivax infections, could be at least partially responsible for this observation (Totino et al, 2014 ). Further, another in vitro study where the role of proinflammatory responses cannot be taken into account, suggests the increase of PS exposure on bystander uRBCs is partially attributed to the presence of methaemoglobin in the extracellular medium.…”

Extracellular Vesicles Could Carry an Evolutionary Footprint in Interkingdom Communication

“…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).…”