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

Abstract

BackgroundApoptosis 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.FindingsApoptosis 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.ConclusionsApoptosis 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.

Evidencing the Role of Erythrocytic Apoptosis in Malarial Anemia

“…Our studies have shown that induction of apoptosis is not limited to parasitized RBCs (pRBCs) but also occurs in non-parasitized RBCs (nRBCs), pointing to an involvement of both pRBC and nRBC in the pathogenesis of malaria through deflagration of suicide processes (Totino et al, 2009, 2011, 2013, 2014). Thus, the present review covers evidence implicating erythrocytic apoptosis in the pathogenesis of severe anemia, a common complication of malaria that represents an important public health concern strongly related to mortality in children and pregnant women living in malaria-hyperendemic regions of sub-Saharan Africa (Schantz-Dunn and Nour, 2009; Muoneke et al, 2012).…”

“…Both erythrophagocytosis and PS-exposing RBCs are increased in P. falciparum infected-children presenting severe anemia as compared to those with uncomplicated malaria (Fendel et al, 2010). Apoptosis can also be induced by incubating RBCs from healthy individuals with plasma from P. falciparum patients, an effect that is not observed with plasma from P. vivax infections, which, comparatively to P. falciparum , are less prone to lead to severe disease (Totino et al, 2014). Furthermore, since CD36 is a key molecule in the RBC clearance process, resistance to severe malarial anemia reported in children with a non-sense CD36 mutation can be explained, in part, by a deficiency in phagocytosis of apoptotic nRBCs mediated by CD36-PS interaction (Pain et al, 2001; Chilongola et al, 2009).…”

Single-Cell RNA Sequencing Reveals Cellular Heterogeneity and Stage Transition under Temperature Stress in Synchronized Plasmodium falciparum Cells

“…Moreover, we monitored the growth of the parasites using Giemsa stain upon temperature treatment, and we did not observe any significant change in the parasitemia after the 6-h temperature treatment as well in the following cycle (15 to 16% parasitemia) of IDC. Furthermore, we analyzed the parasites’ viability under control and temperature treatments using annexin V staining, which is commonly used to identify apoptotic parasites ( 39 ). Importantly, temperature treatment did not cause a significant change in the number of dead parasites, as assessed by fluorescence-activated cell sorter (FACS) analysis with fluorescein isothiocyanate (FITC)-annexin V staining (see Fig.…”

The immunological balance between host and parasite in malaria

“…Both mechanisms shorten the lifespan of RBCs by targeting these prematurely for CR1-mediated hemophagocytosis. Apoptosis of non-infected RBCs, with subsequent deposition of CRP and phagocytosis mediated by Fcγ RIIA may additionally contribute to the development of anemia with P. falciparum and P. yoelii, although this does not seem to occur with P. vivax (Schuldt et al 2010;Totino et al 2010Totino et al , 2014. Different mechanisms may dominate in murine models, since anemia associated with rodent malaria seems to be C3-independent (Harris et al 2012).…”