Despite cruzi have identified genes coding for metacaspase

          Despite the fact that apoptosis has been described in metazoans cells and has
been associated with multicellularity, it had been suggested that unicellular
eukaryotes also undergo apoptosis and to death with typical features of
mammalian programmed cell death. It has been described in several species
including the protozoans 19. Recent
findings have been described programmed cell death in eukaryotic microorganisms
including yeast  20,21, kinetoplastids;
Trypanosoma brucei rhodesiensis, Trypanosoma cruzi, Leishmania amazonensis,
Leishmania donovani and Leishmania major
22-26 and apicomplexans 27-28 and even in protozoa which do not present an
evident mitochondrial system, as in Trichomonas 29-31, Giardia and Entamoeba 32. Similar alterations as multicellular organism
like mitochondrial membrane potential and nuclear DNA fragmentation are
observed in parasitic protozoa submitted to different stress conditions such as
contact with chemotherapeutic agents 33,34 and different temperatures 35.
The phosphotidylserine externalization
induces the phagocytosis of apoptotic cells by macrophages and this mechanism
results in an anti-inflammatory effect and suppression of pro-inflammatory
mediators 36, 37. Two of the major characteristic features of mammalian cell
apoptosis, that occur with protozoa and distinguishes it from the passive and
chaotic destruction process of necrosis, are cell shrinkage and maintenance of
plasma membrane integrity 26. Studies carried out with T. brucei and T. cruzi have
identified genes coding for metacaspase 38-41 which belongs to cystein
protease family as caspase in multicellular organisms. Metacaspase enzymes were
also  reported in Plasmodium and it
exhibits a calcium-dependent, arginine-specific protease activity which induced
cell death in malaria parasite 42.

 

Overview
of PCD in Plasmodium

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Considering the importance of programmed cell death in
metazoan, it is reasonable to ask if such a predetermined behaviour mechanism
or operation exists in Plasmodium. First time in 1997, Picot S and his
colleagues reported PCD in Plasmodium who observed oligonucleosomal DNA
fragmentation during drug pressure of chloroquine in asexual stages of
chloroquine sensitive strain of P. falciparum
by using agrose gel electrophoresis 28 and suggested apoptotic cell death in
malaria parasite. Only single apoptotic marker, taken alone, is not proof of
apoptosis, it is justified to classify a process as apoptosis-like cell death
when several apoptotic markers can be reproducibly shown to occur in a malaria
parasite. That is why researchers need to study other parameters of PCD. In
this direction, TUNEL Assay (terminal deoxynucleotidyl transferase-mediated
dUTP-fluorescein nick end-labeling) was done to evaluate DNA fragmentation in asexual
stages of P. falciparum after exposure of
elevated temperature. In this study parasite crisis forms were observed. Crisis
form is related to apoptotic bodies, retain their staining properties and
appear to be condensed, which are considered as a final hallmark of apoptosis
in Plasmodium 43. In a review article, Deponte and Becker have also reported
TUNEL activity in P. falciparum blood-stage
schizonts treated with antimalarial drugs and H2O2 44.

                In addition Meslin et al have done work by the use of apoptosis inducer
etoposide and antimalarial chloroquine and found evident of apoptosis cell
death in blood stage Plasmodium by the observation of DNA fragmentation and
disruption of mitochondrial membrane potential. They also identified P. falciparum metacaspase protein PfMCA1 which belongs to cysteine protease family as
caspase in metazoans 45. At the same time apoptosis related protein (PfARP) (Gene ID- PF10450C) was also
characterized by other group and they found stage specific expression of PfARP; highest expression in trophozoite and minimum in
schizont stage 46. Recently it was reported that mefloquine induce ROS
mediated apoptosis in asexual stage of Plasmodium 47.

                While
using P.
berghei, Al-olyan and his colleagues
examined the mode of parasite death during sexual stages within the midgut
lumen and obtained an additional process close to cell suicide which is
involved in regulating parasite numbers in Anopheles stephensi, a mosquito
vector of human malaria that will also transmit P. berghei. In addition, the presence of caspase-like activity
in the cytoplasm of the ookinete was observed suggesting once again the
presence of a cellular mechanism, similar to those found in mammalian cells
48. Several other researchers could also be able to found apoptosis like cell
death in sexual stages of Plasmodium life cycle. Whereas few groups failed to
find apoptotic characteristics in P. falciparum after treatment with ceramide, artemisinin, mefloquine 49, etoposide 50, S-nitroso-N-acetyl-penicillamine (SNAP), staurosporine
and CQ 51,52 but they suggest some
other type of programmed cell death occur in parasite like autophagy and
secondary necrosis. Nyakeriga et al. suggested that although P. falciparum die by PCD, this might take place without typical
features of apoptosis. It was reported that P. falciparum die by autophagy after the exposer of CQ, SNAP and
staurosporine, considering the lack of apoptotic characteristics and the
presence of parasites with autophagic vacuolization in cytoplasm 51. Recently
Mary Luz López showed morphological and physiological evidences associated with
some apoptotic-like and autophagic-like cell death characteristics in P. falciparum asexual blood stages treated with compound isolated
from Solanum nudum Dunal (Solanaceae) 53. These differing observations might
be based on several experimental pitfalls. Autophagosome formation is the
central event of autophagy process and is governed by autophagy-related (Atg)
proteins, which were originally identified in yeast 54, 8. Further Noboru and
his colleagues reported biochemical properties and subcellular localization of
Atg8 protein of human malaria parasite Plasmodium falciparum (PfAtg8).   Multiple markers of apoptosis have been
observed in stages of Plasmodium life cycle that occur in the vector
(ookinetes) and the host (liver schizont and blood stages).

                These
reports make it plain that there is no consensus amongst malaria researchers
about which process of PCD takes place in malaria parasites during their
exposure to antimalarials, resulting in their subsequent death, and if just one
or a combination of PCD processes occurs to bring about their death.                   

                                    

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