Avid Bioservices Inc (CDMO)

[jazzbeerman]

Malaria Exploits Exposed PS ------




Cytoadherence of Malaria-Infected Red Blood
Cells Involves Exposure of Phosphatidylserine

http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=224332&Ausgabe=228865&ArtikelNr=67908&filename=67908.pdf


Introduction

Malaria, one of the most life-threatening infectious
diseases in the world, causes 1.5-2.7 million deaths
annually [1]. Of the four species of human malaria
parasites, Plasmodium falciparum causes the severest of
symptoms and the greatest number of deaths. Adherence
of red cells infected with the mature stages of the parasite
to endothelial cells (EC) lining the postcapillary venules,
especially in the deep tissues, enables the parasites to
avoid splenic clearance and parasite growth is favored
by an hypoxic microenvironment. The adherence of
P. falciparum-infected red cells also results in the
occlusion of microvessels and can lead to
unconsciousness, coma, and in some cases, death. The
virulent nature of P. falciparum has been attributed to
mechanical obstruction by adherent infected red cells [2].
In this context, an understanding of the mechanisms of
the adherence of malaria-infected red cells may lead to
the development of anti-adhesive reagents and new
therapies.

......

The asymmetry of phospholipids in the lipid bilayer
of the plasma membrane is maintained by several membrane
enzymes such as scramblase, translocase and
flippase [28]. Disruption of phospholipid asymmetry
results in the exposure of phosphatidylserine (PS)
molecules, which are normally located in the inner leaflet
of the phospholipid bilayer. We and other investigators
have shown that PS is exposed on the malaria-infected
red cell surface coincident with parasite development [29-
31]. PS liposomes or PS-exposed cells bind to CD36 [32]
and TSP [33] both of which serve as receptors for the
adherence of P. falciparum-infected red cells [34, 35].
Here, we demonstrate that PS exposure on the exofacial
surface of the P. falciparum -infected cell is involved in
the binding to CD36 and TSP.

.......

Discussion
Drastic changes in the red blood cell membrane are
induced during the intracellular maturation of the malarial
parasite, P. falciparum. These include visible changes in
the shape of the red cell, the appearance of electron-dense
protrusions (called knobs) [3, 49], increased membrane
permeability [50, 51], decreased deformability [52],
insertion of parasite-derived proteins [8-10], changes in
the composition and oxidative damage of membrane
lipids [53, 54], a reduction in cholesterol content [30],
as well as degradation of membrane proteins [55].

........

Further,
Facer et al. [63] detected elevated levels of antiphospholipid
antibodies in the serum of P. falciparuminfected
patients using an ELISA method, and found the
highest IgG and IgM binding was to PS and other anionic
phospholipids, indicating that infected red cells expose
PS on their surface in vivo. In that report, the percentage
of anti-PS IgG or IgM positive serum of P. falciparuminfected
patients as 89% and 79%, respectively. Thus,
the accumulating data support PS exposure in P.
falciparum infected red cells.

.......

The precise mechanism of PS exposure on
P.falciparum-infected red cells remains undefined.
Several investigators have demonstrated that treatment
of red cells with various oxidants, such as
phenylhydrazine [64], hydrogen peroxide [65], or
diamide [66], also results in PS exposure. And, PS
exposure has been demonstrated in red cells from patients
with sickle cell anemia [36, 67, 68], thalassemia [69],
diabetes [70], all of which may be under oxidative stress
[71-73]. The erythrocytic stages of Plasmodium as they
mature, digest hemoglobin, and release highly oxidative
iron-containing products. And, oxidized membrane lipids
have been detected in trophozoite- or schizont-infected
red cell membranes [54], coincident with the time we
and other investigators have detected PS exposure [29-
31]. It seems plausible that oxidative stress could act as
a trigger for PS exposure on the surface of the malariainfected
red cell.

.......

Since PS exposure was detected in the various strains of
falciparum malaria we tested, as well as strains used by
other workers, we contend that PS exposure can
contribute to the universal binding of infected cells to
CD36 and TSP. Our findings (i.e., PS exposure and PSmediated
infected-cell binding to TSP) is also compatible
with the suggestion that PS is involved in abnormal sickle
red cell binding to TSP [76, 77].

.......

Further investigation of the structural requirement of
inhibition of PS-mediated infected-cell binding, as well
as a determination of the relative contributions of PfEMP-
1, band 3 and PS to cytoadherence, may assist in the
development of novel and effective anti-adhesive agents.
In conclusion, PS exposure, modification in band 3
protein, and PfEMP-1 all contribute to cytoadherence/
sequestration and disease pathogenesis in P. falciparum
malaria.




----------




Evolution has favored pathogenesis that resembles apoptosis,

j







High levels of anti-phospholipid antibodies in uncomplicated and severe Plasmodium falciparum and in P. vivax malaria.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8306506&dopt=Abstract

Facer CA, Agiostratidou G.

London Hospital Medical College, UK.


High levels of anti-phospholipid antibodies in uncomplicated and severe Plasmodium falciparum and in P. vivax malaria.



The majority (75%) of adult patients with uncomplicated Plasmodium falciparum and P. vivax malaria are positive for anti-phospholipid antibodies (aPLA) as demonstrated by ELISA using a panel of anionic and cationic phospholipids. The highest IgG and IgM binding was to the anionic phospholipids, phosphatidylserine (PS), phosphatidic acid (PA) and cardiolipin (CL), but excluding phosphatidylinositol (PI) to which only low antibody levels were found. Comparison of the mean IgG and IgM aPLA showed a trend for anti-PA > CL > PS > PC > PE > PI. Anti-PI levels were compared in two groups of African children, one group with non-severe and the other with severe (cerebral) falciparum malaria. Children with cerebral disease had significantly lower IgM anti-PI. The results are discussed with the view that serum-derived aPLA may have a role in 'anti-disease' immune responses. Their possible role in the opsonization and phagocytosis of parasitized erythrocytes and in thrombocytopenia is also considered.




-------------------------






Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection.


Immunity. 2005 Sep

Comment in:
Immunity. 2005 Sep;23(3):241-2.


Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Churchill Hospital, Oxford OX3 7LJ, United Kingdom.

Understanding the regulation of immune responses is central for control of autoimmune and infectious disease. In murine models of autoimmunity and chronic inflammatory disease, potent regulatory T lymphocytes have recently been characterized. Despite an explosion of interest in these cells, their relevance to human disease has been uncertain. In a longitudinal study of malaria sporozoite infection via the natural route, we provide evidence that regulatory T cells have modifying effects on blood-stage infection in vivo in humans. Cells with the characteristics of regulatory T cells are rapidly induced following blood-stage infection and are associated with a burst of TGF-beta production, decreased proinflammatory cytokine production, and decreased antigen-specific immune responses. Both the production of TGF-beta and the presence of CD4+CD25+FOXP3+ regulatory T cells are associated with higher rates of parasite growth in vivo. P. falciparum-mediated induction of regulatory T cells may represent a parasite-specific virulence factor.




------------




j