Plasmodium falciparum Malaria

Malaria, a disease caused by parasites of the genus Plasmodium, remains a major medical problem worldwide with an incidence of 300 million new cases and 1 to 2 million deaths each year. Of the four species of human malaria parasites, P. falciparum is the most lethal. The clinical manifestations of falciparum malaria are variable. They range from a mild febrile illness to severe and frequently fatal syndromes such as cerebral malaria and multiorgan failure. The mortality due to severe falciparum malaria is about 15 to 20 percent despite effective antimalarial drugs and optimal clinical care. In areas of high endemicity, such as sub-Saharan Africa, severe falciparum malaria mainly affects children less than 5 years of age, accounting for 90 percent of the annual malarial mortality worldwide. There is lower incidence in older children and adults in these areas, because of the acquisition of partial immunity. Almost all the deaths in African children have three main overlapping clinical syndromes: respiratory distress, cerebral malaria, and severe anemia. In areas of low endemicity such as Southeast Asia, severe falciparum malaria can affect all age groups. Acute renal failure, jaundice, and pulmonary edema are common in adults. Cerebral complications may occur by itself or in conjunction with other organ involvement. It generally has a poor prognosis. However, approximately 95 percent of adults and 85 percent of children who recover from cerebral malaria show no persistent neurological sequelae.

Cytoadherence

The most common and consistent pathological feature of severe falciparum malaria is the sequestration of IRBC in the capillaries and postcapillary venules of vital organs. Sequestration has been observed in all major organs such as the brain, heart, lung, kidney, and spleen. The organ distribution of sequestration varies and often reflects the clinical features of the preceding illness. For example, patients with cerebral malaria show increased cerebral sequestration compared with that in other organs. Even within the brain, the cerebral cortex and cerebellum are preferentially affected compared to the midbrain and brain stem. The sequestration of IRBCs in microvessels is thought to allow the parasites to evade splenic clearance. Unfortunately, the resulting impairment of microcirculatory blood flow may lead eventually to the demise of the host.

The molecular basis of cytoadherence in the vasculature has been studied extensively. Under static conditions, a number of adhesion molecules including CD36, ICAM-1, E-selectin, VCAM-1, PECAM-1, and thrombospondin-1 (TSP-1) have been shown to support IRBC adhesion, although the degree of adhesion to the different molecules varies by several orders of magnitude. A unique situation is the sequestration of IRBCs in the human placenta where IRBCs appear to adhere to chondroitin sulfate A (CSA) expressed on syncytiotrophoblasts that line the placental vil-lous space. Under physiological flow conditions, we found that cytoadherence on microvascular endothelium in a parallel-plate flow chamber in vitro and in a human microvas-culature in vivo is mediated by a number of adhesion molecules in a synergistic fashion (Figure 1). IRBCs can tether and roll on several host endothelial receptors such as ICAM-1, VCAM-1, and P-selectin, but not CSA. These low-affinity interactions do not by themselves lead to the arrest of the interacting cells, but enhance the subsequent adhesion of nearly all clinical isolates tested to CD36. ICAM-1 and VCAM-1 mediate their effect by increasing the percentage of rolling cells that become adherent, while P-selectin increases the absolute number of rolling and adherent IRBC, consistent with its ability to tether flowing cells from the bloodstream in leukocyte recruitment. Despite the similarities, there are important differences between leukocyte and IRBC recruitment. Whereas leukocyte recruitment occurs in a stepwise progression from selectins to members of the immunoglobulin superfamily, IRBCs can tether and roll on a number of different molecules before adhesion to CD36. In fact, CD36 by itself can mediate all three components of the adhesive interactions. If the cumulative affinity of all interactions is sufficiently high, the IRBC will adhere.

Figure 1 Schematic model of the cytoadherence cascade under flow conditions. IRBCs are observed to have three distinct types of adhesive interactions with microvascular endothelium: tethering, rolling, and firm adhesion mediated by a number of different adhesion molecules.

Otherwise, they will continue rolling. These findings underscore the pivotal role of CD36 in the pathogenesis of severe falciparum malaria.

CD36

CD36 is an 88-kDa membrane glycoprotein of 471 amino acids with two hydrophobic regions near the amino and carboxyl terminals that serve to anchor the molecule to the plasma membrane (Figure 2). It is expressed on a wide variety of cell types, such as microvascular endothelial cells, erythroblasts, monocytes, platelets, striated muscle cells, adipocytes, and mammary epithelial cells. The natural lig-ands of CD36 include collagen, TSP-1, both native and oxidized low-density lipoproteins (LDLs) and high-density lipoproteins (HDLs), and apoptotic neutrophils. These receptor-ligand interactions can lead to diverse cellular and biological responses including uptake of apoptotic bodies, TGF-b activation, fatty acid transport, and endothelial cell apoptosis. CD36 was first identified as a receptor for IRBCs indirectly by the inhibition of adhesion of IRBCs to C32 melanoma cells and endothelial cells by the anti-CD36 monoclonal antibody OKM5. Direct evidence was obtained subsequently by demonstrating that IRBCs adhered to immobilized purified CD36 protein from platelets and COS cells transfected with CD36. Most clinical parasite isolates studied to date bind CD36, and OKM5 can block the adhesion of all parasite isolates tested. These results imply that a CD36 binding domain is expressed in most parasite isolates and it recognizes a common region on CD36. Peptide mapping studies on CD36 reveal that residues 145 to 171 are important for IRBC adhesion, and OKM5 is thought to bind to residues 155 to 183.

PfEMPl and Recombinant 179 Peptides

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMPl) is the parasite protein directly involved in adhesive interactions with microvascular endothelium. PfEMPl

Binding sites PfEMPI: 145-171 QKM5: 155-1B3 TSP-1; 139-155 & 9S-110

Plasma — Membrane

N-termlnus C-lemtnus

Figure 2 CD36 membrane topology and binding sites. This unique structure contains two cytoplasmic tails and two extracellular loops separated by a hydrophobic section that sits within the outer leaflet of the plasma membrane. Threonine-92 is phosphorylated in platelet CD36.

is a highly variable protein encoded by the large var gene family that is expressed on electron-dense protrusions on the surface of infected erythrocytes. In the early stages of the parasite cycle, many var genes are transcribed in a single IRBC. As the intracellular parasite matures to a trophozoite, at which stage cytoadherence occurs, only one var gene product is expressed, while the remaining genes are silenced by an as yet unknown mechanism. However, a single parasite clone can bind to more than one receptor molecule through its distinct binding modules: the Duffy binding-like domains (DBL) and the cysteine-rich interdomain regions (CIDR) (Figure 3). A critical region of PfEMPI involved in binding to CD36 is localized to a 179-amino-acid sequence within the CIDR1 region. A recombinant 179 amino acid peptide in Escherichia coli from the parasite strain Malayan Camp (MC) varl gene has been shown to bind to CD36 and inhibit and reverse the adhesion of several CD36-binding laboratory-adapted parasite strains in static and flow chamber based assays in vitro. More importantly, we recently demonstrated that a yeast recombinant peptide PpMC-179 could inhibit and reverse cytoadherence of diverse clinical isolates in human microvessels in vivo in a human-SCID mouse chimeric model.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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