Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-12-11
2002-05-21
Navarro, Mark (Department: 1645)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C514S04400A
Reexamination Certificate
active
06392026
ABSTRACT:
BACKGROUND OF THE INVENTION
Malaria infects 200-400 million people each year causing 1-2 million deaths, thus remaining one of the most important infectious diseases in the world. Approximately 25 percent of all deaths of children in rural Africa between the ages of one and four years are caused by malaria. Due to the importance of the disease as a worldwide health problem, considerable effort is being expended to identify and develop malaria vaccines.
Malaria in humans is caused by four species of the parasite Plasmodium:
P. falciparum, P. vivax, P. knowlesi
and
P. malariae
. The major cause of malaria in humans if
P. falciparum
which infects 200 million to 400 million people every year, killing 1 to 4 million.
P. vivax
(one of the four species infective to humans) cannot be cultured in vitro, as has been possible with
P. knowlesi
(a malarial strain found in old world monkeys which also invade human erythrocytes) and
P. falciparum
. Although
P. vivax
bears substantial phylogenetic similarity to
P. knowlesi
, the two species are different in many important respects. For example,
P. vivax
is not infective of many simian species and infection is poorly established in others, whereas
P. knowlesi
is poorly infective of humans while readily infecting many simian species.
The basis of various potential vaccines to combat malaria is appreciated through an understanding of the life cycle of the parasite. Infection in humans begins when young malarial parasites or “sporozoites” are injected into the bloodstream of a human by the mosquito. Following injection, the parasite localizes to liver cells. After approximately one week the parasites or “merozoites” are released into the bloodstream. The entry of the parasites into the bloodstream begins the “erythrocytic” phase. Each parasite enters the red blood cell in order to grow and develop. When the merozoite matures in the red blood cell, it is known as a trophozoite. The trophozoite undergoes several rounds of nuclear division (schizogony) until it ruptures the erythrocyte, releasing from 6 to 24 merozoites. After several asexual schizogonic cycles, some parasites, instead of becoming schizonts through asexual reproduction, develop into morphologically distinct forms known as “gametocytes” which are long-lived and undergo sexual development.
Sexual development of the malaria parasites involve the female or “macrogametocyte” and the male parasite or “microgametocyte.” These gametocytes do not undergo any further development in humans. Upon ingestion of the gametocytes into the mosquito, the complicated sexual cycle begins in the midgut of the mosquito. The red blood cells disintegrate in the midgut of the mosquito after 10 to 20 minutes. The microgametocyte continues to develop through exflagellation and releases 8 highly flagellated microgametes. Fertilization occurs upon fusion of the microgamete and the macrogamete. The fertilized parasite is known as a zygote which develops into an “ookinete.” The ookinete embeds in the midgut of the mosquito, transforming into an oocyst within which many small sporozoites form. Before embedding in the midgut, the ookinete must first penetrate the peritrophic membrane which apparently acts as a barrier for invasion of ingested parasites. When the oocyst ruptures the sporozoites migrate to the salivary gland of the mosquito via the hemolymph. Once in the saliva of the mosquito, the parasite can be injected into a host.
The erythrocytic stage of the Plasmodium life cycle is of special relevance to vaccine development because the clinical and pathologic features of malaria in the host are attributable to this stage. In
P. vivax
, and
P. knowlesi
, Duffy blood group determinants present on Duffy positive erythrocytes are essential for invasion of human erythrocytes (Miller et al., Science 189: 561-563, (1975); Miller et al., N. Engl. J. Med. 295: 302-304, (1976)). In
P. falciparum
, invasion of merozoites into erythrocytes appears to be dependent on binding to sialic acids on glycophorins on the erythrocyte (Miller, et al., J. Exp. Med. 146: 277-281, (1971); Pasvol, et al., Lancet. ii: 947-950 (1982); Pasvol, et al., Nature, 279: 64-66 (1982); Perkins, J. Exp. Med. 160: 788-798 (1984)). Studies with the monkey parasite
P. knowlesi
allow a clearer understanding of the multiple events that occur during invasion. It is likely that even though
P. vivax
and
P. falciparum
bind to the Duffy antigen and sialic acids respectively, they share common strategies of invasion with each other and with
P. knowlesi.
In
P. knowlesi
, during invasion a merozoite first attaches to an erythrocyte on any surface of the merozoite, then reorients so that its apical end is in contact with the erythrocyte (Dvorak et al., Science 187: 748-750, (1975)). Both attachment and reorientation of merozoites occur equally well on Duffy positive and Duffy negative cells. A junction then forms between the apical end of the merozoite and the Duffy positive erythrocyte followed by vacuole formation and entry of the merozoite into the vacuole. Aikawa et al., J. Cell Biol. 77: 72-82 (1978). Junction formation and merozoite entry into the erythrocyte do not occur on Duffy negative cells (Miller et al., J. Exp. Med. 149: 172-184 (1979)), suggesting that a receptor specific for the Duffy determinant is involved in apical junction formation but not initial attachment.
The apical end of the merozoite is defined by the presence of three organelles: rhopteries, dense granules and micronemes. The rhopteries and dense granules release their contents at vacuole formation (Ladda et al., 1969; Aikawa et al., J. Cell Biol., 77: 72-82 (1978); Torn et al., Infection and Immunity 57: 3230-3233 (1989); Bannister and Dluzewski, Blood Cells 16: 257-292 (1990)). To date the function of the microneme is unknown. Nevertheless, the location of the micronemes suggest that they are involved in the invasion process. Duffy Antigen Binding Protein (DABP) and Sialic Acid Binding Protein (SABP) have been localized to the micronemes of
P. knowlesi
and
P. falciparum
respectively (Adams et al., Cell 63.: 141-153 (1990); Sim et al., Mol. Biochem. Parasitol. 51: 157-160. (1992)).
DABP and SABP are soluble proteins that appear in the culture supernatant after infected erythrocytes release merozoites. Immunochemical data indicate that DABP and SABP which are the respective ligands for the
P. vivax
and
P. falciparum
Duffy and sialic acid receptors on erythrocytes, possess specificities of binding which are identical either in soluble or membrane bound form.
DABP is a 135 kDa protein which binds specifically to Duffy blood group determinants (Wertheimer et al., Exp. Parasitol. 69: 340-350 (1989); Barnwell, et al., J. Exp. Med. 169: 1795-1802 (1989)). Thus, binding of DABP is specific to human Duffy positive erythrocytes. There are four major Duffy phenotypes for human erythrocytes: Fy(a), Fy(b), Fy(ab) and Fy(negative), as defined by the anti-Fy
a
and anti-Fy
b
sera (Hadley et al., In Red Cell Antigens and Antibodies, G. Garratty, ed. (Arlington,. Va.:American Association of Blood Banks) pp. 17-33 (1986)). DABP binds equally to both Fy(a) and Fy(b) erythrocytes which are equally susceptible to invasion by
P. vivax
; but not to Fy(negative) erythrocytes.
In the case of SABP, a 175 kDa protein, binding is specific to the glycophorin sialic acid residues on erythrocytes (Camus and Hadley, Science 230:553-556 (1985); Orlandi, et al., J. Cell Biol. 116:901-909 (1992)). Thus, neuraminidase treatment (which cleaves off sialic acid residues) render erythrocytes, immune to
P. falciparum
invasion.
The specificities of binding and correlation to invasion by the parasite thus indicate that DABP and SABP are the proteins of
P. vivax
and
P. falciparum
which interact with sialic acids and the Duffy antigen on the erythrocyte. The genes encoding both proteins have been cloned and the DNA and predicted protein sequences have been determined (B. Kim Lee Sim, et al., J. Cell Biol. 111. 1877-1884 (1990); Fang, X., et al., Mol. Biochem Parasitol. 44: 125-132
Chitnis Chetan
Miller Louis H.
Peterson David S.
Sim Kim Lee
Su Xin-Zhuan
Navarro Mark
The United States of America as represented by the Department of
LandOfFree
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