Download MALARIA RESISTANCE AND SICKLE CELL TRAIT: A REVIEW

Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
ISSN 2250-3137 www.ijlbpr.com
Vol. 3, No. 3, July 2014
© 2014 IJLBPR. All Rights Reserved
Review Article
MALARIA RESISTANCE
AND SICKLE CELL TRAIT: A REVIEW
Otoikhian C S O1*, Osakwe A A2, Utieyin M C1 and Igue U B2
*Corresponding Author:Otoikhian C S O [email protected]
Sickle cell disease or sickle cell anaemia is an autosomal recessive disease caused by
haemoglobin S, an oxygen-carrying protein in blood cells. A single point mutation in the nucleobase
sequence of chromosome 11 (Eleven) causes the sixth amino acid in the haemoglobin protein,
glutamine acid, to be replaced by valine, changing standard haemoglobin beta into haemoglobin
S. Translocation of sickle cell erythrocyte MicroRNAs into plasmodium falciparum inhibits parasite
translation and contributes to malaria resistance. Elucidation of this mechanism can lead to a
better understanding of sickle cell trait protection against plasmodium falciparum infection.
Keywords: Malaria resistance, Sickle cell anaemia, Sixth amino acid
Ronald Ross in 1898. Grassi (1900) proposed
an exerythrocytic stage in the life cycle, later
confirmed by short, Garnham et al. (1948), who
found plasmodium vivax in the human liver.
INTRODUCTION
Malaria is caused by an infection with protozoa
of the genus plasmodium. The name malaria,
from the Italian male aria, meaning “bad air”,
comes from the linkage suggested by Giovanni
Maria Lancisi (1717) of malaria with the poisonous
vapors of swamps. This species name comes
from the Latin falx, meaning “sickle”, and parere
meaning “to give birth”. The organism itself was
first seen by Laveran on November 6, 1880 at a
military hospital in Constantine, Algeria, when he
discovered a microgametocyte exflagellating.
Patrick Manson (1894) hypothesized that
mosquitoes could transmit malaria. This
hypothesis was experimentally confirmed
independently by Giovanni Battista Grassi and
Around the world, malaria is the most
significant parasitic disease of humans, and
claims the lives of more children worldwide than
any other infections disease. Since 1900, the area
of the world exposed to malaria has been halved,
yet two billion more people are presently exposed.
Morbidity, as well as mortality, is substantial.
Infection rates in children in endemic areas are
of the order of 50%. Chronic infection has been
shown to reduce school scores by up to 15%.
Reduction in the incidence of malaria coincides
with increased economic output (Perkins et al.,
1
Department of Biological Sciences, Novena University Ogume, Delta State Nigeria.
2
Department of Chemical Sciences, Novena University Ogume, Delta State Nigeria.
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
52
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
heterozygous for the trait are not prone to the
same severity of symptoms as homozygous
recessive individual (Genetic Home Reference,
2012). Despite the disease’s lethal symptoms, it
protects the carrier from malaria, which is why
sickle cell alleles are not common in people of
African descent (about 7% of people of African
descent carry an allele), and other areas where
malaria is prevalent (Ashley et al., 2000). Sickle
cell trait is hypothesized to have evolved because
of the vital protection from malaria it provides
(Taylor et al., 2013). Furthermore, individuals with
HbAS tend to survive better than individuals with
HbSS as they are not exposed to the same
severity of risks yet still receive protection form
malaria (Ashley et al., 2000).
2011). While there are no effective vaccines for
any of the six or more species that cause human
malaria, drugs have been employed for centuries.
In 1640, Huan del Vego first employed the tincture
of the cinchona bark for treating malaria; the native
Indians of Peru and Ecuador had been using it
even earlier for treating fevers.
Thompson (1650) introduced this “Jesuits’
bark” to England. It is first recorded use there was
by Dr. John Metford of Northampton in 1656.
Mortan (1696) presented the first detailed
description of the clinical picture of malaria and
of its treatment with cinchona. Gize (1816) studied
the extraction of crystalline quinine from the
cinchona bark, and Pelletier and Caventou (1820)
in France extracted pure quinine alkaloids, which
they named quinine and Cinchonine (Rich et al.,
2009). Sickle cell disease, or sickle cell anaemia
is an autosomal recessive disease caused by
haemoglobin S, an oxygen-carrying protein in
blood cells. A single point mutation in the
nucleobase sequence of chromosome 11
(eleven) causes the sixth amino acid in the
haemoglobin protein, glutamic acid, to be replaced
by valine, changing standard haemoglobin beta
into haemoglobin S (National Institute of Health,
2009). The sickle shape is caused by
haemoglobins resulting structural change, and it
is from this structure that the disease gets its
name (Genetic Home Reference, 2012). People
with either HbAS (heterozygous with haemoglobin
A and haemoglobin S) or HbSS (homozygous with
haemoglobin S) are considered to have sickle cell
trait and can show symptoms of sickle cell
disease. However, when an individual is
homozygous recessive for haemoglobin S,
severe symptoms occur and the most infamous
being anemia, which can, in turn, cause shortness
of breath, jaundice, and hypertension. Individuals
SICKLE CELL ANAEMIA
The first report of sickle cell anaemia may have
been in a report in 1846 where the autopsy report
of an executed runaway slave was discussed.
(Lebby, 1846). The author noted the curious
absence of a spleen in this case. In 1910 a
Chicago physician, James B Herrick, reported the
presence of sickle cells in the blood of an anemic
dental student, Walter Clement Noel. (Herrick,
1910). An association with pigmented gall stones
was noted in 1911 by Washborn. A genetic basis
for this disease was proposed in 1915 by Cook
and Meyer. The disease was named sickle cell
anaemia in 1922 by Verne Mason after several
additional cases were reported. All the known
cases had been reported in blacks and he
concluded that this disease was confined to those
of black African descent. The heterozygous
condition was independently recognized in 1923
by Huck and Syndestrickler. Syndestrickler also
was the first to note the splenic atrophy that occurs
in the condition it was recognized as a Mendelian
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
53
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
shrinkage of the spleen. In 1949 Lehmann and
Raper published a map of Uganda and showed
that the presence of sickle cell anaemia
correlated with the presence of malaria.
(Lechmann et al., 1946). In 1950 Singer et al.
noted the abrupt cessation of marrow activity that
may occur and coined the term aplastic crisis.
The role of parvovirus in aetiology of this condition
was not recognized until 1981. Brain also while
working in Northern Rhodesia confirmed the lower
incidence of splenomegaly and suggested that
while homozytotes for the sickle cell gene
suffered from several problems heterozygotes
might be protected against malaria. (Brain, 1952).
autosomal characteristic by Taliaffero and Huck
also in 1923. (Taliaffero et al., 1923). A
predisposition to pneumonia was noted in 1924
by Graham. The concept of progressive splenic
atrophy was proposed by Hahn and Gilespie in
1927. Pneumococcal meningitis in this condition
was first reported in 1928 by Wollstein and Kriedel,
but it was not until 1966 that the association
between splenic atrophy and infection was made
by Robinson and Watson.
In 1927 Vernon Hahn and Elizabeth Biermann
Gillespie showed that sickling of the red cells was
related to low oxygen. (Hahn et al., 1927). In some
individuals that change occurs at partial pressures
of O2 prevalent in the body, and produces anemia
and other disorders, termed sickle-cell disease.
In other persons sickling occurs only at very low
O2 partial pressures; these are asymptomatic
sickle-cell trait carriers. The association with
kidney and lung infarction was noted in 1931 by
Yater and Mollari and Baird in 1934, respectively.
The term sickle cell trait was coined by Samuel
Diggs in Memphis in 1933 to distinguish
heterozygotes from those with sickle cell
anaemia. Digs also reported the association with
splenic fibrosis in 1935. The pathological
mechanism of vaso-occlusion was proposed by
Ham and Castle in 1940. In 1946, EA Beet, a
British medical officer stationed in Southern
Rhodesia (Zimbabwe), observed that blood from
malaria patients who had sickle cell trait had
fewer malarial parasites than blood from patients
without the trait and suggested that this might be
a protective feature. In 1947 Beet published that
the incidence of enlarged spleens in sickle cell
patients was much lower than in non sickle cell
and suggested that this was due to recurrent
thromboses which resulted in fibrosis and
The modern phase of research on this disorder
was initiated by the famous chemist Linus Pauling
in 1949. Pauling postulated that the hemoglobin
(Hb) in sickle-cell disease is abnormal; when
deoxygenated it polymerizes into long, thin, helical
rods that distort the red cell into a sickle shape.
In his laboratory, electrophoretic studies showed
that sickle-cell Hb (S) is indeed abnormal, having
at physiological pH a lower negative charge than
normal adult human Hb (A) (Pauling et al., 1949).
In sickle-cell trait carriers there is a nearly equal
amount of HbA and HbS, whereas in persons with
sickle-cell disease nearly all the Hb is of the S type,
apart from a small amount of fetal Hb. These
observations showed that most patients with
sickle-cell disease are homozygous for the gene
encoding HbS, while trait carriers are heterozygous
for this gene. Persons inheriting a sickle-cell gene
and another mutant at the same locus, e.g., a
thalassemia gene, can also have a variant form of
sickle-cell disease. Pauling also introduced the term
“molecular disease”, which together with molecular
medicine, has become widely used.
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
54
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
through capillaries, the cell sickles, decreasing
its life span and leading to anaemia.
The next major advance was the discovery by
Vernon Ingram in 1959 that HbS differs form HbA
by only a single amino-acid substitution in the βpolypeptide chain (β6Glu Val). (Ingram, 1959). It
was later established that this results from a
substitution of thymine for adenine in the DNA
codon (GAG GTG). This was the first example in
any species of the effects of a mutation on a
protein. Sickle Hb induces the expression of heme
oxygenase-1 in hemoatopoietic cells. Carbon
monoside, a byproduct of heme catabolism by
heme oxygenase-1, prevents an accumulation of
circulating free heme after Plasmodium infection,
suppressing the pathogenesis of experimental
cerebral malaria (Ferreira et al., 2011). Other
mechanisms, such as enhanced tolerance to
disease mediated by HO-1 and reduced parasitic
growth due to translocation of host micro-RNA
into the parasite, have been described (Gong et
al., 2013).
DISTRIBUTION OF THE
SICKLE-CELL GENE
Since sickle-cell homozygotes are at a strong
selective disadvantage, while protection against
malaria favors the heterozygotes, it would be
expected that high frequencies of the HbS gene
would be found only in populations living in regions
where malaria transmission is intense, or was
so until the disease was eradicated. In a second
study conducted in 1953. Allison showed that this
was true in East Africa (Allison, 1954).
Frequencies of sickle-cell heterozygotes were 2040% in malarious areas, whereas they were very
low or zero in the highlands of Kenya, Uganda,
and Tanzania/ later studies by many investigators
filled in the picture (Allison, 2009). High frequencies
of the HbS gene are confined to a broad belt
across Central Africa, but excluding most of
Ethiopia and the East African highlands; this
corresponds closely to areas of malaria
transmission. Sickle-cell heterozygote
frequencies up to 20% also occur in pockets of
India and Grecce that were formerly highly
malarious. Tens of thousands of individuals have
been studied, and high frequencies of abnormal
hemolobins have not been found in any population
that was malaria free.
BIOCHEMISTRY OF SICKLE
CELL TRAIT
Sickle haemoglobin (HbS) is the result of
substitution of valine for the normally occurring
glutamic acid residue at the 6th position of the βchain and so, is designated as: Hbβ6(A3) Glu-Val.
This substitution creates a sticky hydrophobic
contact point which is on the outer surface of the
molecule. These sticky spots cause
deoxygenated haemoglobin (Hb) molecules to
associated abnormally with each other to form
the long fibrous aggregates responsible for
sickling of the red cells. Deoxygenated HbS then
polymerizes and the polymers are in the form of
long needle-like structures that distort the cell.
This reduces the flexibility of the red cell making
it more mechanically fragile and as it passes
INDEPENDENT ORIGINS OF
THE SICKLE-CELL GENE
Two mutations found in nontranscribed
sequences of DNA adjacent to the β-globin
gene are so close to each other that the
likelihood of crossover is very small. Restriction
endonuclease digests of the β-globin gene cluster
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
55
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
showed that in some African Americans the
antimalarial drug primaquine induces hemolytic
anemia, and that those individuals have an
inherited deficiency of G6PD in erythrocytes.
(Alving et al., 1956). G6PD deficiency is sex
linked, and common in Mediterranean, African and
other populations. In Mediterranean countries
such individuals can develop a hemolytic diathesis
(favism) after consuming fava beans. G6PD
deficient persons are also sensitive to several
drugs in addition to primaquine. G6PD deficient
is the most common enzyme deficiency in
humans, estimated to affect some 400 million
people (Beutler, 2008). There are many mutations
at this locus, two of which attain frequencies of
20% or greater in African and Mediterranean
populations; these are termed the A- and Med
mutations (Verelli, 2004), mutant varieties of
G6PD can be more unstable than the naturally
occurring enzyme, so that their activity declines
more rapidly as red cells age.
have shown five different patterns associated with
the sickle-cell (GAG GTG) mutation. Four are
observed in Africa, the Bantu, Benin, Senegal and
Cameroon types, (Dunda et al., 1992), and a fifth
type is found in the India subcontinent and Arabia
(Labie et al., 1989). The cited authors report that
haplotype analysis in the β-globin region shows
strong linkage disequilibrium over the distance
indicated, which is evidence that the HbS mutation
occurred independently at least five times. The
high levels of AS in parts of Africa and India
resulted from independent selections occurring
in different populations living in malarious
environments. In summary, the demonstration that
sickle-cell heterozygotes have some degree of
protection against falciparum malaria was the first
example of genetically controlled innate
resistance to human malaria, as recognized by
experts on inherited factors affecting human
infectious diseases (Able et al., 2009). It was also
the first demonstration of Darwinian selection in
humans, as recognized by evolutionary biologists
(Carroll et al., 2009).
MALARIA IN G6PDDEFICIENT SUBJECT
GLUCOSE-6-PHOSPHATE
DEHYDROGENASE
DEFICIENCY
This question has been studied in isolated
populations where antimalarial drugs were not
used in Tanzania, East Africa (Allison et al., 1961).
And in the Republic of the Gambia, West Africa,
following children during the period when they are
most susceptible of falciparum malaria.
(Ruwende et al., 1995). In both cases parasite
counts were significantly lower in G6PD-deficient
persons than in those with normal red cell
enzymes. The association has also been studied
in individuals, which is possible because the
enzyme deficiency is sex-linked and female
heterozygotes are mosaics due to lionization,
where random inactivation of an X-chromosome
in certain cells creates a population of G6PD
Glucose-6-phosphate dehydrogenase (G6PD) is
an important enzyme in red cells, metabolizing
glucose through the pentose phosphate pathway
and maintaining a reducing environment. G6PD
is present in all human cells but is particularly
important to red blood cells. Since mature red
blood cells lack nuclei and cytoplasmic RNA, they
cannot synthesize new enzyme molecules to
replace genetically abnormal or ageing ones. All
proteins, including enzymes, have to last for the
entire lifetime of the red blood cell, which is
normally 120 days. In 1956 Alving and colleagues
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
56
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
Duffy binding protein, the one and only invasion
ligand DARC, does not bind to Saimiri
erythrocytes although these cells express DARC
and obviously become infected with P. vivax
(Barmwell et al., 1989). The question is whether
these observations are relevant to naturally
occurring human transmission of P. vivax. Ryan
et al., presented evidence for the transmission of
P. vivax infections in Duffy antigen-negative
among a Duffy-negative population in Western
Kenya. (Amon et al., 2006). Independently,
Cavasini et al., have reported P. vivax infections
in Duffy antigen-negative individuals from the
Brazilian Amazon region (Cavasini et al., 2007).
P. vivax and Duffy antigen expression were
identified by genotypic and other methods. A
subsequent investigation in Madagascar has
extended these observations. (Mendes et al.,
2010). The Malagasy people in this island have
an admixture of Duffy-positive and Duffy-negative
people of diverse ethnic backgrounds. At eight
sentinel sites covering different parts of the island
72% of the population were Duffy-negative, as
shown by genotyping of flow cytometry. P. vivax
positivity was found in 8.8% of 476 asymptomatic
Duffy-negative people, and clinical P. vivax
malaria was found in 17 such persons.
Genotyping of polymorphic and microsatellite
markers suggested that multiple P. vivax strains
were invading the red cells of Duffy-negative
people. The authors suggest that among
Malagasy populations there are enough Duffypositive people to maintain mosquito transmission
and liver infection. From this internal source P.
vivax variants can develop, using receptors other
than Duffy to enter red cells and multiply. More
recently, Duffy negative individuals infected with
two different strains (VK247 and classic stains)
of P. vivax were found in Angola and Equatorial
deficient red blood cells coexisting with normal
red cell than in enzyme-deficient cells. An
evolutionary genetic analysis of malarial selection
on G6PD deficiency genes has been published
by Tishkoff and Verelli (Verelli, 2004). The enzyme
deficiency is common in many countries that are,
or were formerly, malarious, but not elsewhere.
DUFFY ANTIGEN RECEPTOR
The malaria parasite Plasmodium vivax is
estimated to infect 75 million people annually. P.
vivax has a wide distribution in tropical countries,
but is absent or rare in a large region in West and
Central Africa, as recently confirmed by PCR
species typing. (Mita et al., 2008). This gap in
distribution has been attributed to the lack of
expression of the Duffy Antigen Receptor for
Chemokines (DARC) on the red cells of many
sub-Saharan Africans. Duffy negative individuals
are homozygous for a DARC allele, carrying a
single nucleotide mutation (DARC 46T C), which
impairs promoter activity by disrupting a binding
site for the hGATA1 crythroid lineage transcription
factor (Collin et al., 1995). In widely cited in vitro
and in vivo studies, Miller et al reported that the
Duffy blood group is the receptor for P. vivax and
that the absence of the Duffy blood group on red
cells is the resistance factor to P. vivax in persons
of African descent. (Miller et al., 1976). This has
become a well-known example of innate
resistance to an infectious agent because of the
absence of a receptor for the agent on target cells.
However, observations have accumulated
showing that the original report needs
qualification. P. vivax can be transmitted in
Squirrel monkeys (Saimiri boliviensis and S.
sciureus), and Barnwell et al. (Barmwell et al.,
1989). Have obtained evidence that P. has an
alternative pathway for invading these cells. The
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
57
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
Guinea; further, P. vavax infection were found
both in humans and mosquitoes, which means
that active transmission is occurring. This finding
reinforces the idea that this parasite is able to
use receptors other than Duffy to invade
erythroucytes, which may have an enormous
impact in P. vivax current distribution (Mendes et
al., 2011). Because of these several report from
different parts of the world it is clear that some
variants of P. vivax are being transmitted to
humans who are not expressing DARC on their
red cells. The frequency of such transmission is
still unknown. Identification of the parasite and
host molecules that allow Duffy-independent
invasion of human erythrocytes is an important
task for the future, because it may facilitate
vaccine development.
PLASMODIUM LIFE CYCLE
PLASMODIUM FALCIPARUM
48 h for P. vivax and P. ovale, and 72 h for P.
malariae (Sylvie et al., 2008). The clinical
The life cycle of all Plasmodium species is
complex. Infection in humans begins with the bite
of an infected female Anopheles mosquito enter
the bloodstream during feeding quickly invading
liver cells (hepatocytes). Sporozoites are cleared
from the circulation within 30 min. During the next
14 days in the case of P. falciparum, the liverstage parasites differentiate and undergo asexual
multiplication, resulting in tens of thousands of
merozoites that burst from the hepatocyte.
Individuals merozoites invade red blood cells
(erythrocytes) and undergo an additional round
of multiplication, producing 12-16 merozoties
within a schizont. The length of this crythroucytic
stage of the parasite lifecycle depends on the
parasite species: irregular cycle for P. falciparum,
Plasmodium falciparum is a protozoan parasite,
manifestations of malaria, fever, and chills are
associated with the synchronous rupture of the
one of the species of Plasmodium that cause
malaria in humans. It is transmitted by the female
infected crythrocytes. The released mcrozoites
go on to invade additional erythrocytes. Not all of
Anophetes mosquito. Malaria caused by this
species (also called malignant (Rich et al., 2009)
the mcrozoites divide into schizonts; some
differentiate into sexual forms, male and female
or falciparum (Perkins et al., 2011) malaria) is the
most dangerous form of malaria, (Perlmann et al.,
gametocytes. These gametocytes are taken up
by a female Anopheles mosquito during a blood
2000) with the highest rates of complication and
mortality. As of 2006, there were estimated 247
meal. Within the mosquito midgut, the male
gametocyte undergoes a rapid nuclear division,
million human malarial infections (98% in Africa,
70% being 5 years or younger). (World malaria
producing eight flagellated microgametes that
fertilize the female macrogamete. The resulting
Report, 2008). It is much more prevalent in subSaharan Africa than in many other regions of the
ookinete traverses the mosquito gut wall and
encysts on the exterior of the gut wall as an
world; in most African countries, over 75% of cases
were due to P. falciparum, whereas in most other
oocyst. Soon, the oocyst ruptures, releasing
hundreds of sporozoites into the mosquito body
countries with malaria transmission, other less
virulent plasmodial species predominate. Almost
cavity, where they eventually migrate to the
mosquito salivary glands.
every malarial death is caused by P. falciparum
(World Malaria Report, 2008).
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
58
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
THE PLASMODIUM
FALCIPARUM GENOME
merozoites infect red blood cells, where they
In 1995, a consortium, the Malaria Genome
Project (MGP), was set up to sequence the
genome of P. flaciparum. The genome of its
mitochondrion was reported in 1995, that of the
nonphotosynthetic plastid known as the
apicoplast in 1996 (Wilson et al., 1996) and the
sequence of the first nuclear chromosome
(chromosome 2) in 1998. The sequence of
chromosome 3 was reported in 1999, and the
entire genome on October 3, 2002 (Gardner et
al., 2002). Annotated genome data can now be
fully analyzed at several database resources
including the Malaria Genome Browser,
PlasmoDB and GeneDB. The 24 megabase
genome is extremely AT-rich (80%) and is
organized into 14 chromosomes: Just over 5,300
genes were described.
develop into ring forms, trophozoites and
P. falciparum and Sickle cell Anemia
schizonts that in turn produce further merozoites.
Individuals with sickle-cell anemia or sickle-cell
trait do have reduced parasitermia when
compared to wild-type individuals for the
hemoglobin protein in red blood cells. Studies have
shown these genetic deviations of hemoglobin
from normal states provide protection against the
deadly parasite that causes malaria (Allison, b of
the six malarial parasites, P. falciparum causes
the most fatal and medically severe form. Malaria
is prevent in tropical countries with an incidence
of 300 million per year and a mortality rate of 1 to
2 million per year. Roughly 50% of all malarial
infections are caused by P. falciparum (Roberts
and Janovy Jr., 2005). Upon infection via a bite
from an infected Anopheles mosquito,
sporozoites devastate the human body by first
infecting the liver. While in the liver, sporozoites
undergo asexual development and merozoites
The life cycle of malaria parasite. A mosquito
causes infection by taking a blood meal. First,
sporozoites enter the bloodstream, and migrate
to the liver. They infect liver cells, where they
multiply into merozoites, rupture the liver cells,
and return to the bloodstream. Then, the
Sexual forms are also produced, which, if taken
up by a mosquito, will infect the insect and
continue the life cycle.
PATHOGENESIS OF
PLASMODIUM FALCIPARUM
Plasmodiuim falciparum causes severe malaria
via a distinctive property not shared by any other
human malaria, that of scquestration. Within the
48 h asexual blood stage cycle, the mature forms
change the surface properties of infected red
blood cells, causing them to stick to blood vessels
(a process called cytoadherence). This leads to
obstruction of the microcirculation and results in
dysfunction of multiple organs, typically the brain
in cerebral malaria (Dandorp et al., 2004).
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
59
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
interfere with the attachment phase, and
Plasmodium falciparum and the other forms of
malaria have trouble with endocytosis.
are released into the bloodstream. The
trophozoites further develop and reproduce by
invading red blood cells. During as reproduction
cycle, Plasmodium falciparum produces up to
40,000 merozoites in one day. Other blood
sporozoans, such as Plasmodium vivax,
Plasmodium ovale, and Plasmodium malaria,
that infect humans and cause malaria do not have
such a productive cycle for invasion. The process
of bursting red blood cells does not have any
symptoms, however destruction of the cells does
cause anemia, since the bone marrow cannot
compensate for the damage. When red blood
cells rupture, hemozoin wastes cause cytokine
release, chills, and then fever (Roberts and
Janovy Jr., 2005).
These individuals have reduced attachment
when compared to red blood cells with the
normally functioning hemoglobin because of
differing protein interactions. In normal
circumstances, merozoites enter red blood cells
through two PfEMP-1 protein-dependent
interactions. These interactions promote the
malaria inflammatory response associated with
symptoms of chills and fever. When these
proteins are impaired, as in sickle-cell cases,
parasites cannot undergo cytoadhereance
interactions and cannot infect the cells; therefore,
sickle-cell anemic individuals and individuals
carrying the sickle-cell trait have lower parasite
loads and shorter time for symptoms than
individuals expressing normal red blood cells
(Mockenhaupt, 2004). Individuals with sickle-cell
anemia may also experience greatly reduced
symptoms of malaria because Plasmodium
falciparum trophozites cannot bind to hemoglobin
in order to form sticky knobs. Without knob-binding
complexes, which is an exclusive feature of
Plasmodium falciparum, red blood cells do not
stick to endothelial walls of blood vessels, and
infected individuals do not experience symptoms
such as cerebral malaria (Cholera et al., 2007).
Many may wonder why natural selection has not
phased out sickle-cell anemia. The answer lies
within answers generated by Cholera et al. (2007).
Individuals with sickle-cell trait are greatly desired
in areas where malarial infections are endemic.
Malaria kills between 1 and 2 million people per
year. It is the leading cause of death among
children in tropical regions. Individuals with sicklecell deformities are able to fight Plasmodium
Plasmodiuim falciparum trophozoties develop
sticky knobs in red blood cells, which then adhere
to endothelial cells in blood vessels, thus evading
clearance in the spleen. The acquired adhesive
nature of the red blood cells may cause cerebral
malaria when sequestered cells prevent
oxygenation of the brain, symptoms of cerebral
malaria include impaired consciousness,
convulsions, neurological disorder, and coma
(Brown University). Additional complications from
Plasmodium falciparum induced malaria include
advanced immunosuppression (Roberts and
Janovy Jr., 2005).
Individuals with sickle-cell trait and sickle-cell
anemia are privileged because they have altered
sticky knobs. Research by Cholera et al. (2007)
has shown that parsitemia (the ability of a parasite
of infect) because merozoites of each parasite
species that cause malaria invade the red blood
cell in three stages: contact, attachment, and
endocytosis. Individuals suffering from sickle-cell
anemia have deformed red blood cells that
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
60
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
parasite infections and do not become victims of
malarial demise. Therefore, individuals
expressing the genes and individual carrying
genes are selected to remain within the population
(Allison, 1964). It is no surprise that the incidence
of sickle-cell anemia malarial infections.
Abnormal Process in M.P.
MECHANISMS OF MALARIAL
PROTECTION BY SICKLE
CELL GENES
During the peripheral blood stage of replication,
malaria parasites have a high rate of oxygen
consumption and ingest large amounts of
haemoglobin A (normal haemoglobin gene). Unlike
haemoglobin A, haemoglobin S (HbS) in endocytic
vesicles of the parasite is deoxygenated,
polymerizes an is poorly digested. In the digestive
process, the toxic portion of the haemoglobin
called haemin (ferriprotoporphyrin IX) is converted
to the non-toxic substance called haemozoin by
the parasite enzyme call malarial haem
polymerase enabling the parasite to survive.
However, HbS is poorly digested by the parasite
and as a result haemin accumulates thereby
inhibiting the replication and survival of the
parasite in HbS containing red blood cell (Vaidya
et al., 2009).
dehydrogenase (G6PD) deficient, oxygen
radicals are produced and malaria parasites
induce additional oxidative stress and this result
in changes in red cells membranes, including
translocation of phosphatidylserine to their
surface, followed by macrophage recognition
and ingestion. This mechanism occurs earlier
in abnormal (HbS) than in normal red cells
(HbA), thereby restricting the multiplication of
malaria parasite. (Elliott et al., 2008).
2. In addition, binding of parasitized sickle cells
to endothelial cells is significantly decreased
because of an altered display of plasmodium
falicparum erythrocyfe membrane protein – 1
1. In red cells containing abnormal haemoglobin
(HbS) or which are glucose-6-phosphate
Normal Heamoglobin 2A
Normal Heamoglobin 1A
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
61
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
Abnormal Heamoglobin 2B
Abnormal Heamoglobin 3B
Percentage Showing the Resistance
of Malaria
(PfMP-1). This protein is the parasite’s main
cytoadherence ligand and virulence factor on
the cell surface. During the late stages of
parasite replication red cells are adherent to
venous endothelium, an inhibiting this
attachment suppresses replication of the
parasite in HbS containing red blood cell (Foller
et al., 2009).
CURRENT RESEARCH
ISSUES ON MALARIA AND
SICKLE CELL GENES
PfMP–1 = Plasmodium Faciparum
Erythrocyte Membrace Protein – I
Translocation of sickle cell Erythrocyte MicroRNAs
into plasmodium falciparum inhibits parasite
translation and contributes to malaria Resistance.
The study finds that individuals have three
microRNAs (miR-223, miR-451, let-7i) that are
effective in reducing Plasmodium falciparum
growth and replication, and the latter two are
increased in HbAS and HbSS individuals when
compared to HbAA individuals. The microRNAs
are transformed into the parasite and are inserted
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
62
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
into its mRNA in a method similar to trans-leader
trans-splicing, inhibiting translation and reducing
plasmodium falciparum growth. Therefore, HbAS
and HbSS individuals have a genetic advantage
over HbAA individuals
these two species originated from a parasite of
birds (Rathore et al., 2001). More recent analyses
do not support this, however, instead suggesting
that the ability to parasitize mammals evolved only
once within the genus Plasmodium (Yotoko et al.,
2006).
Known Vectors
New evidence based on analysis of more than
1,100 mitochondrial, apicoplastic, and nuclear
DNA sequences has suggested that Plasmodium
falciparum may in fact have speciated from a
lineage present in gorillas. (Liv et al., 2010; Dvva
et al., 2010; Rayner et al., 2011). According to
this theory, P. falciparum and P. falciparum and
P. reichenowi may both represent host switches
from an ancestral line that infected primarily
gorillas; P. falciparum went on to infect primarily
humans, while P. reichenowi specialized in
chimpanzees. The ongoing debate over the
evolutionary origin of Plasmodium falciparum will
likely be the focus of continuing genetic study
(Prugnolle et al., 2011). A third species that
appears to related to these two has been
discovered: Plasmodiium gaboni. This putative
species is currently (2009) known only from two
DNA sequences and awaits a full species
description before it can be regarded as valid.
Molecular clock analyses suggest that P.
falciparum is as old as the human line; the two
species diverged at the same time as humans
and chimpanzees. (Escalante et al., 1995).
However, low levels of polymorphism within the
P. falciparum genome suggest a much more
recent origin (Hartl et al, 2004). It may be that this
discrepancy exists because P. falciparum is old,
but its population recently underwent a great
expansion. (Joy et al., 2003). Some evidence still
indicates that P. reichenowi was the ancestor of
P. falciparum (Rich et al., 2009). The timing of
• Anopheles gambiae (Principal vector) (Mbogo
et al., 2003)
Current Research
• Anopheles albimanus
• Anopheles freeborni
• Anopheles maculates
• Anopheles stephensi
ORIGIN AND EVOLUTION OF
PLASMODIUM FALCIPARUM
The closest relative of Plasmodium falciparum
is Plasmodium reichenowi, a parasite of
chimpanzees. P. falciparum and P. reichenowi are
not closely related to the other Plasmodium
species that parasite humans, or indeed
mammals in general. It has been argued that
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
63
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
TREATMENT OF
FALCIPARUM MALARIA
this event is unclear at present but it has been
proposed that it may have occurred about 10,000
years ago.
Treatment of Uncomplicated Falciparum
Malaria
More recently, P. falciparum has evolved in
response to human interventions. Most strains
of malaria can be treated with chloroquine, but P.
falciparum has developed resistance to this
treatment. A combination of quinine and
tetracycline has also been used, but there are
strains of P. falciparum that have grown resistant
to this treatment as well. Different stains of P.
falciparum have grown resistant to different
treatment. Often, the resistant of the strain
depends on where it was contracted. Many cases
of malaria that come from parts of the Caribbean
and west of the Panama Canal as well as the
Middle East and Egypt can often be treated with
chloroquine, since they have not yet developed
resistance. Nearly all cases contracted in Africa,
India and Southeast Asia have grown resistant to
this medication, and there have been cases in
Thailand and Cambodia in which the strain has
been resistant to nearly all treatment. Often the
strain grows resistant to the treatment in areas
where the use is not as tightly regulated. Like most
apicomplexans, malaria parasites harbor a
plastid, an apicoplast, similar to plant
According to WHO guidelines 2010 (WHO, 2010)
artemisinin-based combination therapies (ACTs)
are the recommended first line antimalarial
treatments for uncomplicated malaria caused by
P. falciparum. (WHO, 2010). The following ACTs
are recommended By the WHO (WHO, 2010).
• Artemether plus lumefantrine
• Artesunate plus amodiaquine
• Artesunate plus mefloquine
• Artesunate plus sulfadoxine-pyrimethamine
• Dihydroartemisinin plus piperarquine
The choice of ACT in a country or region will
be based on the level of resistance to the
combination. (WHO, 2010). Arteminsinin and its
derivatives should not be used as monotherapy
in uncomplicated Falciparum malaria. (WHO,
2010). As second-line antimalaria treatment, when
initial treatment doesn’t work or stops working, it
is recommended to use an alternative ACT known
to be effective in the region, such as:
chlorophalsts, which they probably acquired by
engulfing (or being invaded by)a cukaryotic alga,
• Artesunate plus tetracycline or doxycycline or
clindamycin (WHO, 2010).
and retaining the algal plastid as a distinctive
organelle encased within four membranes – (sce
• Quinine plus tetracycline or doxycyline or
clindamycin (WHO, 2010).
endosymbiotic theory). The apicoplast, is an
essential organelle, thought to be involved into
Any of these combination are to be given for 7
days (WHO, 2010).
the synthesis of lipids and several other
compounds, and it provides an attractive target
for antimalarial drug development, in particular in
light of the emergence of parasites resistant to
chloroquine and other existing antimalarial agents.
For pregnant women, the recommended firstline treatment during the first trimester is quinine
plus clindamycin for 7 days (WHO, 2010).
Artesunate plus clindamycin for 7 days is
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
64
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
• Artesunate IV or IM.
indicated if this treatment fails (WHO, 2010). Still,
an ACT is indicated only if this is the only
treatment immediately available, or if treatment
with 7 days quinine plus clindamcin fails or if there
is uncertainty of compliance with a 7 day
treatment (WHO, 2010). In second and third
trimesters, the recommended treatment is an
ACT known to be effective in the country/region
or artesunate plus clindamycin for 7 days, or
quinine plus clindamycin for 7 days (WHO, 2010).
Lactating women should receive standard
antimalarial treatment (including ACTs) except for
dapsone, primaquine and tetracyclines. In infants
and young children, the recommended first-line
treatment is ACTs, with attention to accurate
dosing and ensuring the administered dose is
retained. (WHO, 2010). For travelers returning to
non-endemic countries, any of the following is
recommended (WHO, 2010).
• Quinine (IV infusion or divided IM injection).
• Artemether IM. It should be used only if none
of the alternative are available, as its absorption
may be erratic (WHO, 2010).
Parenteral antimalarials should be
administered for a minimum of 24 h in the
treatment of severe malaria, irrespective of the
patient’s ability to tolerate oral medication earlier.
(WHO, 2010). Thereafter, it is recommended to
complete treatment by giving a complete course
of nay of the following. (WHO, 2010).
• An ACT
• Artesunate plus clindamycin or doxycycline
• Qunine plus clindamycin or doxycycline
If complete treatment of severe malaria is not
possible, it is recommended that patients be
given pre-referral treatment and referred
immediately to an appropriate facility treatment.
The following are options for pre-referral
treatment. (WHO, 2010).
• Atovaquone-proguanil
• Artemether-lumefantrine;
• Quinine plus doxycycline or clindamycin.
Treatment of Severe Falciparum Malaria
• Rectal artesunate
In severe falciparum malaria, it is recommended
that the rapid clinical assessment and
confirmation of the diagnosis be made, followed
by administration of full doses of parenteral
antimalarial treatment without delay with
whichever antimalarial is first available. (WHO,
2010). For adults, intravenous (IV) or
intramuscular (IM) artesunate is recommended
(WHO, 2010). Quinine is an acceptable
alternative if parenteral artesunate is not available
(WHO, 2010). For children, especially in the
malaria-endemic areas of Africa, any the following
antimalarial medicines is recommended (WHO,
2010).
• Quinine IM
• Artesunate IM
• Artemether IM
History of Falciparum Treatment
Attempts to make synthetic antimalarials began
in 1891. Altabrine, developed in 1933, was used
widely throughout the Pacific in World War II but
was deeply unpopular because of the yellowing
of the skin it caused. In the late 1930s, the
Germans developed chloroquine, which went into
use in the North African campaigns. Mao Zedong
encouraged Chinese scientists to find new
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
65
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
antimalarials after seeing the causalities in the
CONCLUSION
Vietnam War. Artemisinin was discovered in the
People with either HbAS or HbSS are considered
to have sickle cell trait and can show symptoms
of sickle cell disease. Recent findings have
showed that translocation of sickle cell erythrocyte
MicroRNAs into plasmodium falicparum inhibits
parasite translation and contributes to malaria
resistance, and that this mechanism is higher in
HbAS and HbSS individuals when compared to
HbAA individuals, thus, people with sickle cell trait
have malaria resistance than those without sickle
cell trait (HbAA).
1980s based on a medicine described in China
in the year 340. This new drug became known to
Western scientists in the late 1980s and early
1990s and is now a standard treatment. In 1976,
P. falciparum was successfully cultured in vitro
for the first time, which facilitated the development
of new drugs substantially. (Trager et al., 1976).
A 2008 study published in the New England
Journal of Medicine highlighted the emergence
of artemisinin-resistant strains of P. falciparum
in Cambodia.
REFERENCES
Vaccination
1.
Asheley-Koch A, Yany Q and Olney R S
(2000), “Sickle Hemoglobin (Hb S) Allele
and Sickle Cell Disease: A HuGE Review”,
American Journal of Epidemiology, Vol. 151,
pp. 839-845.
2.
Allusion A C (2009), “Genetic control of
resistance to human malaria”, Current
Opinion in Immunology, Vol. 21, No. 5, pp.
499-505.
3.
Allison A C (1954), “The distribution of the
Although an antimalarial vaccine is urgently
needed, infected individuals never develop a
sterilizing (complete) immunity, making the
prospects for such a vaccine dim. The parasites
live inside cells, where they are largely hidden
from the immune response. Infection has a
profound effect on the immune system including
immune suppression. Dendritic cells suffer a
maturation defect following interaction with infect
erythrocytes directly adhere to and activate
sickle-cell trait in East Africa and
peripheral blood B cells from nonimmune donors.
elsewhere, and its apparent relationship to
The var gene products, a group of highly
the incidence of subtertain malaria”, Trans
expressed surface antigens, bind in Fab and Fe
Roy Soc Trop Med Hyg, Vol. 48, No. 4, pp.
fragments of human immunoglobulins in a
312-318.
fashion similar to protein A to Staphylococcus
4.
aureus, which may offer some protection to the
Allison A C (2009), “Genetic control of
resistance to human malaria”, Current
parasite from the human immune system. Despite
Opinion in Immunology, Vol. 21, No. 5, pp.
the poor prospects for a fully protective vaccine,
499-505.
it may be possible to develop a vaccine that would
5.
that would reduce the severity of malaria for
Alcais A, Abel L and Cassanova J L (2009),
children living in endemic areas. (Noedl et al.,
“Human genetics of infectious diseases:
2008).
between proof of principle and paradigm” .
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
66
Int. J. LifeSc. Bt & Pharm. Res. 2014
6.
Allison A C and Clyde D F (1961), “Malaria
in African Children with Deficient
Erythrocyte
Glucose-6-phosphate
Dehydrogenase”.
8.
Anstey N M, Handojo T, Pain M C,
Kenangalem E, Tjitra E, Price R N and
Maguire G P (2007), “Lung Injury in Vivax
Malaria: Pathophysiological Evidence for
Pulmorary Vascular Sequestration and
Posttreatment
Alveolar-Capillary
Inflammation”, J Infect Dis, Vol. 195, No. 4,
pp. 589-596.
Beutler E (2008), “Glueose-6-phosphate
dehydrogenase deficiency: a historical
perspective”, Blood, Vol. 111, No. 1, pp. 1624.
10.
Bamwell J W, Nichols M E and Rubinstein
P (1989), “In vitro evaluation of the role of
the Duffy blood group in erythrocyte invasion
by Plasmodium vivax”, J Exp Med, pp. 169179.
11.
Carroll S B (2009), “A sickle-cell safari”,
Chapter 8, pp. 148-165, in: Sean B Carroll,
Into the Jungle: Great Adventures in the
Search for Evolution, San Francisco:
Pearson Benjamin Cummings.
12.
and Central Africa by PCR species typing”,
pp. 174-182.
Alving A S, Carson P E, Flanagan C L and
lckes C E (1956), “Enzymatic deficiency in
primaquine-sensitive erythrocytes”,
Science, Vol. 124, No. 3220.
7.
9.
Otoikhian C S O et al., 2014
Culleton R I, Mita T, Ndounga M, Unger H,
Cravo P V, Paganotti G M, Takahashi N,
Kaneko A, Eto H, Tinto H, Karema C, D
Alessandro U, do Rosario V, Kobayakawa
T, Ntoumi F, Carter R and Tanabe K (2008),
“Failure to detect Plasmodium vivax in West
13.
Cavasini C E, de Mattos L C, Couto A A,
Couto V S, Golino Y, Moretti L J, BoniniDomingos C R, Rossit A R, Castilho L and
Machado R L (2007), “Duffy blood group
gene polymorphisms among malaria vivax
patients in four areas of the Barzilian
Amonzo region”.
14.
Cholera R, Brittain N J, Gillrie M R, LoperaMesa T M, Diakite SA, Arie T, Krause M A,
Guindo A, Tubman A, Fujioka H, Diallo D A,
Dounmbo O K, Ho M, Wellems T E and
Fairhurst R M (2008), “Impaired
cytoadherence of Plasmodium falciparuminfected erythrocytes containing sickle
hemoglobin.
15.
Duval L, Foument M, Nerrient E, Rousset
D, Sadeuh S A, Goodman S M,
Andriaholinirina N V, Randrianarivelojosia M,
Paul R E, Robert V, Ayala F J and Ariey F
(2010), “African apes as reservoirs of
Plasmodium falciparum and the origin and
diversification of the laverania subgenus”,
Proceedings of the National Academy of
Sciences of the United State of America.
16.
Dondorp A M, Pongponratn E and White
N J (February 2004), “Reduced
microcirculatory flow in severe falciparum
malaria pathophysiology and electronmicroscopic pathology”, Elliott DA, McIntosh
MT, Hosgood HD 3rd, Chen S, Zhang G,
Baevova P,
17.
Joiner K A (2008), Four distinct pathways
of hemoglobin uptake in the malaria parasite
Plasmodium falciparum.
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
67
Int. J. LifeSc. Bt & Pharm. Res. 2014
18.
Otoikhian C S O et al., 2014
Nature 419 (6906): Hartl DH (January
2004), “The origin of malaria: mixed
messages from genetic diversity”, Nature
Review Microbiology.
Escalante A A, Barrio E, Ayala F J (1995),
“Evolutionary origin of human and primate
malarias:
evidence
from
the
cicrmsporozoite protein gene”, Molecular
Biology and Evolution.
25.
Herrick J B (1910), “Peculiar elongated and
sickle-shaped red blood corpuscles in a
case of severe anemia”, Arch Intern Med,
Vol. 5, pp. 517-521; Reprinted in Herrick J
B (2001), “Peculiar elongated and sickleshaped red blood corpuscles in a case of
severe anemia”, Med Vol. 74(3).
19.
Ferreira A, Marguti I, Bechmann I, Jeney V,
Chora A, Palha N R, Rebelo S, Henri A,
Beuzard Y, and Soares M P (2001), “Sickle
hemoglobin confers tolerance to
Plasmodium infection”, Vol. 145, pp. 398409.
20.
Foller M, Bobbala D, Koko S, Hubber S M,
Gulbins E and Lang F (2009), “Suicide for
survival-death of infected erythrocytes as
a host mechanism to survive malaria”, Cell
Physiol Biochem, Vol. 24, pp. 133-140.
26.
Hahn E V and Gillespie E B (1927), “Sickle
cell anemia. Report of a case greatly
improved by splenectomy. Experimental
study of sickle cell formation”, Med., Vol.
39, pp. 233-254.
21.
Gergory L, Nisha P, Joseph R, Joshua R
Lacsina, William M, Lesley C, Courtney D
Thornburg, Marilyn J Telen, Uwe Ohler,
Christopher V Nicchitta, Timothy H, JenTsan Chi (2012), “Translocation of Sickle
Cell Erythrocyte MicroRNSs into
Plasmodium falciparum Inhibits Parasite
Translation and Contributes to Malaria
Resistance”, Cell Host and Microbe, 16
August 2012, Vol 12, Issue 2, pp. 187-199.
27.
Ingram V M (1959), “Abnormal human
haemoglobins. III. The chemical difference
between normal and sickle cell
haemoglobins”, Biochim Biophys Acta, Vol.
36, pp. 402-411.
28.
Joy D A; Feng X Mu J, Furuya T, Chotivanich
K, Krettli A U, Ho M, Wang A, White N J,
Suh E, Beerli P and Su X Z (2003-04-11),
“Early origin and recent expansion of
Plasmodium falciparum”, Science, p. 300.
29.
Kuross S A, Rank B H and Hebbel R P
(1988), “Excess heme in sickle erythrocyte
inside-out membrances: possible role in
thiol oxidation”.
30.
Lebby R (1846), “Case of absence of the
spleen”, Southern J of Med Pharmacol., Vol.
1, pp. 481-483.
31.
Liu W; Y Li, G H Learn R S Rudicell, J D
Robertson, B F Keele, J N, Ndjango, S
Locatelli, M K Gonder, P J Kranzusch, P D
22.
Guidelines for the treatment of malaria,
second edition Authors: WHO. Number of
pages: 194. Publication date: 2010.
23.
Gong L, Parikh S, Rosenthal P J and
Greenhouse B (2013), “Biochemical and
immunological mechanisms by which
sickle cell trait protects against malaria”.
24.
Gardner M J , Hall N, Fung E, et al. (October
2002), “Genome sequence of the human
malaria parasite Plasmodium falciparum”,
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
68
Int. J. LifeSc. Bt & Pharm. Res. 2014
Otoikhian C S O et al., 2014
Duffy-blood-group genotype, FyFy”, N.
Engl J Med, 295
Walsh, E Delaporte, E Mpoudi-Ngole, A V
Georgiev, M N Muller, G M Shaw, M Peeters,
P M Sharp, J C Rayner and B H Hahn
(2010), “Origin of the human malaria
parasite Plasmodium falciparum in gorillas”.
32.
33.
Lapoumeroulie C, Dunda, O, Ducrocq R,
Trabuchet G, Mony-Lobe M, Bodo J M,
Camevale P, Labie D, Elion J and
Krishnamoorthy R (1992), “A novel sickle
cell mutation of yet another origin in Africa:
the Cameroon type”, Hum Genet, Vol. 89,
No. 3, pp. 333-337.
Labie D, Srinivas R, Dunda O, Dode C,
Lapoumeroulie C, Devi V, Devi S,
Ramasami K, Elion J, Ducroeq R, et al
(1989), “Haplotypes in tribal India bearing
the sickle-gene: evidence for the unicentric
origin of the S mutation and the unicentric
origin of tribal population in India”, Hum.Biol.,
Vol. 61, pp. 479-491.
34.
Lehmann H and Raper A B (1949),
“Distribution of sickle cell trait in Uganda,
and its ethnological significance”, Nature,
Vol. 164, No. 4168, pp. 494-495.
35.
Mounkaila A Billo, Eric S Jonhson, Seydou
O Doumbia, Bele Poudiugou, Issaka
Sagara, Sory I Diawara, Mohomadou
Diakite, Mouctar Diallo, Ogobara K.
Doumbo, Anotole Tunkara, Janet Rice,
Mark A. James, and Donald J. Krogstad
(2012), “Sickle Cell Trait Protects Against
Plasmodium falciparum Infection”,
American Journal of Epidemiology, Vol.
176, pp. 175-185.
36.
Miller L H, Mason S J, Clyde D F and
McGinniss M H (1976), “The resistance
factor to Plasmodium vivax in blacks. The
37.
Menard D, Barnadas C, Bouchier C, Gray
LR, Ratsimbasoa, A, Thonier V, Carod J F,
Domarle O, Colin Y, Bertrand O, Picot J,
King C L, Grimberg B T, Mereereau-Puijalon
O, Zimmerman P A (2010), “Plasmodium
vivax clinical malaria is commonly
observed in Duffy-negative Malagasy
people”.
38.
Mendes C, Dias F, Figueiredo J, Mora V G,
Cano J, de Sousa B, do Rosario V E,
Benito A, Berzosa P and Arex A P (2011),
“Duffy Negative Antigen is No Longer a
Barrier to Plasmodium vivax – Molecular
Evidences from the African West Coast
(Angola and Equatorial Guinea)”, In FrancoParedes, Carlos. P
39.
Mbogo C M, Mwangangi J M, Nzovu J, et al.
(June 2003), “Spatial and temporal
heterogeneity of Anopheles mosquitoes and
Plasmodium falciparum transmission
along the Kenyan coast”, Am. J. Trop. Med
Hyg., p. 68.
40.
National Institute of Health, “Sickle Cell
Disease”, Genetics Home Reference,
2012.
41.
National Institute of Health, “HBB”, Genetics
Home Reference. 2009.
42.
National Institute of Health, “Life Cycle of
the Malaria Parasite”, National Institute of
Allergy and Infectious Disease, 2012.
43.
Noedi H, Se Y, Schaecher K, Smith B L,
Socheat D and Fukuda M M (December
2008), “Evidence of artemisinin-resistant
malaria in Western Cambodia”,N. Engl. J.
Med., p. 359
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
69
Int. J. LifeSc. Bt & Pharm. Res. 2014
44.
Prugnolle F; P Durand B, Ollomo L, Duval
F, Ariey C, Arnathau J P, Gonzalez E, Leroy
F and Renaud (2011), “A Fresh Look at the
Origin of Plasmodium falciparum, the Most
Malignant Malaria Agent”.
45.
Perkins D J, Were T, Davenport G C,
Kempaiah P, Hittner J B and Ong‘Echa J M
(2011), “Severe malarial anemia: Innate
immunity and pathogenesis”, International
journal of biological sciences, Vol. 7, pp.
1427-1442.
46.
Perlmann P and Troye-Blomberg M (2000),
“Malaria blood-stage infection and its control
by the immune system”, Folia biological,
Vol. 46.
47.
Piel F B, Patil A P, Howes R E, Nyangiri O
A, Gething P W, Williams T N, Weatherall
D J and Hay S I (2010), “Global distribution
of the sickle cell gene and geographical
confirmation of the malaria hypothesis”),
Nat Commun., Vol. 104, pp. 1-7.
48.
49.
50.
Otoikhian C S O et al., 2014
Mtalib R, Koros J, Owour B, Luckhart S,
Wirtz R A, Barnwell J W and Rosenberg R
(2006), “Evidence for transmission of
Plasmodium vivax among a duffy antigen
negative population in Western Kenya”, Am
J Trop Med. Hyg, Vol. 75, No. 4, pp. 575581.
Rich S M, Leendertz F H, Xu G, Lebreton
M, Djoko CF, Aminake M N, Takang E E,
Diffo J L, Pike B L, Rosenthal B M,
Formenty P, Boesch C, Ayala F J andWolfe
N D (2009), “The origin of malignant
malaria”.
Ruwende C, Khoo S C, Snow R W, Yates
S N R, Kwiathowski D, Gupta S, Warn P,
Allsopp C E M, Gilbert S C, Peschu N,
Newbold C I, Greenwood B M, Marsh K and
Hill A V S (1995), “Natural selection of hemiand heterozygotes for G6PD deficiency in
Africa by resistance to severe malaria”,
Nature, Vol. 376, No. 6537, pp. 246-249.
Ryan J R, Stoute J A, Amon J, Dunton R F,
51.
Rayner J, WM Liu, Peeters M, Sharp P M
and Hahn B H (2011), “A plethora of
Plasmodium species in wild apes: a source
of human infection?”, Trends in Parsitology.
52.
Rathore D, Wahi A M, Sullivan M and
McCutehan T F (2001-04-25), “A
phylogenetic comparison of gene trees
constructed from plastid, mitochondrial and
genomic DNA of Plasmodium species”,
Molecular and Biochemical Parasitolgy.
53.
Rich S M, Leendertz F H, Xu G, Djoko C F,
Aminake M N, Takang E E, Diffo J L D, Pike
B L, Rosenthal B M, Formenty P, Boesch
C, Ayala F J and Wolfe N D (2009), “The
origin of malignant malaria”, Proceeding of
the National Academic of Sciences.
54.
Santos-Ciminera P D, Roberts D R, Alecrim
M G C, Costa M RF and Quinnan G V Jr.
(2007), “Malaria Diagnosis and
Hospitalization Trends, Braxil”, Emerg
Infect Dis, Vol. 13, pp. 1597-1600.
55.
Taylor S M, Ceramin C and Fairhurst R M
(2013), “Hemoglobinopathies: Slicing the
Gordian Knot of Plasmodium falciparum
Malaria Pathogenesis”, PLoS, Pathog.
56.
Tishkoff S A and Verelli B J (2004), “G6PD
deficiency and malarial resistance in
human: insights from evolutionary genetic
analysis”, In Evolutionary Aspects of
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
70
Int. J. LifeSc. Bt & Pharm. Res. 2014
57.
58.
59.
Otoikhian C S O et al., 2014
Infectious Disease, Dronamraju K (Ed.),
Cambridge University Press.
human
Tournamille C, Colin Y, Cartron J P and Le
Van Kim C (1995), “Disruption of a GATA
motif in the Duffy gene promoter abolishes
erythroid gene expression in Duffy-negative
individuals”, Nat Genet Vol. 10, No. 2, pp.
224-228.
protein”, Exp Parasitol, Vol. 69, pp. 340-350.
Duffy
blood
glycoprotein:
identification of a parasite receptor-like
61.
Wilson R J, Denny P W, Preiser P R, et al.
(August 1996), “Complete gene map of the
plasted-like DNA of the malaria parasite
Plasmodium falciparum”, Journal of
Molecular Biology.
Taliaffero W H and Huck J G (1923), The
Inheritance of Sickle-cell Anaemia in Man
Genetics, Vol. 8, pp. 594-598.
62.
World Health Organization, “Malaria”.
World Health Organization, 2013.
63.
Vaidaya A B and Mather M W (2009),
“Mitochondrial evolution and functions in
malaria parasites”, Annu Rev Microbiol.,
Vol. 63, pp. 249-267.
Yotoko K S C and Elisei C (November
2006), “Malaria parasite (Apicomplexa,
Haematozoea) and their relationships with
their host: is there an evolutionary cost for
the specialization?”, Journal of Zoological
60.
Wertheimer S P and Barrwell J W (1989),
“Plasmodium vivax interaction with the
Systematics and Evolution.
This article can be downloaded from http://www.ijlbpr.com/currentissue.php
71