Human genetic resistance to malaria

Human genetic resistance to malaria refers to inher- is observed in P. falciparum infections, and progressive
ited changes in the DNA of humans which are thought to alveolar capillary dysfunction is observed after the treat-
be due to pressure from evolving alongside the parasites ment of vivax malaria.[4] Epidemiological studies in the
that cause malaria (parasites of the genus Plasmodium). Amazonian region of Brazil have shown that the num-
These DNA changes confer a selective survival advantage ber and rate of hospital admissions for P. vivax infections
by increasing resistance to disease. Since malaria infects have recently increased while those of P. falciparum have
red blood cells, these genetic changes are most commonly decreased.[5]
alterations to molecules essential for red blood cell func- These inherited changes to hemoglobin or other charac-
tion (and therefore parasite survival), such as hemoglobin teristic erythrocyte proteins which are critical and rather
or other cellular proteins or enzymes of red blood cells. invariant features of mammalian biochemistry, usually
These alterations generally protect red blood cells from result in some kind of anemia, a disease or defect of red
invasion by Plasmodium parasites or replication of para- blood cells. These changes are referred to by the names of
sites within the red blood cell. the diseases resulting from them including sickle cell dis-
Malaria has placed the strongest known selective pressure ease, thalassemia, glucose-6-phosphate dehydrogenase
on the human genome since the origination of agriculture (G6PD) deficiency, and others. These blood disorders
within the past 10,000 years.[1][2] Plasmodium falciparum cause increased morbidity and mortality in areas of the
was probably not able to gain a foothold among African world where malaria is no longer prevalent.
populations until larger sedentary communities emerged
in association with the evolution of domestic agriculture
in Africa (the agricultural revolution). Several inherited
variants in erythrocytes have become common in for-
1 Genetic resistance to parasitic in-
merly malarious parts of the world as a result of selection fection
exerted by this parasite.[3] This selection was historically
important as the first documented example of disease as Microscopic parasites (like viruses, protozoans that cause
an agent of natural selection in humans. It was also the malaria, and others) cannot replicate on their own. They
first example of genetically controlled innate immunity replicate by invading the hosts’ cells, and usurping the
that operates early in the course of infections, preced- cellular machinery to replicate themselves. Eventually,
ing adaptive immunity which exerts effects after several unchecked replication causes the cells to burst, releasing
days. In malaria, as in other diseases, innate immunity the infectious organisms into the bloodstream. There they
leads into, and stimulates, adaptive immunity. spread and infect other cells. As cells die and toxic prod-
One of the key reasons for the high fatality rate in P. fal- ucts of invasive organism replication accumulate, disease
ciparum malaria is the occurrence of so-called cerebral symptoms appear.
malaria. Patients become confused, disoriented and often The process of invading the host cell, hijacking the cel-
lapse into a terminal coma. Clumps of malaria-infested lular machinery, replication and final release is a compli-
red cells adhere to the endothelium and occlude the mi- cated set of steps. Very specific proteins coded by the
crocirculation of the brain with deadly consequences. DNA of the infectious organism as well as the host cells
The P. falciparum parasite alters the characteristics of the allow those steps to happen. Even a very small change in a
red cell membrane, making them more “sticky”. Clusters critical protein might make infection difficult or impossi-
of parasitized red cells exceed the size of the capillary ble. Such changes might arise by a process of mutation in
circulation blocking blood flow and producing cerebral the gene that codes for the protein. If the change is in the
hypoxia. Cerebral malaria accounts for 80% of malaria gamete, that is, the sperm or egg that join to form a zygote
deaths. Thalassemic erythrocytes adhere to parasitized that grows into a human being, the protective mutation
red cells much less readily than do their normal counter- will be inherited. Since lethal diseases kill many persons
parts. This alteration would lessen the chance of devel- who lack protective mutations, in time, many persons in
oping cerebral malaria. regions where lethal diseases are endemic come to inherit
P. vivax is clearly a less potent agent of natural selection protective mutations.
that is P. falciparum. However, the morbidity of P. vi- Mutations may have detrimental as well as beneficial ef-
vax is not negligible. For example, P. vivax infections fects, and any single mutation may have both. Infectivity
induce a greater inflammatory response in the lungs than of malaria depends on specific proteins present in the cell

1
2 3 TYPES OF INNATE RESISTANCE

walls and elsewhere in red blood cells. Protective muta- age of suggestions. During the peripheral blood stage
tions alter these proteins in ways that make them inacces- of replication malaria parasites have a high rate of
sible to malaria organisms. However, these changes also oxygen consumption[10] and ingest large amounts of
alter the functioning and form of red blood cells that may hemoglobin.[11] It is likely that HbS in endocytic vesi-
have visible effects, either overtly, or by microscopic ex- cles is deoxygenated, polymerizes and is poorly digested.
amination of red blood cells. These changes may impair In red cells containing abnormal hemoglobins, or which
the function of red blood cells in various ways that have are G6PD deficient, oxygen radicals are produced, and
a detrimental effect on the health or longevity of the in- malaria parasites induce additional oxidative stress.[12]
dividual. However, if the net effect of protection against This can result in changes in red cell membranes, includ-
malaria outweighs the other detrimental effects, the pro- ing translocation of phosphatidylserine to their surface,
tective mutation will tend to be retained and propagated followed by macrophage recognition and ingestion.[13]
from generation to generation. The authors suggest that this mechanism is likely to oc-
cur earlier in abnormal than in normal red cells, thereby
These alterations which protect against malarial infec-
tions but impair red blood cells are generally considered restricting multiplication in the former. In addition, bind-
ing of parasitized sickle cells to endothelial cells is signif-
blood disorders, since they tend to have overt and detri-
mental effects. Their protective function has only in re- icantly decreased because of an altered display of P. fal-
cent times, been discovered and acknowledged. Some ciparum erythrocyte membrane protein-1 (PfMP-1).[14]
of these disorders are known by fanciful and cryptic This protein is the parasite’s main cytoadherence ligand
names like sickle-cell anemia, thalassaemia, glucose-6- and virulence factor on the cell surface. During the late
phosphate dehydrogenase deficiency, ovalocytosis, ellip- stages of parasite replication red cells are adherent to ve-
tocytosis and loss of the Gerbich antigen and the Duffy nous endothelium, and inhibiting this attachment could
antigen. These names refer to various proteins, enzymes, suppress replication.
and the shape or function of red blood cells. Sickle hemoglobin induces the expression of heme
oxygenase-1 in hematopoietic cells. Carbon monox-
ide, a byproduct of heme catabolism by heme oxyge-
nase−1(HO-1), prevents an accumulation of circulating
2 Innate resistance free heme after Plasmodium infection, suppressing the
pathogenesis of experimental cerebral malaria.[15] Other
The potent effect of genetically controlled innate resis- mechanisms, such as enhanced tolerance to disease medi-
tance is reflected in the probability of survival of young ated by HO-1 and reduced parasitic growth due to translo-
children in malarious environments. It is necessary cation of host micro-RNA into the parasite, have been
to study innate immunity in the susceptible age group, described.[16]
younger than four years; in older children and adults the
effects of innate immunity are overshadowed by those of
adaptive immunity. It is also necessary to study popula-
tions in which random use of antimalarial drugs does not 3 Types of innate resistance
occur.
Some early contributions on innate resistance to infec-
tions of vertebrates, including humans, are summarized
in Table 1.
Table 1. Innate Resistance to Plasmodia
It is remarkable that two of the pioneering studies were
on malaria. The classical studies on the Toll receptor in
Drosophila fruit fly[8] were rapidly extended to Toll-like
receptors in mammals[9] and then to other pattern recog-
nition receptors, which play important roles in innate im-
munity. However, the early contributions on malaria re-
[17]
main as classical examples of innate resistance, which Frequency of malaria cases in 1996.
have stood the test of time.
Evidence has accumulated that the first line of defense
against malaria is provided by genetically controlled in-
2.1 Mechanisms of protection nate resistance, mainly exerted by abnormal hemoglobins
and glucose-6-phosphate dehydrogenase deficiency. The
The mechanisms by which erythrocytes containing ab- three major types of inherited genetic resistance - sickle
normal hemoglobins, or are G6PD deficient, are par- cell disease, thalassemias, and G6PD deficiency - were
tially protected against P. falciparum infections are not present in the Mediterranean world by the time of the
fully understood, although there has been no short- Roman Empire.
3.1 Hemoglobin abnormalities 3

3.1 Hemoglobin abnormalities HbS has a lower negative charge at physiological pH than
does normal adult hemoglobin. The consequences of the
See also: Hemoglobinopathy and Hemolytic anemia simple replacement of a charged amino acid with a hy-
drophobic, neutral amino acid are far ranging, Recent
studies in West Africa suggest that the greatest impact of
Hb S seems to be to protect against either death or severe
3.1.1 Sickle-cell disease—that is, profound anemia or cerebral malaria—
while having less effect on infection per se. Children
who are heterozygous for the sickle cell gene have only
one- tenth the risk of death from falciparum as do those
who are homozygous for the normal hemoglobin gene.
Binding of parasitized sickle erythrocytes to endothelial
cells and blood monocytes is significantly reduced due
to an altered display of P.falciparum erythrocyte mem-
brane protein-1 (PfEMP-1), the parasite’s major cytoad-
herence ligand and virulence factor on the erythrocyte
surface.[21] Protection also derives from the instability of
sickle hemoglobin, which clusters the predominant inte-
gral red cell membrane protein (called band 3) and trig-
gers accelerated removal by phagocytic cells. Natural an-
tibodies recognize these clusters on senescent erythro-
This vein (4) shows the interaction between the malaria sporo- cytes. Protection by HbAS involves the enhancement
zoites (6) with sickle cells (3) and regular cells (1). While malaria of not only innate but also of acquired immunity to the
is still affecting the regular cells (2), the ratio of sickle to regu- parasite.[22] Prematurely denatured sickle hemoglobin re-
lar cells is 50/50 due to sickle cell anemia being a heterozygous
sults in an up regulation of natural antibodies which con-
trait, so the malaria can’t affect enough cells with schizonts (5)
trol erythrocyte adhesion in both malaria and sickle cell
to harm the body.
disease.[23] Targeting the stimuli that lead to endothelial
activation will constitute a promising therapeutic strategy
Main article: Sickle-cell anemia to inhibit sickle red cell adhesion and vasco-occlusion.[24]
See also: Sickle-cell trait and Evolutionary_baggage §
Sickle-Cell and Malaria P. Brain also while working in Northern Rhodesia sug-
gested that while homozygotes for the sickle cell gene
suffered from several problems heterozygotes might be
This was the first time a genetic disease was linked to a protected against malaria.[25]
mutation of a specific protein and Pauling introduced his
fundamentally important concept of sickle cell anemia as
a genetically transmitted molecular disease.[18]
3.1.2 Thalassemias
The molecular basis of sickle cell anemia was finally elu-
cidated in 1959, when Ingram perfected the techniques of Main articles: Thalassemia and Alpha-thalassemia
tryptic peptide fingerprinting. In the mid-1950s, one of
the newest and most reliable ways of separating peptides
and amino acids was by means of the enzyme trypsin, It has long been known that a kind of anemia, termed
which split polypeptide chains by specifically degrading thalassemia, has a high frequency in some Mediterranean
the chemical bonds formed by the carboxyl groups of populations, including Greeks and southern Italians. The
two amino acids, lysine and arginine. Small differences name is derived from the Greek words for sea (thalassa),
in hemoglobin A and S will result in small changes in meaning the Mediterranean sea, and blood (haima). Ver-
one or more of these peptides .[19] To try to detect these non Ingram deserves the credit for explaining the ge-
small differences, Ingram combined paper electrophore- netic basis of different forms of thalassemia as an im-
sis and the paper chromotagraphy methods. By this com- balance in the synthesis of the two polypeptide chains of
[26]
bination he created a two-dimensional method that en- hemoglobin.
abled him to comparatively “fingerprint” the hemoglobin In the common Mediterranean variant, mutations de-
S and A fragments he obtained from the tryspin digest. crease production of the β-chain (β-thalassemia). In
The fingerprints revealed approximately 30 peptide spots, α-thalassemia, which is relatively frequent in Africa
there was one peptide spot clearly visible in the digest of and several other countries, production of the α-chain
haernoglobin S which was not obvious in the haemoglobin of hemoglobin is impaired, and there is relative over-
A “finger print”. The Hb S gene defect is a mutation of a production of the β-chain. Individuals homozygous for
single nucleotide (A to T) of the β-globin gene replacing β-thalassemia have severe anemia and are unlikely to sur-
the amino acid glutamic acid with the less polar amino vive and reproduce, so selection against the gene is strong.
acid valine at the sixth position of the β chain.[20] Those homozygous for α-thalassemia also suffer from
4 3 TYPES OF INNATE RESISTANCE

anemia and there is some degree of selection against the lent hemoglobinopathies with 30 million people affected.
gene. Hemoglobin E is very common in parts of Southeast Asia.
The lower Himalayan foothills and Inner Terai or Doon HbE erythrocytes have an unidentified membrane abnor-
Valleys of Nepal and India are highly malarial due mality that renders the majority of the RBC population
[35]
to a warm climate and marshes sustained during the relatively resistant to invasion by P falciparum.
dry season by groundwater percolating down from the
higher hills. Malarial forests were intentionally main- 3.1.4 Distribution of abnormal hemoglobins
tained by the rulers of Nepal as a defensive measure.
Humans attempting to live in this zone suffered much Malaria does not occur in the cooler, drier climates of
higher mortality than at higher elevations or below on the highlands in the tropical and subtropical regions of
the drier Gangetic Plain. However, the Tharu people the world. Tens of thousands of individuals have been
had lived in this zone long enough to evolve resistance studied, and high frequencies of abnormal hemoglobins
via multiple genes. Medical studies among the Tharu have not been found in any population that was malaria
and non-Tharu population of the Terai yielded the ev- free. The frequencies of abnormal hemoglobins in dif-
idence that the prevalence of cases of residual malaria ferent populations vary greatly, but some are undoubtedly
is nearly seven times lower among Tharus. The basis polymorphic, having frequencies higher than expected by
for resistance has been established to be homozygosity recurrent mutation. There is no longer doubt that malar-
of α-Thalassemia gene within the local population.[27] ial selection played a major role in the distribution of all
Endogamy along caste and ethnic lines appear to have these polymorphisms. All of these are in malarious areas,
prevented these genes from being more widespread in
neighboring populations.[28]

3.1.3 HbC and HbE erythroids

Main articles: Hemoglobin C and Hemoglobin E

There is evidence that the persons with α-thalassemia,

HbC and HbE have some degree of protection against
the parasite.[29][30] Hemoglobin C (HbC) is an abnormal
hemoglobin with substitution of a lysine residue for glu-
tamic acid residue of the β-globin chain, at exactly the
same ß−6 position as the HbS mutation. The “C” des-
ignation for HbC is from the name of the city where
it was discovered—Christchurch, New Zealand. People
who have this disease, particularly children, may have
episodes of abdominal and joint pain, an enlarged spleen,
and mild jaundice, but they do not have severe crises, as
occur in sickle cell disease. Haemoglobin C is common
in malarious areas of West Africa, especially in Burkina
Faso. In a large case–control study performed in Burk-
ina Faso on 4,348 Mossi subjects, that HbC was asso-
ciated with a 29% reduction in risk of clinical malaria in
HbAC heterozygotes and of 93% in HbCC homozygotes.
HbC represents a ‘slow but gratis’ genetic adaptation to
malaria through a transient polymorphism, compared to
the polycentric ‘quick but costly’ adaptation through bal-
anced polymorphism of HbS.[31][32] HbC modifies the
quantity and distribution of the variant antigen P. falci-
parum erythrocyte membrane protein 1 (PfEMP1) on the
infected red blood cell surface and the modified display
of malaria surface proteins reduces parasite adhesiveness
(thereby avoiding clearance by the spleen) and can reduce
the risk of severe disease.[33][34]
Hemoglobin E is due to a single point mutation in the
gene for the beta chain with a glutamate-to-lysine sub-
stitution at position 26. It is one of the most preva-
Old World distribution of hemoglobin-inherited disorders
• Sickle cell - The gene for HbS associated with
sickle-cell is today distributed widely throughout
sub-Saharan Africa, the Middle East, and parts
of the Indian subcontinent, where carrier frequen-
cies range from 5-40% or more of the population.
Frequencies of sickle-cell heterozygotes were 20-
40% in malarious areas of Kenya, Uganda, and
Tanzania. Later studies by many investigators filled
in the picture.[36][37] 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 Greece that were formerly highly malarious.
The thalassemias have a high incidence in a broad band
extending from the Mediterranean basin and parts of
Africa, throughout the Middle East, the Indian subcon-
tinent, Southeast Asia, Melanesia, and into the Pacific Is-
lands.
• α-thalassemia, which attains frequencies of 30% in
parts of West Africa;[29]
3.2 Other erythrocyte mutations 5

• β-thalassemia, with frequencies up to 10% in parts

of Italy;

• HbE, which attains frequencies up to 55% in Thai-

land and other Southeast Asian countries;[38] HbE is
found in the eastern half of the Indian subcontinent
and throughout Southeast Asia, where, in some ar-
eas, carrier rates may exceed 60% of the population.

• HbC, which attains frequencies approaching 20%

in northern Ghana and Burkina-Faso. HbC is re-
stricted to parts of West and North Africa.

• concurrent polymorphisms - double heterozygotes

for HbS and β-thalassemia, and for HbS and HbC,
suffer from variant forms of sickle-cell disease,
milder than SS but likely to reduce fitness before
modern treatment was available. As predicted, these
variant alleles tend to be mutually exclusive in pop-
ulations. There is a negative correlation between
frequencies of HbS and β-thalassemia in differ-
ent parts of Greece and of HbS and HbC in West
Africa.[39] Where there is no adverse interaction of Hemolytic anemia due to G6PD deficiency following Fava beans
consumption
mutations, as in the case of abnormal hemoglobins
and G6PD deficiency, a positive correlation of these
variant alleles in populations would be expected and G6PD deficiency is sex-linked, and common in Mediter-
is found.[39] ranean, African and other populations. In Mediter-
ranean countries such individuals can develop a hemolytic
diathesis (favism) after consuming fava beans. G6PD de-
3.2 Other erythrocyte mutations ficient persons are also sensitive to several drugs in addi-
tion to primaquine.
Other genetic mutations besides hemoglobin abnormali-
ties that confer resistance to Plasmodia infection involve G6PD deficiency is the most common enzyme defi-
ciency in humans, estimated to affect some 400 million
alterations of the cellular surface antigenic proteins, cell
membrane structural proteins, or enzymes involved in people.[41] There are many mutations at this locus, two
glycolysis. of which attain frequencies of 20% or greater in African
and Mediterranean populations; these are termed the A-
and Med mutations.[42] Mutant varieties of G6PD can be
3.2.1 Glucose-6-phosphate dehydrogenase defi- more unstable than the naturally occurring enzyme, so
ciency that their activity declines more rapidly as red cells age.
This question has been studied in isolated populations
Main article: Glucose-6-phosphate dehydrogenase defi- where antimalarial drugs were not used in Tanzania,
ciency East Africa[43] and in the Republic of the Gambia, West
See also: Glucose-6-phosphate dehydrogenase Africa, following children during the period when they
Glucose-6-phosphate dehydrogenase (G6PD) is an im- are most susceptible to falciparum malaria.[44] In both
portant enzyme in red cells, metabolizing glucose through
cases parasite counts were significantly lower in G6PD-
the pentose phosphate pathway, an anabolic alternative to
deficient persons than in those with normal red cell en-
catabolic oxidation (glycolysis), while maintaining a re-
zymes. The association has also been studied in in-
ducing environment. G6PD is present in all human cells dividuals, which is possible because the enzyme defi-
but is particularly important to red blood cells. Since ma-
ciency is sex-linked and female heterozygotes are mo-
ture red blood cells lack nuclei and cytoplasmic RNA, saics due to lyonization, where random inactivation of
they cannot synthesize new enzyme molecules to replace an X-chromosome in certain cells creates a population
genetically abnormal or ageing ones. All proteins, includ-
of G6PD deficient red blood cells coexisting with nor-
ing enzymes, have to last for the entire lifetime of the red
mal red blood cells. Malaria parasites were significantly
blood cell, which is normally 120 days. more often observed in normal red cells than in enzyme-
In 1956 Alving and colleagues showed that in some deficient cells.[45] An evolutionary genetic analysis of
African Americans the antimalarial drug primaquine in- malarial selection of G6PD deficiency genes has been
duces hemolytic anemia, and that those individuals have published by Tishkoff and Verelli.[42] The enzyme defi-
an inherited deficiency of G6PD in erythrocytes.[40] ciency is common in many countries that are, or were
6 3 TYPES OF INNATE RESISTANCE

formerly, malarious, but not elsewhere.

3.2.2 PK deficiency

Main article: PK deficiency

See also: Pyruvate kinase

Pyruvate kinase (PK) deficiency, also called erythrocyte

pyruvate kinase deficiency, is an inherited metabolic dis-
order of the enzyme pyruvate kinase. In this condition, a
lack of pyruvate kinase slows down the process of glycol-
ysis. This effect is especially devastating in cells that lack
mitochondria, because these cells must use anaerobic gly-
colysis as their sole source of energy because the TCA cy-
cle is not available. One example is red blood cells, which
in a state of pyruvate kinase deficiency rapidly become
deficient in ATP and can undergo hemolysis. Therefore,
pyruvate kinase deficiency can cause hemolytic anemia.
There is a significant correlation between severity of PK
deficiency and extent of protection against malaria.[46]
stained red blood cell membrane proteins on electrophoresis gel
strip[47]
3.2.3 Elliptocytosis

Main article: Elliptocytosis stress and more susceptible to permanent deformation.

Elliptocytosis a blood disorder in which an abnormally

large number of the patient’s erythrocytes are elliptical.
There is much genetic variability amongst those affected.
There are three major forms of hereditary elliptocytosis:
common hereditary elliptocytosis, spherocytic elliptocy-
tosis and southeast Asian ovalocytosis.

3.2.4 Southeast Asian ovalocytosis

Main article: Southeast Asian ovalocytosis

Ovalocytosis is a subtype of elliptocytosis, and is an in-
herited condition in which erythrocytes have an oval in-
stead of a round shape. In most populations ovalocy-
tosis is rare, but South-East Asian ovalocytosis (SAO)
occurs in as many as 15% of the indigenous people of
Malaysia and of Papua New Guinea. Several abnormal-
ities of SAO erythrocytes have been reported, includ-
ing increased red cell rigidity and reduced expression of
some red cell antigens.[48] SAO is caused by a muta-
tion in the gene encoding the erythrocyte band 3 protein.
There is a deletion of codons 400-408 in the gene, leading
to a deletion of 9 amino-acids at the boundary between
the cytoplasmic and transmembrane domains of band 3
protein.[49] Band 3 serves as the principal binding site for
the membrane skeleton, a submembrane protein network
composed of ankyrin, spectrin, actin, and band 4.1. Oval-
ocyte band 3 binds more tightly than normal band 3 to
ankyrin, which connects the membrane skeleton to the
band 3 anion transporter. These qualitative defects cre-
ate a red blood cell membrane that is less tolerant of shear
Red Blood Cell membrane major proteins
SAO is associated with protection against cerebral
malaria in children because it reduces sequestration of
erythrocytes parasitized by P. falciparum in the brain
microvasculature.[50] Adhesion of P. falciparum-infected
red blood cells to CD36 is enhanced by the cerebral
malaria-protective SAO trait . Higher efficiency of se-
questration via CD36 in SAO individuals could deter-
mine a different organ distribution of sequestered in-
fected red blood cells. These provide a possible explana-
tion for the selective advantage conferred by SAO against
cerebral malaria.[51]
3.2.5 Duffy antigen receptor negativity
Main article: Duffy antigen system
3.3 Human leucocyte antigen polymorphisms 7

Plasmodium 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.[52] 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 ho-
mozygous for a DARC allele, carrying a single nucleotide
mutation (DARC 46 T → C), which impairs promoter
activity by disrupting a binding site for the hGATA1 ery-
throid lineage transcription factor.[53] In widely cited in
vitro and in vivo studies, Miller et al. reported that the Old World distribution of enzymopathies and immunogenetic
Duffy blood group is the receptor for P. vivax and that the variants
absence of the Duffy blood group on red cells is the resis-
tance factor to P. vivax in persons of African descent.[7]
This has become a well-known example of innate resis- 3.2.6 Gerbich antigen receptor negativity
tance to an infectious agent because of the absence of a
receptor for the agent on target cells. Main article: Gerbich antigen system
However, observations have accumulated showing that
the original Miller report needs qualification. In hu- The Gerbich antigen system is an integral membrane pro-
man studies of P. vivax transmission, there is evidence tein of the erythrocyte and plays a functionally important
for the transmission of P. vivax among Duffy-negative role in maintaining erythrocyte shape. It also acts as the
populations in Western Kenya,[54] the Brazilian Amazon receptor for the P. falciparum erythrocyte binding pro-
region,[55] and Madagascar.[56] The Malagasy people on tein. There are four alleles of the gene which encodes the
Madagascar have an admixture of Duffy-positive and antigen, Ge-1 to Ge-4. Three types of Ge antigen neg-
Duffy-negative people of diverse ethnic backgrounds. ativity are known: Ge-1,−2,−3, Ge-2,−3 and Ge-2,+3.
72% of the island population were found to be Duffy- persons with the relatively rare phenotype Ge-1,−2,−3,
negative. P. vivax positivity was found in 8.8% of 476 are less susceptible (~60% of the control rate) to invasion
asymptomatic Duffy-negative people, and clinical P. vi- by P. falciparum. Such individuals have a subtype of a
vax malaria was found in 17 such persons. Genotyp- condition called hereditary elliptocytosis, characterized
ing indicated that multiple P. vivax strains were invad- by oval or elliptical shape erythrocytes.
ing the red cells of Duffy-negative people. The au-
thors suggest that among Malagasy populations there are
enough Duffy-positive people to maintain mosquito trans- 3.2.7 Other rare erythrocyte mutations
mission and liver infection. More recently, Duffy neg-
ative individuals infected with two different strains of See also: GYPA, GYPB, and MNS antigen system
P. vivax were found in Angola and Equatorial Guinea;
further, P. vivax infections were found both in humans Rare mutations of glycophorin A and B proteins are also
and mosquitoes, which means that active transmission is known to mediate resistance to P. falciparum.
occurring. The frequency of such transmission is still
unknown.[57] Because of these several reports from dif-
ferent parts of the world it is clear that some variants of 3.3 Human leucocyte antigen polymor-
P. vivax are being transmitted to humans who are not ex- phisms
pressing DARC on their red cells. The same phenomenon
has been observed in New World monkeys. [Note 1] How- Main article: Human leukocyte antigen
ever, DARC still appears to be a major receptor for hu-
man transmission of P. vivax.
Human leucocyte antigen (HLA) polymorphisms com-
The distribution of Duffy negativity in Africa does not mon in West Africans but rare in other racial groups,
correlate precisely with that of P. vivax transmission.[52] are associated with protection from severe malaria. This
Frequencies of Duffy negativity are as high in East Africa group of genes encodes cell-surface antigen-presenting
(above 80%), where the parasite is transmitted, as they proteins and has many other functions. In West Africa,
are in West Africa, where it is not. The potency of P. they account for as great a reduction in disease incidence
vivax as an agent of natural selection is unknown, and may as the sickle-cell hemoglobin variant. The studies suggest
vary from location to location. DARC negativity remains that the unusual polymorphism of major histocompatibil-
a good example of innate resistance to an infection, but ity complex genes has evolved primarily through natural
it produces a relative and not an absolute resistance to P. selection by infectious pathogens.
vivax transmission.
Polymorphisms at the HLA loci, which encode pro-
8 5 SEE ALSO

teins that participate in antigen presentation, influence Consortium in a Gambian population and the other by
the course of malaria. In West Africa an HLA class Rolf Horstmann (Bernhard Nocht Institute for Tropical
I antigen (HLA Bw53) and an HLA class II haplotype Medicine, Hamburg) and his colleagues on a Ghanaian
(DRB1*13OZ-DQB1*0501) are independently associ- population. In both cases the only signal of association
ated with protection against severe malaria.[60] However, reaching genome-wide significance was with the HBB lo-
HLA correlations vary, depending on the genetic consti- cus encoding the β-chain of hemoglobin, which is abnor-
tution of the polymorphic malaria parasite, which differs mal in HbS.[66] This does not imply that HbS is the only
in different geographic locations.[61] gene conferring innate resistance to falciparum malaria;
there could be many such genes exerting more modest ef-
fects that are challenging to detect by GWA because of
4 Validating the malaria hypothe- the low levels of linkage disequilibrium in African popu-
lations. However the same GWA association in two pop-
sis ulations is powerful evidence that the single gene confer-
ring strongest innate resistance to falciparum malaria is
Evolutionary biologist J.B.S. Haldane was the first to give that encoding HbS.
a hypothesis on the relationship between malaria and the
genetic disease. He first delivered his hypothesis at the
Eighth International Congress of Genetics held in 1948 4.1 Fitnesses of different genotypes
at Stockholm on a topic “The Rate of Mutation of Hu-
man Genes”.[62] He formalised in a technical paper pub- The fitnesses of different genotypes in an African re-
lished in 1949 in which he made a prophetic statement: gion where there is intense malarial selection were es-
“The corpuscles of the anaemic heterozygotes are smaller timated by Anthony Allison in 1954.[67] In the Baamba
than normal, and more resistant to hypotonic solutions. population living in the Semliki Forest region in West-
It is at least conceivable that they are also more resistant ern Uganda the sickle-cell heterozygote (AS) frequency
to attacks by the sporozoa which cause malaria.”[63] This is 40%, which means that the frequency of the sickle-
became known as 'Haldane’s malaria hypothesis’, or con- cell gene is 0.255 and 6.5% of children born are SS ho-
cisely, the 'malaria hypothesis’.[64] mozygotes. [Note 2] It is a reasonable assumption that until
modern treatment was available three quarters of the SS
homozygotes failed to reproduce. To balance this loss
of sickle-cell genes, a mutation rate of 1:10.2 per gene
per generation would be necessary. This is about 1000
times greater than mutation rates measured in Drosophila
and other organisms and much higher than recorded for
the sickle-cell locus in Africans.[68] To balance the poly-
morphism, Anthony Allison estimated that the fitness of
the AS heterozygote would have to be 1.26 times than
that of the normal homozygote. Later analyses of sur-
vival figures have given similar results, with some differ-
ences from site to site. In Gambians, it was estimated that
Survival curves of Luo children in an area of Kenya where AS heterozygotes have 90% protection against P. falci-
malaria transmission is intense. HbAS: Heterozygous sickle- parum-associated severe anemia and cerebral malaria,[60]
cell hemoglobin; HbAA: normal hemoglobin; HbSS: homozygous whereas in the Luo population of Kenya it was estimated
sickle-cell hemoglobin. [65] that AS heterozygotes have 60% protection against severe
malarial anemia.[65] These differences reflect the inten-
Detailed study of a cohort of 1022 Kenyan children liv- sity of transmission of P. falciparum malaria from local-
ing near Lake Victoria, published in 2002, confirmed this ity to locality and season to season, so fitness calculations
prediction.[65] Many SS children still died before they at- will also vary. In many African populations the AS fre-
tained one year of age. Between 2 and 16 months the quency is about 20%, and a fitness superiority over those
mortality in AS children was found to be significantly with normal hemoglobin of the order of 10% is sufficient
lower than that in AA children. This well-controlled in- to produce a stable polymorphism.
vestigation shows the ongoing action of natural selection
through disease in a human population.
Analysis of genome wide association (GWA) and fine-
resolution association mapping is a powerful method for
5 See also
establishing the inheritance of resistance to infections and
other diseases. Two independent preliminary analyses • Adaptive immunity
of GWA association with severe falciparum malaria in
Africans have been carried out, one by the Malariagen • Malaria vaccine
 9

6 Notes molecules in living organisms to form simpler ones, to-

gether with the release of energy; destructive metabolism
[1] P. vivax can be transmitted in Squirrel monkeys (Saimiri (contrast anabolic)
boliviensis and S. sciureus), and Barnwell et al.[58] have ob- chemokine - are a family of small cytokines, or signaling
tained evidence that P. vivax enters Saimiri monkey red proteins secreted by cells
cells independently of the Duffy blood group, showing
that P. vivax has an alternative pathway for invading these codon - a sequence of three nucleotides which specify
cells. The Duffy binding protein found on Plasmodia, the which amino acid will be added next during protein syn-
one and only invasion ligand for DARC, does not bind to thesis
Saimiri erythrocytes although these cells express DARC
and obviously become infected with P. vivax.[59] corpuscle - obsolete name for red blood cell
cytoadherance - infected red blood cells may adhere to
[2] If the frequency of the heterozygote is 0.40 the sickle- blood vellel walls and uninfected red blood cells
cell gene frequency (q) can be calculated from the Hardy-
Weinberg equation 2q(1-q) = 0,40, whence q = 0.255 and cytoplasm - clear jelly-like substance, mostly water, in-
q2 , the frequency of sickle-cell homozygotes, is 0.065. side a cell
diathesis - a tendency to suffer from a particular medical
condition
7 Glossary DNA - deoxyribonucleic acid, the hereditary material of
the genome
actin, ankrin, spectrin - proteins that are the major Drosophila - a kind of fruit fly used for genetic experi-
components of the cytoskeleton scaffolding within a cell’s mentation because of ease of reproduction and manipu-
cytoplasm lation of its genome
aerobic - uses oxygen for the production of energy (con- endocytic - the transport of solid matter or liquid into a
trast anaerobic) cell by means of a coated vacuole or vesicle
allele - one of two or more alternative forms of a gene endogamy - the custom of marrying only within the lim-
that arise by mutation its of a local community, clan, or tribe
α-chain / β-chain (hemoglobin) - subcomponents of the endothelial - of or referring to the thin inner surface of
hemoglobin molecule; two α-chains and two β-chains blood vessels
make up normal hemoglobin (HbA)
enzyme - a protein that promotes a cellular process, much
alveolar - pertaining to the alveoli, the tiny air sacs in the like a catalyst in an ordinary chemical reaction
lungs
epidemiology - the study of the spread of disease within
amino acid - any of twenty organic compounds that are a population
subunits of protein in the human body
erythrocyte - red blood cell, which with the leucocytes
anabolic - of or relating to the synthesis of complex make up the cellular content of the blood (contrast leu-
molecules in living organisms from simpler ones together cocyte)
with the storage of energy; constructive metabolism (con-
trast catabolic) erythroid - of or referring to erythrocytes, red blood cells
anaerobic - refers to a process or reaction which does fitness (genetic) - loosely, reproductive success that tends
not require oxygen, but produces energy by other means to propagate a trait or traits (see natural selection)
(contrast aerobic) genome - (abstractly) all the inheritable traits of an or-
anion transporter (organic) - molecules that play an es- ganism; represented by its chromosomes
sential role in the distribution and excretion of numerous genotype - the genetic makeup of a cell, an organism, or
endogenous metabolic products and exogenous organic an individual usually with reference to a specific trait
anions
glycolysis - the breakdown of glucose by enzymes, re-
antigen - any substance (as an immunogen or a hapten) leasing energy
foreign to the body that evokes an immune response either
alone or after forming a complex with a larger molecule glycophorin - transmembrane proteins of red blood cells
(as a protein) and that is capable of binding with a com- haplotype - a set of DNA variations, or polymorphisms,
ponent (as an antibody or T cell) of the immune system that tend to be inherited together.
ATP - (Adenosine TriPhosphate) - an organic molecule Hb (HbC, HbE, HbS, etc.) hemoglobin (hemoglobin
containing high energy phosphate bonds used to transport polymorphisms: hemoglobin type C, hemoglobin type E,
energy within a cell hemoglobin type S)
catabolic - of or relatig to the breakdown of complex
10 7 GLOSSARY

hematopoietic (stem cell) - the blood stem cells that give with their environment (closely related to fitness)
rise to all other blood cells nucleotide - organic molecules that are subunits, of nu-
heme oxygenase-1 (HO-1) - an enzyme that breaks cleic acids like DNA and RNA
down heme, the iron-containing non-protein part of nucleic acid - a complex organic molecule present in liv-
hemoglobin
ing cells, esp. DNA or RNA, which consist of many nu-
hemoglobin - iron based organic molecule in red blood cleotides linked in a long chain.
cells that transports oxygen and gives blood its red color oxygen radical - a highly reactive ion containing oxygen,
hemolysis - the rupturing of red blood cells and the re- capable of damaging microorganisms and normal tissues.
lease of their contents (cytoplasm) into surrounding fluid pathogenesis - the manner of development of a disease
(e.g., blood plasma)
PCR - Polymerase Chain Reaction, an enzymatic reac-
heterozygous - possessing only one copy of a gene for a tion by which DNA is replicated in a test tube for subse-
particular trait
quent testing or analysis
homozygous - possessing two identical copies of a gene phenotype - the composite of an organism’s observable
for a particular trait, one from each parent characteristics or traits, such as its morphology
hypotonic - denotes a solution of lower osmotic pressure Plasmodium - the general type (genus) of the protozoan
than another solution with which it is in contact, so that microorganisms that cause malaria, though only a few of
certain molecules will migrate from the region of higher them do
osmotic pressure to the region of lower osmotic pressure,
until the pressures are equalized polymerize - to combine replicated subunits into a longer
molecule (usually referring to synthetic materials, but also
in vitro - in a test tube or other laboratory vessel; usually organic molecules)
used in regard to a testing protocol
polymorphism - the occurrence of something in several
in vivo - in a live human (or animal); usually used in re- different forms, as for example hemoglobin (HbA, HbC,
gard to a testing protocol etc.)
leucocyte - white blood cell, part of the immune system, polypeptide - a chain of amino acids forming part of a
which together with red blood cells, comprise the cellular protein molecule
component of the blood (contrast erythrocyte)
receptor (cellular surface) - specialized integral mem-
ligand - an extracellular signal molecule, which when it brane proteins that take part in communication between
binds to a cellular receptor, causes a response by the cell the cell and the outside world; receptors are responsive to
locus (gene or chromosome) - the specific location of a specific ligands that attach to them.
gene or DNA sequence or position on a chromosome reducing environment (cellular) - reducing environ-
macrophage - a large white blood cell, part of the im- ment is one where oxidation is prevented by removal of
mune system that ingests foreign particles and infectious oxygen and other oxidising gases or vapours, and which
microorganisms may contain actively reducing gases such as hydrogen,
major histocompatibility complex (MHC) - proteins carbon monoxide and gases that would oxidize in the
presence of oxygen, such as hydrogen sulfide.
found on the surfaces of cells that help the immune sys-
tem recognize foreign substances; also called the human RNA - ribonucleic acid, a nucleic acid present in all living
leucocyte antigen (HLA) system cells. Its principal role is to act as a messenger carrying
micro-RNA - a cellular RNA fragment that prevents the instructions from DNA for controlling the synthesis of
production of a particular protein by binding to and de- proteins
stroying the messenger RNA that would have produced sequestration (biology) - process by which an organism
the protein. accumulates a compound or tissue (as red blood cells)
microvasculature - very small blood vessels from the environment

mitochondria - energy producing organelles of a cell sex-linked - a trait associated with a gene that is carried
only by the male or female parent (contrast with autoso-
mutation - a spontaneous change to a gene, arising from mal)
an error in replication of DNA; usually mutations are
referred to in the context of inherited mutations, i.e. Sporozoa - a large class of strictly parasitic nonmotile
changes to the gametes protozoans, including Plasmodia which cause malaria

natural selection - the gradual process by which biolog- TCA cycle - TriCarboxylic Acid cycle is a series of
ical traits become either more or less common in a popu- enzyme-catalyzed chemical reactions that form a key part
lation as a function of the effect of inherited traits on the of aerobic respiration in cells
differential reproductive success of organisms interacting translocation (cellular biology) - movement of molecules

from outside to inside (or vice versa) of a cell
transmembrane - existing or occurring across a cell
membrane
venous - of or referring to the veins
vesicle - a small organelle within a cell, consisting of fluid [10] Vaidya AB, Mather MW (2009).
enclosed by a fatty membrane
virulence factors - enable an infectious agent to repli-
cate and disseminate within a host in part by subverting
or eluding host defenses.
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9 Further reading

• Dronamraju KR, Arese P (2006) Malaria: Genetic

and Evolutionary Aspects, Springer; Berlin, ISBN 0-
387-28294-7 / ISBN 978-0-387-28294-7

• Faye FBK (2009) Malaria Resistance or Susceptibil-

ity in Red Cells Disorders, Nova Science Publishers
Inc, New York. ISBN 9781606929438
 15

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