Human Genetic Resistance To Malaria
Human Genetic Resistance To Malaria
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]
3.2.2 PK deficiency
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
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
11
from outside to inside (or vice versa) of a cell Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beut-
ler B (1998). “Defective LPS signaling in C3H/HeJ and
transmembrane - existing or occurring across a cell C57BL/10ScCr mice: mutations in Tlr4 gene”. Science.
membrane 282 (5396): 2085–2088. Bibcode:1998Sci...282.2085P.
venous - of or referring to the veins doi:10.1126/science.282.5396.2085. PMID 9851930.
vesicle - a small organelle within a cell, consisting of fluid [10] Vaidya AB, Mather MW (2009). “Mitochon-
enclosed by a fatty membrane drial evolution and functions in malaria par-
asites”. Annu Rev Microbiol. 63: 249–267.
virulence factors - enable an infectious agent to repli- doi:10.1146/annurev.micro.091208.073424. PMID
cate and disseminate within a host in part by subverting 19575561.
or eluding host defenses.
[11] Elliott DA, McIntosh MT, Hosgood HD 3rd,
Chen S, Zhang G, Baevova P, Joiner KA (2008).
“Four distinct pathways of hemoglobin uptake
8 References in the malaria parasite Plasmodium falciparum”
(PDF). Proc. Natl. Acad. Sci. U.S.A. 105 (7):
[1] Kwiatkowski DP (2005). “How Malaria Has Affected the 2463–2468. Bibcode:2008PNAS..105.2463E.
Human Genome and What Human Genetics Can Teach doi:10.1073/pnas.0711067105. PMC 2268159 .
Us about Malaria”. American Journal of Human Genetics. PMID 18263733.
77 (2): 171–192. doi:10.1086/432519. PMC 1224522 .
PMID 16001361. [12] Kuross SA, Rank BH, Hebbel RP (1988). “Excess heme
in sickle erythrocyte inside-out membranes: possible role
[2] Hedrick PW (2011). “Population genetics of malaria in thiol oxidation” (PDF). Blood. 71 (4): 876–882. PMID
resistance in humans”. Heredity. 107 (4): 1–22. 3355895.
doi:10.1038/hdy.2011.16. PMC 3182497 . PMID [13] Föller M, Bobbala D, Koka S, Huber SM, Gulbins E,
21427751. Lang F (2009). “Suicide for survival--death of infected
erythrocytes as a host mechanism to survive malaria”
[3] Anstee DJ (2010). “The relationship between blood
(PDF). Cell Physiol Biochem. 24 (3–4): 133–140.
groups and disease”. Blood. 115 (23): 4635–4643.
doi:10.1159/000233238. PMID 19710527.
doi:10.1182/blood-2010-01-261859. PMID 20308598.
[14] Cholera R, Brittain NJ, Gillrie MR, Lopera-Mesa TM,
[4] Anstey NM, Handojo T, Pain MC, Kenangalem E, Tji-
Diakité SA, Arie T, Krause MA, Guindo A, Tubman A,
tra E, Price RN, Maguire GP (2007). “Lung In-
Fujioka H, Diallo DA, Doumbo OK, Ho M, Wellems
jury in Vivax Malaria: Pathophysiological Evidence
TE, Fairhurst RM (2008). “Impaired cytoadherence of
for Pulmonary Vascular Sequestration and Posttreatment
Plasmodium falciparum-infected erythrocytes containing
Alveolar-Capillary Inflammation”. J Infect Dis. 195 (4):
sickle hemoglobin” (PDF). Proc. Natl. Acad. Sci. U.S.A.
589–596. doi:10.1086/510756. PMC 2532499 . PMID 105 (3): 991–996. Bibcode:2008PNAS..105..991C.
17230420.
doi:10.1073/pnas.0711401105. PMC 2242681 . PMID
[5] Santos-Ciminera PD, Roberts DR, Alecrim MG, Costa 18192399.
MR, Quinnan GV Jr (2007). “Malaria Diagnosis and Hos-
[15] Ferreira A, Marguti I, Bechmann I, Jeney V, Chora A,
pitalization Trends, Brazil” (PDF). Emerg Infect Dis. 13
Palha NR, Rebelo S, Henri A, Beuzard Y, Soares MP
(10): 1597–1600. doi:10.3201/eid1310.070052. PMC
(2011). “Sickle hemoglobin confers tolerance to Plas-
2851511 . PMID 18258018. modium infection” (PDF). Cell. 145 (3): 398–409.
doi:10.1016/j.cell.2011.03.049. PMID 21529713.
[6] Allison AC (1954). “Protection Afforded by Sickle-cell
Trait Against Subtertian Malarial Infection” (PDF). Br [16] Gong L, Parikh S, Rosenthal PJ, Greenhouse B (2013).
Med J. 1 (4857): 290–294. doi:10.1136/bmj.1.4857.290. “Biochemical and immunological mechanisms by which
PMC 2093356 . PMID 13115700. sickle cell trait protects against malaria” (PDF). Malaria
Journal. 12 (1): 317. doi:10.1186/1475-2875-12-317.
[7] Miller LH, Mason SJ, Clyde DF, McGinniss MH (1976). PMID 24025776.
“The resistance factor to Plasmodium vivax in blacks.
The Duffy-blood-group genotype, FyFy”. N Engl J Med. [17] “CHU Hôpitaux de Rouen. Fréquence et origine des cas
295 (6): 302–4. doi:10.1056/NEJM197608052950602. de paludisme”. .chu-rouen.fr. Retrieved 2010-08-24.
PMID 778616.
[18] Pauling L, Itano H, Singer SJ, Wells I (1949). “Sickle
[8] Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoff- cell anemia, a molecular disease” (PDF). Science.
mann JA (1996). “The dorsoventral regulatory gene cas- 110 (2865): 543–548. Bibcode:1949Sci...110..543P.
sette spätzle/Toll/cactus controls the potent antifungal re- doi:10.1126/science.110.2865.543. PMID 15395398.
sponse in Drosophila adults”. Cell. 86 (6): 973–983.
doi:10.1016/S0092-8674(00)80172-5. PMID 8808632. [19] Ingram VM (1959). “Abnormal human haemoglobins.
III. The chemical difference between normal and sickle
[9] Poltorak A, He X, Smirnova I, Liu MY, Van Huffel cell haemoglobins”. Biochim Biophys Acta. 36: 543–548.
C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, doi:10.1016/0006-3002(59)90183-0. PMID 13852872.
12 8 REFERENCES
[20] Ingram VM (2004). “Sickle-Cell Anemia J Infect Dis. 179 (1): 283–286. doi:10.1086/314561.
Hemoglobin: The Molecular Biology of the JSTOR 30117260. PMID 9841856.
First “Molecular Disease”—The Crucial Impor-
tance of Serendipity” (PDF). Genetics. 167: 1–7. [31] Modiano D, Luoni G, Sirima BS, Simporé J, Verra F,
Konaté A, Rastrelli E, Olivieri A, Calissano C, Pagan-
doi:10.1534/genetics.167.1.1. PMC 1470873 . PMID
otti GM, D'Urbano L, Sanou I, Sawadogo A, Modi-
15166132.
ano G, Coluzzi M (2001). “Haemoglobin C protects
[21] Cholera R, Brittain NJ, Gillrie MR, Lopera-Mesa TM, against clinical Plasmodium falciparum malaria”. Nature.
Diakité SA, Arie T, Krause MA, Guindo A, Tub- 414 (6861): 305–308. Bibcode:2001Natur.414..305M.
man A, Fujioka H, Diallo DA, Doumbo OK, Ho M, doi:10.1038/35104556. PMID 11713529.
Wellems TE, Fairhurst RM (2008). “Impaired cytoad- [32] Modiano D, Bancone G, Ciminelli BM, Pompei F,
herence of Plasmodium falciparum-infected erythrocytes Blot I, Simporé J, Modiano G (2008). “Haemoglobin
containing sickle hemoglobin”. Proc Natl Acad Sci S and haemoglobin C: 'quick but costly' versus 'slow
USA. 105: 991–996. Bibcode:2008PNAS..105..991C. but gratis’ genetic adaptations to Plasmodium falci-
doi:10.1073/pnas.0711401105. PMC 2242681 . PMID parum malaria”. Hum Mol Genet. 17 (6): 789–799.
18192399. doi:10.1093/hmg/ddm350. PMID 18048408.
[22] Williams T N, Mwangi T W, Roberts D J, Alexander N D, [33] Rihet P, Flori L, Tall F, Traore AS, Fumoux F
Weatherall D J, Wambua S, Kortok M, Snow R W, Marsh (2004). “Hemoglobin C is associated with reduced
K (2005). “An Immune Basis for Malaria Protection by Plasmodium falciparum parasitemia and low risk of
the Sickle Cell Trait” (PDF). PLoS Medicine. 2: e128. mild attack” (PDF). Hum Mol Genet. 13 (1): 1–6.
doi:10.1371/journal.pmed.0020128. PMC 1140945 . doi:10.1093/hmg/ddh002. PMID 14613965.
PMID 15916466.
[34] Fairhurst RM, Baruch DI, Brittain NJ, Ostera
[23] Hebbel RP (2003). “Sickle hemoglobin instability: a GR, Wallach JS, Hoang HL, Hayton K, Guindo
mechanism for malarial protection”. Redox Rep. 8 (5): A, Makobongo MO, Schwartz OM, Tounkara
238–240. doi:10.1179/135100003225002826. PMID A, Doumbo OK, Diallo DA, Fujioka H, Ho
14962356. M, Wellems TE (2005). “Abnormal display of
PfEMP-1 on erythrocytes carrying haemoglobin C
[24] Kaul DK (2008). “Sickle red cell adhesion: Many issues
may protect against malaria” (PDF). Nature. 435
and some answers”. Transfus Clin Biol. 15 (1-2): 51–55.
(7045): 1117–1121. Bibcode:2005Natur.435.1117F.
doi:10.1016/j.tracli.2008.03.012. PMID 18495516.
doi:10.1038/nature03631. PMID 15973412.
[25] Brain P (1952). “Sickle-cell Anaemia in Africa”. Br
[35] Chotivanich K, Udomsangpetch R, Pattanapanyasat K,
Med J. 2: 880. doi:10.1136/bmj.2.4789.880. PMC
Chierakul W, Simpson J, Looareesuwan S, White N (Au-
2021738 . gust 2002). “Hemoglobin E: a balanced polymorphism
protective against high parasitemias and thus severe P.
[26] Ingram VM, Stretton AO (1959). “Genetic basis of the
falciparum malaria”. Blood. 100 (4): 1172–6. PMID
thalassaemia diseases”. Nature. 184 (4703): 1903–1909.
12149194.
Bibcode:1959Natur.184.1903I. doi:10.1038/1841903a0.
PMID 13852871. [36] Allison AC. (2009). “Genetic control of resistance to
human malaria”. Current Opinion in Immunology. 21
[27] Modiano G, Morpurgo G, Terrenato L, Novelletto A,
(5): 499–505. doi:10.1016/j.coi.2009.04.001. PMID
Di Rienzo A, Colombo B, Purpura M, Mariani M,
19442502.
Santachiara-Benerecetti S, Brega A, Dixit KA, Shrestha
SL, Lania A, Wanachiwanawin W, Luzzatto L (1991). [37] Piel FB, Patil AP, Howes RE, Nyangiri OA, Geth-
“Protection Against Malaria Morbidity: Near Fixation of ing PW, Williams TN, Weatherall DJ, Hay SI (2010).
the α-Thalassemia gene in a Nepalese Population” (PDF). “Global distribution of the sickle cell gene and geograph-
Am. J. Hum. Genet. 48 (2): 390–397. PMC 1683029 . ical confirmation of the malaria hypothesis” (PDF). Nat
PMID 1990845. Commun. 1 (8): 104. Bibcode:2010NatCo...1E.104P.
doi:10.1038/ncomms1104. PMC 3060623 . PMID
[28] Terrenato L, Shrestha S, Dixit KA, Luzzatto L, Modiano 21045822.
G, Morpurgo G, Arese P (1988). “Decreased malaria
morbidity in the Tharu people compared to sympatric [38] Flatz G (1967). “Hemoglobin E: distribution and pop-
populations in Nepal”. Ann Trop Med Parasitol. 82 (1): ulation dynamics”. Humangenetik. 3 (3): 189–234.
1–11. PMID 3041928. doi:10.1007/BF00273124. PMID 6074385.
[29] May J, Evans JA, Timmann C, Ehmen C, Busch [39] Allison AC (1955). “Aspects of polymorphism in man”.
W, Thye T, Agbenyega T, Horstmann RD (2007). Cold Spring Harb Symp Quant Biol. 20: 239–251. PMID
“Hemoglobin variants and disease manifestations in se- 13433567.
vere falciparum malaria”. JAMA. 297 (20): 2220–2226.
doi:10.1001/jama.297.20.2220. PMID 17519411. [40] Alving AS, Carson PE, Flanagan CL, Ickes CE
(1956). “Enzymatic deficiency in primaquine-
[30] Hutagalung R, Wilairatana P, Looareesuwan S, Britten- sensitive erythrocytes”. Science. 124 (3220):
ham GM, Aikawa M, Gordeuk VR (1999). “Influence of 484–485. Bibcode:1956Sci...124..484C.
hemoglobin E trait on the severity of Falciparum malaria”. doi:10.1126/science.124.3220.484-a. PMID 13360274.
13
[50] Allen SJ, O'Donnell A, Alexander ND, Mgone CS, [58] Barnwell JW, Nichols ME, Rubinstein P (1989). “In vitro
Peto TE, Clegg JB, Alpers MP, Weatherall DJ (1999). evaluation of the role of the Duffy blood group in ery-
“Prevention of cerebral malaria in children in Papua New throcyte invasion by Plasmodium vivax”. J Exp Med.
Guinea by southeast Asian ovalocytosis band 3”. Am J 169 (5): 1795–802. doi:10.1084/jem.169.5.1795. PMC
Trop Med Hyg. 60 (6): 1056–1060. PMID 10403343. 2189319 . PMID 2469769.
[51] Cortés A, Mellombo M, Mgone CS, Beck HP, Reeder [59] Wertheimer SP, Barnwell JW (1989). "Plasmodium vi-
JC, Cooke BM (2005). “Adhesion of Plasmodium vax interaction with the human Duffy blood group gly-
falciparum-infected red blood cells to CD36 under flow is coprotein: identification of a parasite receptor-like pro-
enhanced by the cerebral malaria-protective trait South- tein”. Exp Parasitol. 69 (4): 340–350. doi:10.1016/0014-
East Asian ovalocytosis”. Mol Biochem Parasitol. 142 4894(89)90083-0. PMID 2680568.
14 10 EXTERNAL LINKS
[60] Hill AV, Allsopp CE, Kwiatkowski D, Anstey NM, Twu- 10 External links
masi P, Rowe PA, Bennett S, Brewster D, McMichael
AJ, Greenwood BM (1991). “Common west African • Favism
HLA antigens are associated with protection from se-
vere malaria”. Nature. 352 (6336): 595–600. • Hemoglobinopathies
Bibcode:1991Natur.352..595H. doi:10.1038/352595a0.
PMID 1865923. • Malaria and the Red Cell
[66] Jallow M, Teo YY, Small KS, Rockett KA, et al. (2009).
“Genome-wide and fine-resolution association analysis of
malaria in West Africa”. Nat Genet. 41 (6): 657–665.
doi:10.1038/ng.388. PMC 2889040 . PMID 19465909.
9 Further reading
11.2 Images
• File:Ambox_important.svg Source: https://upload.wikimedia.org/wikipedia/commons/b/b4/Ambox_important.svg License: Public do-
main Contributors: Own work, based off of Image:Ambox scales.svg Original artist: Dsmurat (talk · contribs)
• File:Edit-clear.svg Source: https://upload.wikimedia.org/wikipedia/en/f/f2/Edit-clear.svg License: Public domain Contributors: The
Tango! Desktop Project. Original artist:
The people from the Tango! project. And according to the meta-data in the file, specifically: “Andreas Nilsson, and Jakub Steiner (although
minimally).”
• File:Jaundice.jpg Source: https://upload.wikimedia.org/wikipedia/commons/0/00/Jaundice.jpg License: CC BY 3.0 Contributors: Own
work Original artist: Sab3el3eish
• File:Lock-green.svg Source: https://upload.wikimedia.org/wikipedia/commons/6/65/Lock-green.svg License: CC0 Contributors: en:File:
Free-to-read_lock_75.svg Original artist: User:Trappist the monk
• File:Paludisme_-_Frequence_statistique.png Source: https://upload.wikimedia.org/wikipedia/commons/0/08/Paludisme_-_
Frequence_statistique.png License: CC-BY-SA-3.0 Contributors: CHU de Rouen - Frequence du paludisme Original artist: Percherie
• File:RBC_Membrane_Proteins_SDS-PAGE_gel.jpg Source: https://upload.wikimedia.org/wikipedia/commons/8/8c/RBC_
Membrane_Proteins_SDS-PAGE_gel.jpg License: Public domain Contributors: Ernst Hempelmann Original artist: Ernst Hempelmann
• File:RBC_membrane_major_proteins.png Source: https://upload.wikimedia.org/wikipedia/commons/8/8b/RBC_membrane_major_
proteins.png License: Public domain Contributors: Derivative work of RBC_membrane_major_proteins.jpg Original artist:
RBC_membrane_major_proteins.jpg: Author is Ernst Hempelmann
• File:Red_Blood_Cell_abnormalities.png Source: https://upload.wikimedia.org/wikipedia/commons/2/26/Red_Blood_Cell_
abnormalities.png License: Public domain Contributors: Original work of Armando Moreno Vranich Original artist: Armando
Moreno Vranich
• File:Red_Blood_Cell_abnormalities_2.png Source: https://upload.wikimedia.org/wikipedia/commons/9/97/Red_Blood_Cell_
abnormalities_2.png License: Public domain Contributors: Original work of Armando Moreno Vranich Original artist: Armando Moreno
Vranich
• File:SICKLEMARLIA.svg Source: https://upload.wikimedia.org/wikipedia/commons/f/ff/SICKLEMARLIA.svg License: CC BY-SA
4.0 Contributors: Own work Original artist: AlexBatchelder
• File:Survival_Curves_for_Hemoglobin_Genotypes.png Source: https://upload.wikimedia.org/wikipedia/commons/8/8c/Survival_
Curves_for_Hemoglobin_Genotypes.png License: Public domain Contributors: Michael Aidoo Original artist: Michael Aidoo
• File:Wiki_letter_w.svg Source: https://upload.wikimedia.org/wikipedia/en/6/6c/Wiki_letter_w.svg License: Cc-by-sa-3.0 Contributors:
? Original artist: ?