Pathogenesis of malaria - UpToDate 12/18/19, 11:36 PM

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Pathogenesis of malaria
Author: Danny A Milner, Jr, MD, MSc(Epi)
Section Editor: Johanna Daily, MD, MSc
Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Nov 2019. | This topic last updated: Apr 26, 2019.

INTRODUCTION

Understanding the pathogenesis of malaria requires investigation of mechanisms including

parasite invasion, parasite biology, and host defense. Detailed descriptions of the
understanding of the underlying molecular biology are provided in the literature [1-3]. The
parasite life cycle illustrates the interplay of parasite and host interactions (figure 1).
Pathogenesis of Plasmodium falciparum is the area of greatest study, since this species causes
the most severe clinical disease (other species include P. ovale, P. vivax, P. malariae, and P.
knowlesi). P. knowlesi malaria can also cause life-threatening illness [4], and, although rare,
severe illness (including severe respiratory disease and anemia) and death due to P. vivax have
been reported.

Issues related to the pathogenesis of malaria will be reviewed here. Issues related to
epidemiology, clinical manifestations, diagnosis, and treatment are discussed in detail
separately. (See related topics.)

THE PARASITE

Life cycle — Human malaria occurs by transmission of Plasmodium sporozoites via a bite from
an infected female anopheline mosquito (figure 1). The sporozoites travel from the salivary
glands of the mosquito through the bloodstream of the host to the liver, where they invade

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hepatocytes. These cells divide many 1000-fold until mature tissue schizonts are formed, each
containing thousands of daughter merozoites. This exoerythrocytic stage is asymptomatic.

The liver schizonts rupture after 6 to 30 days; 98 percent of patients experience liver
schizogony by 90 days (there is typically a longer liver phase in species other than P.
falciparum). This event releases thousands of merozoites into the bloodstream, where they
invade red blood cells (the erythrocytic or asexual stage) in a matter of seconds. P. falciparum
may invade any red cell, while P. vivax and P. ovale prefer the younger, slightly larger
reticulocytes. The merozoites mature successively from ring forms to trophozoites to mature
schizonts (asexual forms) over 24 hours (P. knowlesi), 48 hours (P. vivax, P. ovale, P.
falciparum), or 72 hours (P. malariae). Within red blood cells, the parasites digest hemoglobin.
As hemoglobin is digested, the toxic metabolite hemozoin (a polarizable crystal) is formed and
isolated in the parasite's food vacuole.

The intracellular parasites modify the erythrocyte in several ways. They derive energy from
anaerobic glycolysis of glucose to lactic acid, which may contribute to clinical manifestations of
hypoglycemia and lactic acidosis [5]. Parasites reduce red cell membrane deformability,
resulting in hemolysis and accelerated splenic clearance, which may contribute to anemia.
Alterations to uninfected red blood cells, such as the addition of P. falciparum
glycosylphosphatidylinositol (GPI) to the membrane, may play a role in increased clearance of
uninfected cells and contribute to anemia [6]. (See "Anemia in malaria".)

Ultimately, new daughter merozoites are released from the schizont stage of infected
erythrocytes. The remnants of cell membrane and the hemozoin crystal are phagocytized by
circulating macrophages, an important stimulus in the activation of the immune cascade [7,8]. In
addition, free heme is released into the peripheral blood, an important stimulus for endothelial
activation; endothelial cell damage also occurs in some patients [7-9].

Red cell lysis stimulates release of proinflammatory cytokines, including tumor necrosis factor
(TNF). TNF suppresses hematopoiesis, which also contributes to the anemia. The liver and
spleen enlarge over time; the spleen may become massively enlarged [10]. Thrombocytopenia
is caused by a combination of hypersplenism (ie, increased splenic sequestration and
decreased platelet survival time) and, in the case of P. falciparum, deposition of platelets
adjacent to parasite microvascular sequestration and fibrin thrombi [11-14]. (See 'Coagulation'
below.)

Merozoites continue the asexual cycle and infect new red cells, although a few differentiate into

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male or female gametocytes (sexual forms), which cause no symptoms. These gametocyte-
committed parasites leave the bloodstream and develop in the bone marrow over three to four
days [15]. Mature male and female gametocytes then circulate in the bloodstream until they are
ingested by a blood-feeding female anopheline mosquito. These sexual forms complete their
life cycle within the midgut of the Anopheles mosquito (including an ookinete and oocyst stage)
with development into sporozoites, which migrate to the salivary glands of the mosquito; from
there, they can infect another human through another bite.

In the setting of P. vivax and P. ovale infection, some parasites remain dormant in the liver as
hypnozoites and can cause late relapse by reactivating after many months [16]. In the setting of
P. falciparum and P. malariae infection, hypnozoite parasites do not develop in the liver.
However, P. malariae can cause attacks even decades after exposure; the mechanism of
persistence is unknown. In addition, the chronic infection of P. malariae may result in immune
complex formation and deposition leading to renal damage and failure.

Genetic diversity — Surveys of the P. falciparum genome from different geographic regions
have demonstrated remarkable genetic diversity, particularly in surface antigens. The parasite
genome is much more diverse than the human genome; single nucleotide polymorphisms,
insertions/deletions, and microsatellites are very common in particular genes (genes that are
under immune selection, for example) [17-19].

Using these polymorphisms as markers in genome-wide association studies allows

identification of the source of clinical and experimental phenotypes of the parasites, improving
understanding of pathogenesis and potential for development of new therapies. Genetic
diversity can also be used as a tool to measure effective population size and the effects of
interventions on a given population.

Variation in gene copy number among genes known to be involved in metabolic pathways may
influence drug susceptibility [20]. Comprehensive genetic mapping will enable further
identification of genes mediating drug resistance as well as potential vaccine targets.

PATHOPHYSIOLOGY

Microvascular disease and sequestration — All species of Plasmodium in human infections

are likely cytoadherent to human cell surfaces at some point during the life cycle but, for all
species but P. falciparum, this period of sequestration is very short: For P. falciparum, it is more

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than half of the 48-hour life cycle. Cytoadherence to human cell surfaces is an important
component of P. falciparum pathogenesis. As P. falciparum parasites mature from rings to
trophozoites within red blood cells, they induce the formation of sticky knobs on the surface of
erythrocytes [21,22]. The knobs are composed of a combination of parasite-produced proteins
including P. falciparum erythrocyte membrane protein-1 (PfEMP-1, the product of var gene
expression and proposed primary cytoadherence factor), KAHRP, PfEMP-2, and RESA as well
as human proteins including spectrin, actin, and band 4.1 [23-25]. Each P. falciparum parasite
has ≥60 different var genes; of these, one protein product is present in individual parasites [26].

The knobs bind to receptors on a variety of cell types in capillaries and venules, including
endothelial cells. Notable human receptors include ICAM-1 and ePCR (vascular endothelium),
CD36 (on endothelium and platelets), and CSA (in the placenta); a variety of other binding
interactions have also been elucidated [27-30]. Endothelial binding leads to sequestration of
infected red cells within these small vessels (thereby removing parasites from the peripheral
circulation during a prolonged period of the life cycle). This leads to partial blood flow
obstruction, endothelial barrier breakdown, and inflammation [21].

Sequestration can be demonstrated in any organ of a patient infected with P. falciparum. The
most catastrophic clinical manifestation of sequestration results in cerebral malaria [31]. Renal
failure in the setting of malaria may occur in part as a result of mechanical obstruction by
infected erythrocytes; immune-mediated glomerular pathology and fluid loss due to alterations
in the renal microcirculation also probably contribute to renal failure [32]. Clearance of infected
red cells by macrophages in the spleen through antibody-mediated mechanisms is a crucial
control point for preventing severe disease, which is damaged in HIV-infected children [33-35].

Rosetting can occur when infected red cells stick to uninfected red cells and form rosettes that
block the microcirculation and contribute to microvascular disease [36,37]. Rosetting is
mediated by an interaction between PfEMP-1 within knobs and receptors on the surface of
uninfected red cells, such as complement-receptor 1 (CR1) [36,37].

Parasite biomass — Vascular beds harboring sequestered parasites allow accumulation of

high levels of parasite biomass in the host. HRP-2 (a secreted P. falciparum antigen expressed
on the erythrocyte membrane) can be used as an indirect measure of parasite biomass both in
the circulation and sequestered in the microvasculature. The concentration of this antigen has
been observed to correlate with severity of clinical disease [38].

Cytokines — The interaction between host endothelium and immune cells with malaria

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parasites is complex and not fully understood. The "cytokine storm" hypothesis suggests that, in
the setting of severe malaria, damaging cytokines and small molecules become unregulated
and lead to a systemic inflammatory response syndrome (SIRS)-like state with high circulating
levels of tumor necrosis factor (TNF) and nitric oxide. However, evidence of direct correlation
between severe malaria and the activity of these markers is limited.

Some markers, such as the acute phase reactant C-reactive protein (CRP), correlate directly
with parasitemia. Cytokines TNF, lymphotoxin, interleukin (IL)-6, IL-10, IL-12, IL-18, and
macrophage inflammatory protein (MIP)-1 are consistently elevated in the setting of malaria.
However, it is not clear whether these precede or follow clinical markers of severe infection.

Molecular evidence for endothelial and tissue damage includes elevated levels of lactate, CK-
MB, myoglobin, and angiopoietin-2 as well as increased soluble ligands/receptors (eg, sELAM-
1, sICAM-1, sTNF-R1, sTNF-R2, sVCAM-1) [39]. Microparticles (small circulating bodies
released from the surface of human cells) are another interesting component of pathogenesis;
more data are needed to understand their exact role.

Coagulation — The initiation of tissue factor production in the coagulation cascade has been
proposed as a unifying mechanism of pathogenesis in severe malaria, based on the following
observations [11,40-42]:

● Thrombocytopenia is a common feature of severe malaria; it may also be observed in

uncomplicated malaria [11,40].

● Activation of the coagulation cascade in the absence of overt bleeding (eg, elevated D-
dimer and thrombin-antithrombin complexes with normal prothrombin time and
thromboplastin time) is also common [41].

● Autopsies of patients with cerebral malaria frequently demonstrate fibrin microthrombi

admixed with platelets in the cerebral vasculature (as well as other organs) [42].

Nitric oxide — Low nitric oxide, low arginine (the precursor of nitric oxide), and elevated
arginase activity in peripheral blood have been observed in severe malaria [43]. Metabolic
studies have demonstrated that the parasite's arginase enzyme (which converts arginine to
ornithine) may contribute to hypoargininemia in severely ill patients, thus shutting down nitric
oxide production [44]. Children with nitric oxide depletion due to intravascular hemolysis in the
setting of malaria subsequently develop pulmonary hypertension and myocardial wall stress

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[43]. Replenishment of nitric oxide via peripheral arginine has been suggested as a possible
treatment [45,46].

THE HOST

Genetic factors — Several genetic polymorphisms and mutations appear to influence the
severity of malaria infection; examples are summarized in the table (table 1) and studies have
elucidated addition polymorphisms [47,48].

Hemoglobin and red cell antigens — Hemoglobin and red cell antigens can confer
variable protection against malaria. (See "Protection against malaria in the
hemoglobinopathies".)

● A classic example is the Duffy blood group factor, a red cell antigen necessary for invasion
by P. vivax [49]. Absence of the Duffy antigen on red cells (largely observed in individuals
from West and sub-Saharan Africa) is protective for P. vivax malaria [49]. However, cases
of P. vivax in Duffy-negative individuals have been identified in Brazil and in Kenya,
suggesting that P. vivax has evolved alternate red blood cell invasion pathways to invade
Duffy-negative red cells [50,51].

● There is strong evidence that sickle cell genetic alterations evolved in part because of the
survival advantage against lethal P. falciparum infections [52-54]. Children with HbAS have
a significantly lower risk of P. falciparum malaria, lower parasite densities, and lower rates
of hospital admissions than children with HbAA [55]. Possible mechanisms are discussed
in detail separately. (See "Protection against malaria in the hemoglobinopathies".)

The potential protective effect of sickle hemoglobin against malaria may be augmented in
malaria-endemic areas; individuals outside endemic areas may have a lesser degree of
protection. In a family living in the United States in which two children had sickle cell
anemia and three had sickle cell trait, travel to an endemic region without
chemoprophylaxis led to hemolytic crisis in three of the children [56]. Thalassemia may
indirectly protect against P. falciparum infection by mediating increased susceptibility to
nonlethal P. vivax, particularly in young children [57,58].

● Red blood cells in individuals with thalassemia appear to be susceptible to P. falciparum

invasion but are associated with significantly reduced parasite multiplication [59,60]. This

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may be due to the variable degree of persistence of hemoglobin F, which is relatively

resistant to hemoglobin digestion by malarial hemoglobinases [58,61,62]. (See
"Pathophysiology of beta thalassemia".)

● Ovalocytosis in Southeast Asia appears to confer protection against malarial infection.

Possible mechanisms include diminished invasion, poor intraerythrocytic growth, or
diminished cytoadherence of infected erythrocytes [63,64].

● Hereditary elliptocytosis appears to confer protection against malaria, although malaria

infection in the setting of this condition has been described [65]. (See "Protection against
malaria by abnormalities in red cell surface antigens and cytoskeletal proteins", section on
'Hereditary elliptocytosis'.)

● The haptoglobin (Hp) genotype determines the efficiency of hemoglobin clearance after
malaria-induced hemolysis. A particular polymorphism of the haptoglobin genotype (Hp2/2)
has been associated with a reduction in the number of clinical malarial episodes; this was
illustrated in a study of 312 children in Kenya [66].

● Pyruvate kinase deficiency appears to be protective against infection and replication of P.

falciparum in human erythrocytes. Therefore, mutant pyruvate kinase alleles may confer
protection against malaria in endemic areas [67].

Tumor necrosis factor — Polymorphisms in tumor necrosis factor (TNF) genes appear to
influence the severity of P. falciparum infection [68,69]. This was illustrated in a study of
approximately 1000 Gambian children; a sevenfold increased risk of severe neurological
sequelae or death from cerebral malaria was observed among those who were homozygous for
a polymorphism in the promoter region of the TNF gene (TNF2 allele). Severe anemia was
associated with a different TNF allele, suggesting that different genetic factors affect
susceptibility to these two disease manifestations [68].

Immunity — Individuals living in endemic areas appear to develop partial immunity to clinical
episodes of malaria following repeated infections; the degree of protective immunity appears to
be proportional to transmission intensity and increases with age. Individuals in highly endemic
areas (eg, sub-Saharan Africa) acquire nearly complete protection from clinical disease by early
adulthood [70-72]. Individuals in low transmission areas (eg, Southeast Asia) remain at risk for
clinical disease and fatal disease into adulthood; these individuals are referred to as "semi-
immune."

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Individuals not living in endemic areas (eg, travelers) infected with malaria form a detectable
antibody response (which can be measured by enzyme-linked immunosorbent assay [ELISA]),
although this response is not protective against the initial infection of malaria and may serve
only as a marker of past exposure [72].

Immunity in pregnancy is also important. The risk of parasitemia during the first years of life is
higher among children born to multigravid women than primigravid women [73,74]. The
immunologic basis for this observation is not fully understood.

Humoral response — The humoral immune response to malaria appears to correlate with
severity of clinical infection, with progression in maturation of the humoral response in the
setting of ongoing parasite antigen stimulation. Elevated levels of immunoglobulin (Ig)G4, IgE,
and IgM are associated with severe disease in individuals with ≤5 previous clinical episodes of
malaria, while elevated levels of IgG (IgG, IgG1, IgG2, and IgG3) are associated with mild
disease in individuals with >5 previous clinical episodes [75,76].

These observations suggest that persistence of humoral immunity requires ongoing parasite
antigen stimulation. In addition, individuals who leave endemic areas appear to lose some
humoral protection; these individuals are "semi-immune," and their protection is lessened when
they return to endemic areas after prolonged periods without parasite antigen stimulation. (See
"Prevention of malaria infection in travelers".)

Cellular response — The ability to mount a robust interferon-gamma response

(predominantly through CD56+ gamma T cells) has been associated with protection against
high parasitemia [77]. Phagocytosis of hemozoin or trophozoites impairs the ability of
monocytes and macrophages to mount oxidative burst, kill ingested bacteria, present antigens
correctly, and mature to functioning dendritic cells [7]. These cells produce TNF and other
proinflammatory cytokines and release peroxidation derivatives of polyunsaturated fatty acids
[7]. In addition, these cells have increase in activity and release of MMP-9, which is correlated
with TNF- and interleukin (IL)-1 gamma production and leads to disruption of the basal lamina
of endothelial cells [7,8].

SUMMARY

● Understanding the pathogenesis of malaria requires investigation of mechanisms including

parasite invasion, parasite biology, and host defense. The parasite life cycle illustrates the

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interplay of parasite and host interactions (figure 1). (See 'Introduction' above.)

● The Plasmodium life cycle consists of an exoerythrocytic (asymptomatic) stage and

erythrocytic (symptomatic) stage. Plasmodium sporozoites are transmitted by the bite of an
infected female anopheline mosquito. The sporozoites invade hepatocytes, which divide
until schizonts are formed containing thousands of daughter merozoites. These rupture and
release merozoites into the bloodstream, where they invade red blood cells. (See 'Life
cycle' above.)

● Intracellular parasites alter the red cell, digesting hemoglobin to form hemozoin and making
the membrane less deformable, resulting in hemolysis or splenic clearance. The
merozoites invade the red cell and mature to ring forms, trophozoites, and schizonts.
Schizonts rupture and release new daughter merozoites. This release can result in
proinflammatory cytokines response including tumor necrosis factor. Most released
merozoites infect new red cells; a few differentiate into gametocytes, which circulate until
they are ingested by a mosquito to continue the transmission cycle. (See 'Life cycle' above
and 'Cytokines' above.)

● Endothelial binding of infected red cells leads to sequestration of infected red cells within
small vessels (thereby removing parasites from the peripheral circulation during a
prolonged period of the life cycle). This can lead to partial blood flow obstruction,
endothelial barrier breakdown, and inflammation. Mechanisms of microvascular disease
include formation of sticky knobs on the cell surface and rosetting (eg, adherence of
infected red cells to uninfected cells, forming rosettes that clog the microcirculation). (See
'Microvascular disease and sequestration' above.)

● Several human genetic polymorphisms and mutations have been observed to influence the
severity of malaria infection, particularly hemoglobin and red cell antigens. (See 'Genetic
factors' above and "Protection against malaria in the hemoglobinopathies" and "Anemia in
malaria".)

● Individuals living in endemic areas develop partial immunity to malaria following repeated
infections; they develop protection from severe disease and can be asymptomatic despite
infection. The degree of protective immunity appears to be proportional to transmission
intensity. The cellular immune response consists of a variety of cytokines including
interferon-gamma and tumor necrosis factor. (See 'Immunity' above.)

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Topic 5703 Version 16.0

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GRAPHICS

Plasmodium life cycle

(1) Plasmodium-infected Anopheles mosquito bites a human and transmits sporozoites into
the bloodstream. (2) Sporozoites migrate through the blood to the liver where they invade
hepatocytes and divide to form multinucleated schizonts (preerythrocytic stage). (3)
Hypnozoites are a quiescent stage in the liver that exist only in the setting of P. vivax and P.
ovale infection. This liver stage does not cause clinical symptoms, but with reactivation and
release into the circulation, late-onset or relapsed disease can occur up to many months
after initial infection. (4) The schizonts rupture and release merozoites into the circulation
where they invade red blood cells. Within red cells, merozoites mature from ring forms to
trophozoites to multinucleated schizonts (erythrocytic stage). (5) Some merozoites
differentiate into male or female gametocytes. These cells are ingested by the Anopheles
mosquito and mature in the midgut, where sporozoites develop and migrate to the salivary
glands of the mosquito. The mosquito completes the cycle of transmission by biting another
host.

Graphic 58397 Version 5.0

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Gene polymorphism effects

Gene/polymorphism Effect/association Theoretical mechanism Ref.

LTA + 80 Parasitemia reduction Lymphotoxin production [1]

GNAS Severe malaria Red cell signaling; invasion inhibition [2]

iNOS Severe malaria Decreased iNOS [3]

Pyruvate kinase Infection Unknown [4]

ABO glycosyltransferase Severe malaria anemia Decreased resetting of red blood cells [5]

Toll-like receptors (TLR-1, -6, Malaria and high Innate immunity [6]
and -9) parasitemia

FLT1 Placental malaria Unknown [7]

TIM1 Cerebral malaria Induction of Th2 antiinflammatory [8]

responses

IL-10 Severe malaria anemia Antiinflammatory activity of enhanced IL- [9]

10 production

CR-1 (promoter) Cerebral malaria Increased clearance of infected cells [10,11]

LTA: lymphotoxin-alpha; iNOS: inducible nitric oxide synthase; IL: interleukin; CR: complement receptor.

1. Barbier M, et al. Family-based association of a low producing lymphotoxin-alpha allele with reduced Plasmodium
falciparum parasitemia. Microbes Infect 2008; 10:673.
2. Auburn S, et al. Association of the GNAS locus with severe malaria. Human Genetics 2008; 124:499.
3. Dhangadamajhi G, et al. The CCTTT pentanucleotide microsatellite in iNOS promoter influences the clinical
outcome in P. falciparum infection. Parasitology Research.
4. Durand PM, Coetzer TM. Pyruvate kinase deficiency protects against malaria in humans. Haematologica 2008;
93:939.
5. Fry AE, et al. Common variation in the ABO glycosyltransferase is associated with susceptibility to severe
Plasmodium falciparum malaria. Hum Mol Genet 2008; 17:567.
6. Leoratti FM, et al. Variants in the toll-like receptor signaling pathway and clinical outcomes of malaria. J Infect
Dis 2008; 198:772.
7. Muehlenbachs A, et al. Natural selection of FLT1 alleles and their association with malaria resistance in utero.
Proc Natl Acad Sci U S A 2008; 105:14488.
8. Nuchnoi P, et al. Significant Association Between TIM1 Promoter Polymorphisms and Protection Against Cerebral
malaria in Thailand. Annals of Human Genetics 2008; 72:327.
9. Ouma C, et al. Haplotypes of IL-10 promoter variants are associated with susceptibility to severe malarial
anemia and functional changes in IL-10 production. Hum Genet 2008; 124:515.
10. Cockburn IA, et al. A human complement receptor 1 polymorphism that reduces Plasmodium falciparum
rosetting confers protection against severe malaria. Proc Natl Acad Sci U S A 2004; 101:272.
11. Teeranaipong P, et al. A functional single-nucleotide polymorphism in the CR1 promoter region contributes to
protection against cerebral malaria. J Infect Dis 2008; 198:1880.

Graphic 55135 Version 2.0

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Contributor Disclosures
Danny A Milner, Jr, MD, MSc(Epi) Employment: American Society for Clinical Pathology [Laboratory
testing (Medical education resources)]. Johanna Daily, MD, MSc Nothing to disclose Elinor L Baron, MD,
DTMH Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
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