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Abstract | Innate immune receptors have a key role in immune surveillance by sensing
microorganisms and initiating protective immune responses. However, the innate immune
system is a classic double-edged sword that can overreact to pathogens, which can have
deleterious effects and lead to clinical manifestations. Recent studies have unveiled the
complexity of innate immune receptors that function as sensors of Plasmodium spp. in the
vertebrate host. This Review highlights the cellular and molecular mechanisms by which
Plasmodium infection is sensed by different families of innate immune receptors. We also discuss
how these events mediate both host resistance to infection and the pathogenesis of malaria.
Apicomplexa
A large group of protozoa that
includes the Plasmodium
genus. They possess an apical
complex structure that is
involved in penetrating host
cells.
Division of Infectious
Diseases and Immunology,
University of Massachusetts
Medical School,
0160502324 Worcester,
Massachusetts, USA.
2
Laboratrio de
Imunopatologia, Centro de
Pesquisa Ren Rachou,
Fundao Oswaldo Cruz,
30190002 Belo Horizonte,
Minas Gerais, Brazil.
3
Departamento de
Bioqumica e Imunologia,
Instituto de Cincias
Biolgicas, Universidade
Federal de Minas Gerais,
31270901 Belo Horizonte,
Minas Gerais, Brazil.
Correspondence to R.T.G.
e-mail: ritoga@cpqrr.fiocruz.br
doi:10.1038/nri3742
Published online
17 October 2014
1
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2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
the more severe forms of the disease. If left untreated,
the uncomplicated symptomatic malaria caused by
P.falciparum can rapidly evolve into severe illness and
lethality. Children with severe malaria may develop anaemia, jaundice, respiratory distress in relation to metabolic
acidosis, and/or cerebral disease. In adults, multi-organ
involvement is also frequent, and impairment of kidney
b Pathogenesis of malaria
Ring
stage
Gametocytes
Schizont
Merozoite
Parasite sequestration
(brain and lungs)
Coagulation and
disruption of vascular
endothelial cells
Activation of vascular
endothelial cells
Placental malaria
Sepsis (spleen)
Uptake of infected or
altered RBCs resulting
in macrophage activation
and cytokine production
Acute respiratory
distress
Destruction
of RBCs
Pro-inammatory
cytokines
Sporozoite infects
hepatocyte
Male
gamete
Leukocyte
inltration into the
tissue parenchyma
Cerebral malaria
Pro-inammatory
cytokines
P. vivax
Zygote
Tissue inammation
Fever
Merozoite
Ookinete
Endothelial dysfunction
Augmented expression of
adhesion molecules and
adherence of infected RBCs
Hypnozoite
Impaired
erythropoiesis
(bone marrow)
Anaemia (bloodstream)
Adhesion and rupture of
infected and altered RBCs
Low levels
of RBCs
Oocyst
Midget
lumen
Female
gamete
REVIEWS
the more severe forms of the disease. If left untreated,
the uncomplicated symptomatic malaria caused by
P.falciparum can rapidly evolve into severe illness and
lethality. Children with severe malaria may develop anaemia, jaundice, respiratory distress in relation to metabolic
acidosis, and/or cerebral disease. In adults, multi-organ
involvement is also frequent, and impairment of kidney
b Pathogenesis of malaria
Ring
stage
Gametocytes
Schizont
Merozoite
Parasite sequestration
(brain and lungs)
Coagulation and
disruption of vascular
endothelial cells
Activation of vascular
endothelial cells
Placental malaria
Sepsis (spleen)
Uptake of infected or
altered RBCs resulting
in macrophage activation
and cytokine production
Acute respiratory
distress
Destruction
of RBCs
Pro-inammatory
cytokines
Sporozoite infects
hepatocyte
Male
gamete
Leukocyte
inltration into the
tissue parenchyma
Cerebral malaria
Pro-inammatory
cytokines
P. vivax
Zygote
Tissue inammation
Fever
Merozoite
Ookinete
Endothelial dysfunction
Augmented expression of
adhesion molecules and
adherence of infected RBCs
Hypnozoite
Impaired
erythropoiesis
(bone marrow)
Anaemia (bloodstream)
Adhesion and rupture of
infected and altered RBCs
Low levels
of RBCs
Oocyst
Midget
lumen
Female
gamete
REVIEWS
Sporozoites
The Plasmodium stage that
develops in the salivary glands
of the mosquito and infects
humans during the blood meal.
When they are in the
bloodstream, the sporozoites
are transported to the liver
where they invade hepatocytes
for the first round of replication
in the vertebrate host.
Merozoites
The pathogenic Plasmodium
stage that infects red blood
cells (RBCs) and rapidly
reproduces asexually, forming
schizonts that contain multiple
parasites. RBCs are destroyed
by the end of this process,
which releases many
merozoites that will infect
other host cells.
Clinical features
Mechanism
Refs
Anaemia
Systemic
inflammation
3,10,11,13,
1719,23,
24,31
Metabolic
acidosis
Hyperventilation
Hypoxia
Headache
Altered mental status
Nausea
Vomiting
Abdominal pain
Muscle weakness
3,10,11,17,
23, 24,31
Cerebral
malaria
Lethargy
Unbalanced movements
Seizures
Impaired consciousness
Coma
Neurological sequelae
3,10,11,17,
25,28,29,31
Placental
malaria
Placental insufficiency
Fetal growth retardation
Low birth weight
Premature delivery
Stillbirth
Miscarriage
Neonatal and maternal morbidity
and mortality
10,25,30,31
1013,18,19
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Schizogeny
The replicative process of
malaria parasites, either in
hepatocytes or red blood cells,
that involves nuclear division
without cytoplasmic
segmentation, followed by a
cell budding to form the
progeny called merozoites.
Pathogen-associated
molecular patterns
(PAMPs). Molecular structures
that are normally abundant in
certain pathogens and are
detected by innate immune
receptors known as pattern
recognition receptors. PAMPs
are often used as vaccine
adjuvants.
Malaria-associated
syndromes
A collection of signs and
symptoms that are
characteristic of a specific
manifestation of malaria,
such as anaemia, respiratory
distress or cerebral malaria.
Paroxysms
In malaria, paroxysms refer to
sudden attacks of disease that
are characterized by high fever,
chills and various other
symptoms. This sudden
worsening of malaria
symptoms is cyclic and
coincides with the synchronous
rupture of Plasmodiuminfected red blood cells.
Glycosylphosphatidylinositol
anchors
(GPI anchors). Glycolipid
structures that link surface
proteins to the surface
membrane of eukaryotic cells.
In protozoa, most surface
proteins are linked via GPIs,
and free GPIs are also
expressed at the surface.
Haemozoin
The crystalline product
resulting from the digestion of
haemoglobin during different
intraerythrocytic Plasmodium
stages.
Toll-like receptors
(TLRs). A family of pattern
recognition receptors that
sense pathogen-associated
molecular patterns and initiate
pro-inflammatory responses
during microbial infection.
REVIEWS
Table 2 | Malaria PAMPs and their role in pathogenesis
Parasite
component
Properties
Receptor activation
Pathways
Role in pathogenesis
Refs
TLR1TLR2 heterodimer
(activated by GPI anchors
containing three fatty
acid chains)
TLR4 homodimer
TLR2TLR6 heterodimer
(activated by GPI anchors
containing two fatty acid
chains)
MYD88NFB
3741
Haemozoin
A detoxification crystal
formed by haem released
from haemoglobin, which is a
main nutrient for the parasite
during the erythrocytic stage
TLR9 (induced by
haemozoin bound to
parasite DNA)
NLRP3, AIM2 and other
cytosolic sensors (owing
to haemozoin-induced
liberation of phagosome
contents including DNA)
Mediates induction of
MYD88NFB
pro-inflammatory cytokine
Assembly of
production by DCs and
NLRP3 and AIM2
macrophages
inflammasomes
Promotes caspase 1 activation
STINGIRF3
and cleavage of proIL1
Mediates induction of typeI
IFN production
4455
TLR9
MYD88NFB
DNA
Immunostimulatory The P. falciparum genome
CpG motifs
contains ~300CpG motifs
The P.vivax genome
contains ~2,500CpG motifs
45,62,63
ATrich motif
Undefined
STINGIRF3
64
Unknown motif
AIM2
Assembly of AIM2
inflammasomes
53
Unknown motif
TLR7
MYD88NFB
Undefined
Unknown motif
MDA5MAVS
TypeI IFN
RNA
66,68
66,67,69
AIM2, absent in melanoma 2; CpG, a cytosine and a guanine separated by one phosphate; DC, dendritic cell; GIPL, glycoinositol phospholipids; GPI, glycosylphosphatidylinositol; IFN, interferon; IL, interleukin; IRF3, IFN-regulatory factor 3; MAVS, mitochondrial antiviral signalling protein; MDA5, melanoma differentiationassociated protein 5; MYD88, myeloid differentiation primary response protein 88; NFB, nuclear factorB; NLRP3, NOD-, LRR- and pyrin domain-containing 3;
P.falciparum, Plasmodium falciparum; P. vivax, Plasmodium vivax; STING, stimulator of IFN genes protein; TLR, Toll-like receptor; TNF, tumour necrosis factor.
Cytosolic sensors
Inflammasomes
Molecular platforms formed
by members of the NOD-like
receptors family, which activate
caspase 1 to cleave proIL1
and proIL18 and release the
active form of these cytokines.
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Urate
crystals
Sporozoite
Microvesicles
Infected RBC
Haemozoin
dsDNA
Hepatocyte
Haem
GPI
TLR1
Macrophage
or DC
TLR9
Merozoite
MYD88
IRAK4
RNA
MYD88
TLR4
TLR2
MAL
MAL
TRAM
MYD88
MYD88
TRIF
IRAK1
IRAK1
TBK1
TRAF6
TRAF6
IKK
TRAF6
TLR7
?
IB
RNA
p65 p50
Phagolysosome
dsDNA
MDA5
NF-B
AT-rich DNA
TRAF3
IKK IRAK1
GTP cGAS
ATP
MAVS
NLRP3
Mitochondrion
NLRP12
AIM2
ASC
23 cGAMP
Pro-caspase 1
Pro-caspase 1
TBK1
IRF7 IRF7
STING
ER
Active caspase 1
IRF3 IRF7
Type I
IFNs
Cytosol
Nucleus
IL-1
IL-18
Pro IL-1
Pro IL-18
Type I
IFNs
TBK1
Pro-inammatory
cytokines
IRF3 IRF3
Type I
IFNs
IRF3 IRF3
Nucleus
REVIEWS
a TLR-independent manner in both human and mouse
phagocytes64,66 (FIG.2; TABLE2). A potentially novel cytosolic DNA sensor seems to detect Plasmodium DNA
as TLR9, DNA-dependent activator of IFN-regulatory
factors (DAI; also known as ZBP1), RNA polymeraseIII, IFNinducible protein 16 (IFI16), retinoic acidinducible gene I (RIGI) and mitochondrial antiviral
signalling protein (MAVS) could not recognize the
P.falciparum ATrich hairpin motifs64. Nevertheless, it
was shown that the unidentified receptor for plasmodial
ATrich DNA signals through stimulator of IFN genes
protein (STING; also known as TMEM173), serine/
threonine-protein kinase TBK1 and IFN-regulatory
factor 3 (IRF3), which leads to typeI IFN production.
The role of cyclic GMPAMP synthase (cGAS) in this
pathway remains to be determined.
Plasmodial RNA. Recent studies indicate that
RNA derived from either mouse parasites (such as
Plasmodiumberghei and Plasmodiumyoelii) or human
parasites (such as P.falciparum) activate PRRs6668 (FIG.2;
TABLE2). A pronounced signature of IFN-inducible genes
is observed in hepatocytes soon after mice are infected
with sporozoites67,69. The invasion of hepatocytes by
sporozoites activates a typeI IFN response via melanoma differentiation-associated protein 5 (MDA5; also
known as IFIH1) through MAVS and the transcription
factors IRF3 and IRF7 (REF.67). In addition, the erythro
cytic stage of P.yoelii induces the production of typeI
IFN invivo, which is dependent on RNA polymerase III,
MDA5 and MAVS, but not RIGI66. In addition, the RNA
sensor TLR7 has a role in the initial activation of innate
immunity in a mouse model of malaria68. In all of these
studies, the cytosolic sensors and the typeI IFN response
had a modest but significant role in controlling parasite
growth and parasitaemia66,67,69.
Malaria DAMPs
DAMPs are endogenous components released from
stressed, damaged or dying cells that activate PRRs
and inflammasomes, regardless of whether the cells are
infected70. Uric acid, microvesicles and haem have been recognized as important malaria DAMPs7173 (FIG.2; TABLE3).
In addition to the association with severe disease, malaria
DAMPs possess intrinsic pro-inflammatory activity,
which is in part mediated by the activation of PRRs7173.
Microvesicles
Vesicles derived from platelets,
red blood cells, endothelial
cells and leukocytes that serve
as a communication system
between host cells, and display
important pro-inflammatory
activity.
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Table 3 | Malaria DAMPs
Host
component
Properties
Receptors
Pathways
Role in pathogenesis
Refs
Uric acid
NLRP3
Assembly
of NLRP3
inflammasomes
Caspase 1
activation and
cleavage of
pro-IL1
72,77,78
Microvesicles
TLR4
MYD88NFB
71,7982
Haem
TLR4
MYD88NFB
TLR4-independent
induction of
oxidative stress
Catalyses the
formation of
reactive oxygen
species
8387
TLR4-independent
induction of haem
oxygenase 1
Degrades toxic
haem
8387
73
DAMP, damage-associated molecular pattern; IL, interleukin; MYD88, myeloid differentiation primary response protein 88; NF-B, nuclear factorB;
NLRP3, NOD-, LRR- and pyrin domain-containing 3; RBC, red blood cell; TLR4, Toll-like receptor 4.
antibodies3,10,88. When infected, hyper-immune individuals will develop low parasitaemia and asymptomatic
infection. The merozoite-specific antibodies are thought
to mediate host resistance to infection by blocking parasite invasion of RBCs, or by opsonizing infected RBCs
and promoting phagocytosis and parasite elimination
by macrophages88,89. In addition, studies carried out in
mice and humans indicate that both sporozoite-specific
neutralizing antibodies and cytotoxic CD8+ Tcells are
important components of immune-mediated resistance
to the hepatocytic stage of the Plasmodium life cycle88,89.
However, it is not clear whether sporozoite-specific
immune responses contribute to natural acquired immunity or whether they are only relevant to vaccine-induced
protection88. Different studies have disclosed mechanisms
by which innate immunity influences the development of
acquired immunity, but the role of innate immune receptors in this process is still elusive89. The studies discussed
above have unveiled the complexity of innate immune
receptors that function as sensors of malaria parasites and
we are beginning to understand how they mediate host
resistance to Plasmodium infection. In this section, we
discuss the known mechanisms of host defence that are
triggered by the activation ofPRRs.
Innate immunity. Sporozoites stimulate the expression of typeI IFN-inducible genes in hepatocytes during Plasmodium replication inside a parasitophorous
vacuole67,69 (FIG.3). TypeI IFN-induced proteins mediate the recruitment of natural killer (NK) cells and
NKTcells, which are important sources of IFN, and
trigger the expression proteins that mediate control of
parasite replication, such as those that are involved in the
REVIEWS
Immunologically silent (asymptomatic)
Leukocyte adhesion
and inltration
MDA5 Chemokines
Adhesion
MAVS
molecules
iNOS
Merozoite
Infected
RBC
Type I
IFNs
DNA
Dysfunction of
endothelial wall
IFN
TH1 cell
Haemozoin
Type I IFNs
STING
DNA and
RNA sensors
Phagolysosome
Chemokines and
adhesion molecules
B cell
IL-1
TNF
Bacteria
Antibodies
CD8+
CD4
T cell
IL-12
TLR1
TLR4
MAL TRAM
MAL
MYD88 MYD88 TRIF
Phagolysosome
MYD88
TLR2
MHC
class II
TLR9
TLR7
TNF
receptor
MHC
class I
Fever
Blood vessel
NK cell
NKT cell
T cell
RNA
c Disease
MYD88
IB
p65 p50
TLR9
Pro-caspase 1
88
TLR7
IB
p65 p50
NF-B
Inammasome
assembly
YD
88
RNA
b Acquired immunity
Hepatocyte
YD
a Innate immunity
Pro-IL-1
Active
caspase 1
Macrophage or DC
Innate sensing
IFN priming
TLR hyperresponsiveness
Nature
Reviews
| Immunology
Figure 3 | Pattern recognition receptors and the pathophysiology of malaria. a | Plasmodium
RNA
translocates
from
the parasitophorous vacuole to the hepatocyte cytosol and activates melanoma differentiation-associated protein 5 (MDA5),
which induces the production of typeI interferons (IFNs). Macrophages and dendritic cells (DCs) phagocytose either free
haemozoin or infected red blood cells (RBCs). In the phagolysosomes, nucleic acids are released from destroyed parasites
orhaemozoin and activate Toll-like receptors (TLRs). The release of the nuclear factorB (NFB) subunits p50 and p65
induces the expression of interleukin12 (IL12) that promotes production of IFN by CD4+ Tcells, CD8+ Tcells and natural
killer (NK) cells. Haemozoin also destabilizes the membrane of phagolysosomes, which leads to the release of crystals and
parasite DNA into host cell cytoplasm, and the activation of inflammasomes and DNA sensors. b|TypeI IFN-inducible
proteins promote the recruitment of leukocytes (such as NKTcells) and control parasite replication in the liver. TypeI IFNs
also interfere with DC function. IFN has multiple effects in phagocytic cells, including the induction of IL12 production
that favours the differentiation of T helper 1 (TH1) lymphocytes. The IFN-inducible IgG isotypes opsonize infected RBCs
that are internalized and destroyed by activated macrophages. c | IFN priming makes macrophages prone to produce
extreme levels of cytokines upon a secondary microbial challenge. Circulating cytokines lead to fever and promote parasite
sequestration by inducing the expression of adhesion molecules on endothelial cells. The sequestration of infected RBCs
results in an alteration in blood flow, rupture of the vascular wall, extravasation of vascular content and leukocyte migration
into the parenchyma, leading to organ-specific syndromes such as cerebral malaria, respiratory distress and placental
malaria. IB, inhibitor of NFB; iNOS, inducible nitric oxide synthase; MAVS, mitochondrial antiviral signalling protein;
MYD88, myeloid differentiation primary response protein 88; STING, stimulator of IFN genes protein; TRAM, TRIF-related
adaptor molecule; TRIF, TIR domain-containing adaptor protein inducing IFN; TNF, tumour necrosis factor.
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Plasmodium strains subvert the function of DCs, and
thereby impair the production of IL12 and the development of T cell-mediated immunity 104,110. Consistent
with this, the function of human DCs is impaired when
they are exposed to infected RBCs or haemozoin111,112.
Furthermore, patients with symptomatic P.falciparum
or P.vivax malaria have decreased levels of circulating
DCs113. Hence, modulation of DC function is an important mechanism of parasite escape from host immune
responses.
Adjuvant
An agent that is mixed with an
antigen to increase the immune
response to that antigen
following immunization.
Reticulocyte
Immature red blood cells
(RBCs) that correspond to
1% of total circulating RBCs
in humans.
REVIEWS
Plasmodium infection also lowers the threshold
for bacteria-induced septic-shock. Malaria loads the
gun and bacteria pull the trigger is an expression that
reflects the mechanism by which Plasmodium infection enhances sensitivity to microbial infection. By promoting TLR hyperresponsiveness and the assembly of
inflammasomes, IFN priming lowers the threshold for
septic shock in mice by more than 100fold15,16. Although
IFN-deficient mice infected with P.chabaudi are highly
resistant to LPS challenge, the role of TLR9 and IL12 in
pro-inflammatory priming is partial, which suggests that
other PRRs and IFN-inducing cytokines also contribute
to this response15,16.
In addition, MYD88deficient mice infected with
P.chabaudi are more resistant to systemic manifestations, such as cytokinaemia, changes in body weight,
temperature and liver damage14,137. Similarly, in the
P.berghei model of placental malaria, mice lacking functional MYD88 had reduced levels of IL6 and TNF, and
unaltered fetal body weight, contrasting with the lower
body weight of fetuses from infected wild-type mice138.
Furthermore, inflammatory infiltrates and cytokinaemia are reduced and pathology of experimental cerebral
malaria is attenuated in MYD88deficient mice103,139.
Although the role of TLR2 and TLR4 in Plasmodium
infection is controversial14,66,102,106,139,140, the data indicating a role for TLR9 in experimental cerebral malaria
are more consistent. Therapy with the TLR antagonist
E6446, which binds both DNA and RNA within lyso
somes, is highly effective at protecting mice against
experimental cerebral malaria 127. Since protection
against experimental cerebral malaria is only partial
in TLR9deficient mice, it is possible that the E6446 is
also blocking the activation of TLR7, and other cytosolic
DNA and RNA sensors53,64,68.
Hence, PRRs promote the development of cerebral
malaria and sepsis-like syndrome by stimulating the
production of extreme levels of the same cytokines that
are involved in host resistance to Plasmodium infection. For instance, the development of experimental
cerebral malaria is attenuated in mice deficient for
functional genes encoding IFN-inducible adhesion
molecules, such as CXC-chemokine ligand 9 (CXCL9)
and CXCL10, which are important for the recruitment
of CD8+ Tcells to the central nervous system141,142.
Furthermore, treatment with TNF-specific monoclonal
antibodies prevents the development of cerebral malaria
in mice143. However, in small clinical trials, treatment
with TNF-specific antibodies or the anti-inflammatory
drug pentoxifylline was not shown to be effective in
preventing human disease caused by P. falciparum144,145,
and the role of cytokines and inflammation in cerebral
malaria is still a matter of debate28,29.
Inflammasomes and IL1. Despite strong invitro
evidence that haemozoin triggers the formation of
NLRP3 inflammasomes, different studies show that
the lack of functional NLRP3, ASC, caspase 1, IL18
or IL1 receptor has only a minor impact (or no
impact) on the control of parasitaemia and the development of mouse cerebral malaria16,46,140. Thus, the
role of inflammasomes, IL1 and IL18 in host resistance to Plasmodium infection is questionable16,46,140.
Nevertheless, in both humans and mice, Plasmodium
infection results in expression of an inflammasome
gene signature, the formation of NLRP3, NLRP12
and AIM2 inflammasomes, and caspase 1 activation16.
In addition, NLRP3, ASC and caspase 1 were shown
to have an important role in mediating haemozoininduced local inflammation, and may be involved in
organ damage observed during malaria. During mouse
malaria, inflammasomes and IL1 are also key players in enhanced sensitivity to bacteria-induced septic
shock16. As a result, hypersensitivity to bacterial superinfection is prevented by treating mice with an IL1R
antagonist 16. Furthermore, as IL1 is highly pyrogenic,
inflammasomes are probably important mediators of
malaria paroxysms in humans10,11,65.
Cytosolic sensors and typeI IFNs. The importance of
nucleic acid sensors and typeI IFN release is now being
appreciated in the context of various infectious diseases,
beyond their traditional roles in antiviral immunity. In
a mouse model of cerebral malaria using the ANKA
strain of P.berghei mice deficient for the typeI IFN
receptor, IRF3 or IRF7 exhibited less severe symptoms
and delayed mortality compared with infected wild-type
mice64,66,108,146,147. TypeI IFNs dampen the development
of TH1 cell responses that control of parasitaemia at a
very early stage of infection and thereby cause a worsening the disease67,69,84,109. However, in another study, it
was shown that therapy with IFN protects mice from
cerebral malaria, suggesting that the involvement typeI
IFNs in this process is more complex 148.
Genetics and human disease. Various studies have
associated single nucleotide polymorphisms (SNPs) in
inflammatory genes with resistance or susceptibility
to P.vivax or P.falciparum malaria. Although most of
these studies are inconclusive because they used a small
cohort of patients, protection against severe disease has
been associated with SNPs in the genes encoding TNF149,
IFNAR1 (a subunit of the typeI IFN receptor)146,150, IL12
(REF.151), IFN152,153, IL1154, CD40 ligand (CD40L; also
known as TNFRSF5)155 and inducible nitric oxide synthase (also known as NOS2)156. Several SNPs identified
in the genes encoding TLRs, such as TLR4 (REF.157) and
TLR9 (REF.158), were associated with low birth weight
and maternal anaemia. SNPs in TLR9 are also associated
with increased levels of IFN in children with cerebral
malaria159 and increased parasitaemia in patients with
P.vivax malaria160. Furthermore, hemizygosity for a
SNP in the gene encoding the TLR2 and TLR4 MYD88
adaptor-like protein (MAL; also known as TIRAP) may
protect against death due to malaria161.
Concluding remarks
More than 150years after the discovery of Plasmodium
by Laveran in 1861, malaria remains a devastating disease that accounts for ~1 million deaths every
year. Although there are tools with which to eliminate the disease, the eradication of malaria will be
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extraordinarily expensive in the absence of an effective
vaccine. Years of research on malaria pathogenesis have
culminated in the consensus that the clinical manifestations are mostly owing to a deleterious activation of
innate immune cells. It is now clear that Plasmodium
infection activates innate immune cells through signalling pathways downstream of PRRs, but further investigation is required to develop a better understanding
of the biological role of specific receptors in malaria.
We highlight studies indicating the crucial role of
haemozoin in the activation of TLRs, inflammasomes
REVIEWS
53. Kalantari,P. etal. Dual engagement of the NLRP3
and AIM2 inflammasomes by Plasmodium-derived
hemozoin and DNA during malaria. Cell Rep.
6, 196210 (2014).
This study describes the trafficking of haemozoin
in phagocytic cells and the relevance of this process
for activating endosomal and cytosolic innate
immune receptors.
54. Coban,C. etal. Immunogenicity of whole-parasite
vaccines against Plasmodium falciparum involves
malarial hemozoin and host TLR9. Cell Host Microbe
7, 5061 (2010).
This study proposes the use of haemozoin as a
vaccine adjuvant.
55. Torgbor,C. etal. A multifactorial role for P.falciparum
malaria in endemic Burkitts lymphoma pathogenesis.
PLoS Pathog. 10, e1004170 (2014).
56. Reimer,T. etal. Experimental cerebral malaria
progresses independently of the Nlrp3 inflammasome.
Eur. J.Immunol. 40, 764769 (2010).
57. Rock,K.L., Latz,E., Ontiveros,F. & Kono,H.
The sterile inflammatory response. Annu. Rev.
Immunol. 28, 321342 (2010).
58. Griffith,J.W., Sun,T., McIntosh,M.T. & Bucala,R.
Pure hemozoin is inflammatory invivo and activates
the NALP3 inflammasome via release of uric acid.
J.Immunol. 183, 52085220 (2009).
59. Caetano,B.C. etal. Requirement of UNC93B1 reveals
a critical role for TLR7 in host resistance to primary
infection with Trypanosoma cruzi. J.Immunol. 187,
19031911 (2011).
60. Schamber-Reis,B.L. etal. UNC93B1 and nucleic acidsensing Toll-like receptors mediate host resistance to
infection with Leishmania major. J.Biol. Chem. 288,
71277136 (2013).
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Acknowledgements