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Department of Immunology,
University of Texas
Southwestern Medical Center,
5323 Harry Hines Boulevard,
Dallas, Texas 75390-9093,
USA.
email: Felix.Yarovinsky@
UTSouthwestern.edu
doi:10.1038/nri3598
Toxoplasma gondii is a protozoan apicomplexan parasite that can infect all mammals and birds, normally
through contaminated food (BOX1). The parasite has
received considerable scientific and medical attention
as it causes severe disease in immunocompromised
individuals, such as patients with AIDS. In otherwise
healthy adults, this intracellular parasite is controlled
by the immune system and remains in a dormant state
in the brain, although in rare instances it can cause
uveitis. However, in patients with AIDS, the development of an immunocompromised state leads to
the reactivation of the T.gondii parasites and to the
development of toxoplasmosis. Uncontrolled parasite
replication ensues, which causes life-threatening brain
damage that is characterized by brain abscesses and
necroticareas.
These clinical observations, coupled with the
knowledge that HIV infection results in CD4+ Tcell
depletion, have led to the development of a model in
which Tcell activation is thought to determine the
outcome of T.gondii infection. As such, the scientific
community has mainly focused on exploring CD4+
and CD8+ Tcell responses to this parasite13. In recent
years, progress has also been made in identifying the
T.gondii virulence factors that regulate host immune
responses 4. However, an appreciation of the role of
the host innate immune system in controlling the
parasite is lagging behind. This Review aims to fill
this gap in knowledge by covering the major innate
immune mechanisms that are essential to promote
interferon (IFN)-mediated host protection against
T.gondii.
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Box 1 | Major routes of human infection with T.gondii
There are three major ways of acquiring Toxoplasmagondii infection (see the figure): first, foodborne transmission;
second, animal to human (zoonotic) transmission; and third, mother to child (congenital) transmission. Food-borne
infection is most commonly caused by the ingestion of undercooked meat that contains encysted bradyzoites. However,
both humans and livestock can become infected by accidental ingestion of soil that contains T.gondii oocysts as a result of
poorly washed fruit and vegetables or by drinking water that is contaminated with oocysts. T.gondii oocytes are shed
from the faeces of infected cats into the environment or a litter box. Contaminated litter boxes are of special concern for
pregnant women, as a first-time infection during pregnancy can result in the transmission of the parasite to the fetus
a condition that is known as congenital toxoplasmosis. Although the exposure of adults to the parasite rarely results in
severe disease, congenital toxoplasmosis can lead to severe neurological and ocular diseases in children. Rare forms of
transmission that are not depicted here include parasite transmission during organ transplantation and blood transfusion.
It has been estimated that at least one-third of the worlds human population has been exposed to the parasite, but the
relative importance of the different routes of infection is unknown.
T.gondii is an obligate intracellular parasite. Following exposure to the parasite, infection is divided into acute and chronic
stages. The acute stage of infection is characterized by the replication of tachyzoites, which are the fast-replicating forms of
the parasite. As the infection progresses, tachyzoites differentiate into bradyzoites, which are the slow-replicating forms
of the parasite. Bradyzoites in the form of cysts (encysted bradyzoites) are responsible for establishing the chronic
stages of the infection. In a mouse model of infection, intraperitoneally injected bradyzoites rapidly differentiate into
tachyzoites, disseminate into peripheral tissue and establish a persistent infection within 2 weeks of infection.
Although ingestion of the parasite is a major physiological route of T.gondii infection, experimental injection of cysts
into the peritoneal cavity results in identical infection stages but bypasses the mucosal response to the parasite.
Humans
Domestic animals
Encysted bradyzoites
(food- and water-borne)
Oocysts
Congenital
toxoplasmosis
induced by
tachyzoites
Fetus
Mice
Oocysts
(in faeces)
Encysted
bradyzoites
Cats
Sexual reproduction
in the feline denitive host
Oocysts
Ovoid structures that contain
two sporocysts, each of which
contains four sporozoites. The
sporozoites may then become
tachyzoites or bradyzoites.
Cats shed faecal
Toxoplasmagondii oocysts in
the soil, grass and water. The
oocyst wall is an extremely
resistant multilayer structure
that protects the parasite from
mechanical and chemical
damage, which enables the
parasite to survive for long
periods of time.
Oocysts
Nature Reviews | Immunology
that is passively released from parasites. T.gondii profilin is an essential protein for the parasite7: conditional
deletion of profilin in T.gondii revealed that this protein
regulates parasite motility and host cell invasion7. As
T.gondii is an obligatory intracellular pathogen, failure
to invade host cells because of profilin deficiency results
in the loss of parasite viability. Thus, TLR11mediated
sensing of T.gondii profilin fits the general idea that
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Prolin
TLR12
TLR11
UNC93B1
UNC93B1
Endolysosome
TLR12
UNC93B1
UNC93B1
DNA
RNA
TLR7
TLR1
UNC93B1
UNC93B1
TLR9
MYD88
UNC93B1
UNC93B1
TLR2
GPI
IRF8
TLR4
IL-12
NF-B
p50 p65
IL-12
and IFN
Dendritic cell
Figure 1 | TLRs involved in the recognition of T. gondii. Toll-like receptor 11 (TLR11) and TLR12 are the major
Reviews | Immunology
receptors for the Toxoplasmagondii-derived protein profilin. Although many cells expressNature
TLR11 and
TLR12,
IFN-regulatory factor 8 (IRF8)+ dendritic cells (DCs), in particular CD8+ DCs, have a crucial role in detecting T.gondii
profilin and in the subsequent induction of IL12 production downstream of myeloid differention primary-response
protein 88 (MYD88). A novel MYD88dependent signalling pathway that depends on activation of IRF8 is an
explanation for the potent induction of IL12 expression by CD8+ DCs that have been exposed to T.gondii, but the
direct connection between MYD88 and IRF8 has not been established. In addition, both TLR7 and TLR9 have been
implicated in detecting T.gondii RNA and genomic DNA, respectively. UNC93 homologue B1 (UNC93B1), an
endoplasmic reticulumresident protein, has a central role in the function of all of the depicted endosomal TLRs
and is essential for resistance to T.gondii. In addition to endosomal TLRs, TLR2 and TLR4 are involved in detecting
T.gondii glycosylphosphatidylinositol (GPI) during infection. IFN, interferon-; NF-B, nuclear factor-B.
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Box 2 | Species-specific differences in TLR11, TLR12 and TLR13
The Toll-like receptor 11 (TLR11) family includes three closely related TLRs, TLR11,
TLR12 and TLR13, all of which localize within endosomal compartments. Although all
of the TLR11 family members are expressed in mice, human TLR11 is a nonfunctional
pseudogene and humans completely lack TLR12 and TLR13. An important point relating
to the sequences of TLR11 and TLR12 is that the National Center for Biotechnology
Information (NCBI) database contains a DNA sequence for TLR11 that is actually the
sequence for TLR12 and vice versa.
Parasitophorous vacuole
A vacuole surrounded by a
parasitophorous vacuolar
membrane (PVM), which forms
as a result of the invasion of
Toxoplasma gondii into the
host cell. The PVM is formed
during active invasion of the
host cell and depends on actin
polymerization in T.gondii, but
not in the host. The physical
force created by the parasite
initiates the formation of a
membrane, which surrounds
the intracellular parasite within
the parasitophorous vacuole
and which differs from
endosomal or phagolysosomal
membranes.
both TLR11 and T.gondii profilin6,16,18. In an alternative model it was suggested that both TLR11TLR12
heterodimers and TLR12 homodimers are sufficient for
DC responsiveness to T.gondii profilin19. Finally, in a
third model it was suggested that, although the TLR11
TLR12 heterodimer promotes the activation of MYD88
in response to T.gondii, TLR7 and TLR9 can induce sufficient MYD88 activation to compensate for a lack of
TLR11mediated parasite recognition20. It is of interest to
note that, although TLR11 is a pseudogene in the human
genome, TLR12 is not present in the human genome.
Thus, although the endosomal TLR11dependent and
TLR12dependent recognition system is central for host
defence in mice, it is not applicable to human innate
immune defence against T.gondii.
The models from the Gazzinelli20 and Yarovinsky6,18
laboratories are in agreement that the TLR11TLR12
heterodimer complex is a central sensory unit for the recognition of T.gondii profilin by mouse DCs. Biochemical
experiments using the highly purified extracellular
domains of TLR11 and TLR12 have shown that there is a
direct receptorligand interaction between T.gondii profilin and TLR11 or TLR12, and that the formation of profilinTLR11 and profilinTLR12 complexes occurs18. An
alternative model jointly suggested by the Ghosh and Sher
laboratories suggests that TLR12 alone is sufficient for the
initiation of immune signalling cascades in the absence
of TLR11 (REF.19). However, this model is in contrast to
experiments showing that DCs from TLR11deficient
mice fail to produce IL12 and other cytokines, including IFN, in response to T.gondii extracts or to highly
purified T.gondii profilin6,7,16,21. Furthermore, TLR11 but
not TLR12 recruits MYD88 to initiate MYD88dependent
signalling events downstream of profilin recognition18.
How the TLR12 signalling receptor complex alone
contributes to cytokine production in the absence
of MYD88 recruitment has not been explained.
Roles for other endosomal TLRs: TLR7 and TLR9.
In addition to TLR11 and TLR12, several other TLRs
have been implicated in the recognition of T.gondii. It
has been suggested that the combined action of two
additional endosomal receptors, TLR7 and TLR9, can
induce protective MYD88 activation in the absence of
TLR11 (REF.20) (FIG.1). The involvement of these endosomal TLRs in mediating host defence to T.gondii is consistent with the observed role for UNC93 homologue
B1 (UNC93B1), a chaperone-like protein that regulates
the trafficking of endosomal TLRs, in the regulation of
IL12dependent host resistance to the parasite16. An
alternative TLR-independent function of UNC93B1
in cell-autonomous parasite killing has also been suggested on the basis of the colocalization of UNC93B1
and the parasitophorous vacuole22, but this mechanism
was recently dismissed by the original authors20.
TLR7 is a receptor for single-stranded RNAs that
are produced by RNA viruses23,24. In addition, TLR7
can detect bacterial RNA in the endolysosomes of conventional DCs25. Uridine and ribose, which are the two
defining features of RNA, are both necessary and sufficient for TLR7 stimulation, and short single-stranded
RNAs function as TLR7 agonists in a sequence-independent manner as long as they contain several uridines in close proximity 26. Thus, it is not surprising that
T.gondii RNA is capable of inducing TLR7 activation, as
even host RNA can trigger TLR7 activation27. However,
it is not clear how TLR7 regulates immunity to T.gondii
and why its function is only apparent in the absence of
TLR11. TLR7 is not expressed in CD8+ DCs28, which
are the main DC subset responsible for T.gondii recognition. Furthermore, CD8 conventional DCs that
express high levels of TLR7 (REF.28) fail to produce IL12
invitro or invivo when stimulated with T.gondii or with
T.gondii soluble tachyzoite antigen (STAg)6,29.
These unanswered questions are also pertinent to
TLR9, which was discovered as a receptor for unmethylated DNA that has CpG motifs derived from bacteria
and viruses30. Although the CpG motif was thought
to be essential for TLR9 stimulation, the DNA sugar
backbone of 2 deoxyribose also mediates TLR9 recognition31. TLR9 can also recognize host DNA32,33. Thus, it
is expected that synthetic oligonucleotides that contain
sequences present in the T.gondii genome are capable
of inducing TLR9 activation20. Furthermore, T.gondii
lacks detectable DNA cytosine methylation34, which
highlights it as a putative target for TLR9mediated
recognition invivo. Nevertheless, for reasons we do not
understand, activation of TLR9 in response to T.gon
dii is not readily detected in DCs that express TLR9,
and the IFN-mediated priming of DCs is essential
for the induction of TLR9mediated responsiveness to
T.gondii DNA20. Furthermore, non-infected DCs are
the major source of IL12 during T.gondii infection16.
Future studies are needed to understand how T.gon
dii RNA and DNA can access the endolysosomes of
non-infectedDCs.
It is worth mentioning that TLR9 has a broad influence on immune responses to protozoan parasites other
than T.gondii. In addition to DNA, TLR9 also recognizes haemozoin a crystalline metabolite of haemoglobin that is produced by an apicomplexan parasite
Plasmodium falciparum, which is phylogenetically
related to T.gondii35. However, whether TLR9 directly
interacts with haemozoin is currently under debate, as
it has been suggested that haemozoin only transports
malarial DNA to the endosome, where TLR9 is present36.
Furthermore, intestinal damage that is caused by parasitic infection can result in TLR9 activation by intestinal
bacteria10,37,38. This mechanism of bystander TLR9 activation during T.gondii infection has a role in coordinating DCmediated IL12 production and subsequent
IFN secretion by CD4+ Tcells10,39.
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Congenital toxoplasmosis
A disease that occurs when a
developing child is infected
with the parasite Toxoplasma
gondii. The developing
child can be infected during
pregnancy, labour or delivery.
REVIEWS
Bradyzoites
A slow replicating form of
Toxoplasmagondii. Bradyzoites
in the form of cysts are
responsible for the chronic
stage of T.gondii infection.
Cysts
Structures that contain
bradyzoites. Cysts grow and
remain intracellular despite
variations in their size. Young
cysts may be as small as
5m and may contain only
two bradyzoites, whereas older
cysts may contain hundreds
of bradyzoites.
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TLR11
IL-12
Intracellular
T. gondii infection
TLR12
CD4+ T cell
Parasitophorous
vesicle
NK cell
Parasite
destruction
DC
Prolin
IFN
Free
tachyzoite
Primed for
intracellular
killing
Neutrophil
Macrophage
Priming of
CD8+ T cell
CD8+ T cell
Infected DC
Figure 2 | Cellular sources of IFN during T.gondii infection. Interferon (IFN) is crucial for survival during
Nature Reviews
| Immunology
Toxoplasma gondii infection. Production of this cytokine by natural killer (NK) cells is dependent
on the Toll-like
+
receptor 11 (TLR11)-mediated recognition of T.gondii profilin by dendritic cells (DCs). Both CD4 T cell-derived
and CD8+ Tcell-derived IFN is essential for resistance to T.gondii during the chronic stage of infection, but TLR
signalling in DCs is dispensable for this Tcell-derived IFN. Instead, the CD4+ Tcell-intrinsic myeloid differentiation
primary-response protein 88 (MYD88) pathway regulates T helper 1 (TH1) cell responses to the parasite, and the
activation of CD8+ Tcells is mediated by T.gondii antigens that are expressed on infected DCs. Neutrophils provide
an important innate source for IFN; the mechanisms that regulate neutrophil-derived IFN are not well understood
because this IFN is not regulated by TLRs or by interleukin12 (IL12).
Non-professional APCs
Cells that do not constitutively
express MHC class II
molecules, but that upregulate
MHC class II following
stimulation with certain
cytokines, particularly
interferon-. Important
examples of non-professional
APCs include fibroblasts and
thymic epithelial cells.
by DCs are not completely understood. The parasitophorous vacuole that contains T.gondii in infected APCs
does not fuse with lysosomes83,84, thus T.gondii-infected
DCs and macrophages do not degrade the parasite and
are not likely to function as efficientAPCs.
Restricted antigen-presentation is further exaggerated by the active suppression of maturation of DCs and
macrophages by the parasite8587. The inability of the
infected APC to activate endolysosomal machinery can
be overcome by previous stimulation with IFN (that
is, priming), which provides evidence that early IFN is
required for the potent induction of Tcell responses to
the parasite. CD8+ DCspecific recognition of parasites
leads to IL12dependent NK cell activation and production of IFN, which enables DCs to degrade T.gondii
and to present parasite antigens to Tcells. In addition,
antigen presentation as a result of uptake of the killed
parasite is indistinguishable from a conventional pathway of antigen presentation88. Overall, although not
formally examined invivo, it is likely that the induction
of CD4+ Tcell responses during T.gondii infection is
initiated by IFN-primedDCs.
Detailed analysis has been carried out to understand
the induction of CD8+ Tcell responses to the parasite1. It
was shown that infected DCs and non-professional APCs
can prime CD8+ Tcell responses against secreted T.gon
dii antigens89,90. T.gondii-containing parasitophorous
vacuoles in infected cells, including DCs, establish a
close contact with the host endoplasmic reticulum (ER),
REVIEWS
CD4+ Tcells are the major IFN-producing cells that
control parasites in the brains of chronically infected
mice. IL12 is indispensable for IFN production during both acute and chronic stages of the infection97,98 and,
although TLR11dependent activation of MYD88 regulates early IL12 production by CD8+ DCs6, the mechanisms that are responsible for the maintenance of IL12
production during the chronic stage of the infection are
mostly unknown. Following infection with attenuated
parasites, IL12independent and MYD88independent
IFN production by CD8+ Tcells is sufficient to control
and eliminate the parasites17,99, but this mechanism is not
sufficient to control the T.gondii strains that are typically responsible for human infection and that are widely
studied in experimental animals17.
IFN
IDO
Tryptophan
Inhibition of
T. gondii growth
iNOS
Arginine
NO
NO-mediated
toxicity
T. gondii
Destruction of
parasitophorous
vesicle
Parasitophorous
vesicle
Macrophage
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This is particularly evident from studies that involve the
chemical inhibition of both IDO1 and IDO2 in T.gondiiinfected mice: these mice did not show acute susceptibility to T.gondii, but were unable to control T.gondii
parasites during the chronic stage of the infection108.
Tachyzoites
Fast-replicating forms of
Toxoplasmagondii that are
responsible for the acute
stage of infection.
REVIEWS
Sexual cycle
Sexual replication of
Toxoplasma gondii occurs in
the gut of the cat during the
enteroepithelial stage of the
parasite life cycle, which takes
about 310days. Sexual
replication leads to the
production of oocysts. A host
in which parasites sexually
reproduce is known as the
definitive, final or primary host.
Mice that lack IFN-induced IRG family M protein 3 (IRGM3; also known as IGTP) or IRGM1 (also
known as LRG47) are highly susceptible to T.gondii
infection and succumb to lethal disease with equal or
even more striking kinetics than those seen in IFNdeficient mice124,125, despite showing normal induction
of IL12, IFN and iNOS production; this suggests a
cell-autonomous role for these IRGs in mediating parasite destruction. Deficiency of IRGD (also known as
IRG47)125, IFN-inducible IRGA6 (also known as IIGP1
and GTPase 1)126 or IRGB6 (also known as TGTP)127,128
also increases susceptibility to T. gondii infection,
although not to the same extent as deficiency in either
IRGM1 or IRGM3. Under steady-state conditions, IRG
proteins are distributed in different cellular compartments, including in the Golgi (in the case of IRGM1
and IRGM2)129131, in the endolysosomal compartment
(in the case of IRGM1)132, in the endoplasmic reticulum (in the case of IRGA6, IRGB6 and IRGM3)130,133
135
or within the cytosol (in the case of IRGB6 and
IRGD)129,135. Infection with T.gondii results in the highly
coordinated loading of IRGs onto the T.gondii parasitophorous vacuole136. The process is initiated by IRGB6
and IRGB10, and is then followed by the recruitment
of IRGA6, IRGD and IRGM2 (REF.136). This assembly of
IRG proteins on the parasitophorous vacuole leads to
vesiculation of the vacuole membrane, disruption of the
vacuole and elimination of the parasite by lysosomemediated degradation137,138. Such coordinated assembly
of the IRG proteins may be an explanation for the strong
susceptibility to infection of cells that are deficient in a
single member of thefamily.
Despite its importance in mediating host resistance
to T.gondii125, IRGM1 does not localize to the T.gondiicontaining parasitophorous vacuole136. Instead, IRGM1
seems to function as a master regulator of the IRGmediated host defence programme139,140. Lack of IRGM1
leads to uncontrolled and mislocalized activation of
other IRG family members, which results in cytopathic
effects because of overactivation of the endolysosomal and the autophagic pathways in macrophages141,
Tcells142 and haematopoietic stem cells143.
The importance of IRGs in determining the outcome ofhostparasite interactions is evident from the
analysis of virulence factors in T.gondii4. T.gondii can
be subdivided into three main strain types (BOX3) and,
although many typeII and typeIII strains of T.gon
dii are controlled by IRGs, typeI strains of T.gondii
counteract this host defence system. Genetic mapping
strategies identified ROP5 and ROP18 as the major virulence factors produced by typeI strains of T.gondii that
inhibit the loading of IRGs onto the parasitophorous
vacuole membrane144,145 and thus prevent IRG-mediated
T.gondii elimination127,146,147.
In contrast to mice, a role for IRGs in human cells
is still under debate148. First, only one IRG homologue,
IRGM, is present in the human genome123. Furthermore,
IRGM is severely truncated compared with other IRG
gene products and is not regulated by IFN123. However,
human IRGM participates in phagosome maturation
and in autophagy of intracellular bacteria. In addition,
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REVIEWS
recognition receptor for these pathogens, with the
exception of Plasmodium spp., which cause malaria6,7.
Malaria profilin avoids recognition by TLR11 through
poorly characterized mutations 6. As apicomplexan
parasites are an ancient monophyletic group of pathogens, appreciation of the benefits of TLR11dependent
and TLR11independent immunity may shed light on
hostparasite interactions across multiple species.
REVIEWS
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Acknowledgements
F.Y. gratefully thanks colleagues and the members of his laboratory for the many discussions that contributed to this
manuscript. Work in F.Y.s laboratory is supported by the US
National Institutes of Health (AI085263) and the Burroughs
Wellcome Fund.
Reproduced with permission of the copyright owner. Further reproduction prohibited without
permission.