Leishmaniasis (Nature)

REVIEWS
Leishmaniasis: complexity at the

hostpathogen interface
Paul Kaye* and Phillip Scott
Abstract | Leishmania is a genus of protozoan parasites that are transmitted by the bite of
phlebotomine sandflies and give rise to a range of diseases (collectively known as
leishmaniases) that affect over 150 million people worldwide. Cellular immune mechanisms
have a major role in the control of infections with all Leishmania spp. However, as discussed in
this Review, recent evidence suggests that each hostpathogen combination evokes
different solutions to the problems of parasite establishment, survival and persistence.
Understanding the extent of this diversity will be increasingly important in ensuring the
development of broadly applicable vaccines, drugs and immunotherapeutic interventions.
*Centre for Immunology and

Infection, Department of
Biology and Hull York
Medical School, University
of York, Wentworth Way,
York YO10 5YW, UK.
Penn Institute for

Immunology, Department of
Pathobiology, School of
Veterinary Medicine,
University of Pennsylvania,
Philadelphia, Pennsylvania
191044539, USA.
Correspondence to P.K.
email: paul.kaye@york.ac.uk
doi:10.1038/nrmicro2608
Published online 11 July 2011
Leishmaniasis is one of the most significant of the

neglected tropical diseases, with 350 million people in 88
countries worldwide living at risk of developing one of
the many forms of the disease1. It is caused by infection
with one of several different species of protozoan parasites of the genus Leishmania, which maintain their life
cycle through transmission between an insect (sandfly)
and a mammalian host. The flagellated, motile forms
of Leishmania spp. are called promastigotes. They are
found within the sandfly and progress through various
morphologically distinct stages of differentiation to ultimately become the non-dividing, infectious metacyclic
promastigotes that are transmitted during a sandfly bite.
Amastigotes do not have an exteriorized flagellum and
live as intracellular parasites in a variety of mammalian
cells, most notably within professional phagocytes such
as macrophages (FIG.1). Some Leishmania spp. cause
chronic, slow-to-heal diseases that are known as cutaneous, mucocutaneous or diffuse cutaneous leishmaniasis.
In these diseases, the symptoms remain localized to the
skin or mucosal surfaces. Other Leishmania spp. disseminate to internal organs such as the liver, spleen and bone
marrow to cause visceral leishmaniasis, which accounts
for most of the ~70,000 deaths per year that are due
to leishmaniasis1. Importantly, the clinical presentation of
leishmaniasis is dependent upon both the parasite species
and the hosts immune response. For example, Leishmania
major, Leishmania mexicana, Leishmania amazonensis and
Leishmania braziliensis primarily cause cutaneous lesions,
whereas Leishmania donovani and Leishmania infantum
(known as Leishmania chagasi in South America) cause
visceral leishmaniasis (TABLE1). Similarly to other intracellular pathogens such as Mycobacterium tuberculosis or
Mycobacterium leprae, the same microorganism can cause

a range of diseases depending upon the hosts immune
response, including subclinical infections, self-resolving
lesions and chronic disseminateddisease.
Recent years have seen major advances in our understanding of leishmanial biology: the genomes of several
Leishmania spp. have been sequenced2; post-genomic
analysis of these parasites and the host response is proceeding rapidly 3; sexual recombination between parasites has been shown to occur 4; and the intricacies of life
within an insect vector 5,6 and of natural transmission7 are
beginning to be understood. In this Review, we focus on
some of the major advances from the past few years in
our understanding of the immunology and cell biology
of the interactions between the host and Leishmaniaspp.,
and highlight some of the differences in immune regulation that have been uncovered from studies of various Leishmania spp. in animal models and in humans.
Although this Review is not completely comprehensive,
we aim to provide a picture of the complexity that underpins the host response to these parasites, and hence to
highlight the potential pitfalls that are associated with
developing one simple model for leishmaniasis pathogenesis. To what extent this complexity derives from intrinsic
differences in the parasites themselves, from differences in
human versus mouse host cell responses or from subtle
ties of experimental design remains largely unknown,
as few truly comparative studies have been performed.
Nevertheless, understanding diversity in hostparasite
interactions in models, and ultimately in humans, should
help to determine whether new tools for leishmaniasis
control can be truly broad spectrum or whether they will
require specific tailoring to each form ofthe disease.
604 | AUGUST 2011 | VOLUME 9
www.nature.com/reviews/micro
2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
Proliferation in the midgut
Procyclic
promastigotes
Amastigotes
Metacyclic
promastigotes
Sandfly bite
Sandfly bite
Attachment
Reinvasion
Lysis
Phagocyte
Uptake
Proliferation
Phagolysosome
Intracellular amastigote
Figure 1 | The life cycle of Leishmania parasites. Leishmania

procyclic
Nature
Reviewspromastigotes
| Microbiology
differentiate in sandflies into infective, non-dividing metacyclic promastigotes, which
are located ready for transmission at the stomodeal valve (an invagination of the
foregut into the midgut). During blood feeding, the sandfly regurgitates metacyclic
promastigotes, together with immunomodulatory parasite-derived proteophosphoglycans and various salivary components. The metacyclic promastigotes are then
phagocytosed by one of several possible cell types that are found in the local
environment (FIG. 2). After establishing an intracellular residence, metacyclic
promastigotes transform into aflagellate amastigotes. Amastigotes undergo
replication within host cells, which rupture when too many amastigotes are present,
allowing reinfection of local phagocytes. The transmission cycle is complete when
infected phagocytes are taken up by another sandfly with the blood meal, and
amastigotes then convert into promastigotes in the sandfly midgut.
Two-photon intravital
imaging
A fluorescent-laser-based
microscopy technique that
allows real-time imaging of cells
that are deep within the tissues
of live animals.
Chemokines
A family of small (~810kDa)
chemotactic cytokines that
regulate cell migration and
function. Different chemokine
families are defined by the
presence of specific motifs
known as C, CC, CXC and CX3C.
Host cells for Leishmania parasites

Leishmania spp. had been widely regarded as fastidious,
obligate intracellular pathogens of macrophages, but
recent studies have confirmed that these parasites have a
far greater degree of promiscuity in host cell range than
previously thought. Infections of multiple cell types, both
invitro and invivo, have been reported, including for
haematopoietic cells that arise from a common myeloid
precursor (BOX1; FIG.2), and for non-haematopoietic
cells such as fibroblasts. On a cautionary note, parasites
may spread between cells during tissue homogenization,
posing an additional challenge to invitro studies of host
range8,9. In this section, we describe studies on the relative
roles of different cell types as hosts for Leishmaniaspp.
The importance of the neutrophil. One of the major challenges that is faced by the metacyclic promastigote after
it enters the mammalian host is to establish intracellular
residence in long-lived macrophages without triggering their innate antimicrobial defences. In 2003, Laskay
and colleagues suggested that neutrophils could act as
Trojan Horses to help promastigotes to achieve this
goal. Through studying L.major, they observed that
promastigotes were readily phagocytosed by neutrophils
invitro, but survived within neutrophil phagosomes. The
infected neutrophils were induced to undergo apoptosis and became a phagocytic meal for macrophages that
were added to the culture. As apoptotic neutrophils are
phagocytosed through receptor-mediated pathways that
fail to trigger macrophage defence responses10, their cargoes of promastigotes were thereby efficiently and safely
shuttled into the macrophage phagosome11. Neutrophils
are indeed present in the early lesions that follow L.major
infection in mice, and they are also detectable by histo
pathology in many forms of human leishmaniasis.
Two-photon intravital imaging has recently provided a strikingly visual demonstration of the rapidity with which
neutrophils descend upon L.major promastigotes after
sandfly (or needle) transmission, and these cells can now
reasonably be regarded as one of the main early hosts for
L.major invivo12.
Rapid infiltration of neutrophils into the skin is not
limited to those Leishmania spp. that cause cutaneous
disease, as it also occurs with L.infantum, which causes
visceral leishmaniasis13. The cues that drive this neutrophil response are yet to be defined. The rapidity of the
response and its association with local tissue damage suggests a role for alarmins, which are endogenous molecules
that signal tissue and cell damage14. However, candidate
alarmins such as interleukin33 (IL33)15 have not yet
been directly measured in leishmaniasis. Mononuclear
phagocytes that are infected with Leishmania parasites
produce various chemokines, which are known to attract
neutrophils (reviewed in REF.16). Cytokines also exert
control over neutrophil recruitment. For example, IL17
can promote17 and typeI interferons (IFNs) can inhibit18
neutrophil recruitment, but their precise contribution
to this immediate immune response is unclear. Finally,
unlike needle infection, sandflies may co-transmit bacteria and viruses, which may help drive inflammatory
responses19,20. In situ imaging has shown that most
infected neutrophils, which rapidly engulf promastigotes on infection, are short-lived and release the parasites
before being actively phagocytosed by macrophages12. In
fact, the same study showed that the numbers of parasites in macrophages and dendritic cells (DCs) of mice
are unchanged after neutrophil depletion, which suggests
that neutrophils may merely scavenge parasites that are
otherwise ignored. Further insitu analysis using transgenic mice to visualize other potential host cells should
prove to be equally informative (see later). In summary,
although neutrophils clearly participate in the early
response to infection, their role as a Trojan Horse has yet
to be directly confirmed invivo.
Although the studies noted above suggest that uptake
by neutrophils contributes to L.major infectivity and may
assist in life cycle progression, this may not be the case
during infections with other Leishmania spp., or indeed
under all circumstances with L.major. For example,
NATURE REVIEWS | MICROBIOLOGY
VOLUME 9 | AUGUST 2011 | 605

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Table 1 | The main species of Leishmania that affect humans*
Main disease manifestation
Species
Old World, subgenus Leishmania

Visceral leishmaniasis
Leishmania donovani and Leishmania

infantum
Cutaneous leishmaniasis
Leishmania major, Leishmania tropica and

Leishmania aethiopica
Diffuse cutaneous leishmaniasis
L.aethiopica
New World, subgenus Leishmania

Visceral leishmaniasis
L.infantum
L.infantum, Leishmania mexicana, Leishmania

pifanol and Leishmania amazonensis
Diffuse cutaneous leishmaniasis
L.mexicana and L.amazonensis
New World, subgenus Viannia

Leishmania braziliensis, Leishmania

guyanensis, Leishmania panamensis and
Leishmania peruviana
Mucocutaneous leishmaniasis
L.braziliensis and L.panamensis
*Adapted from REF. 119.
neutrophil depletion in mice increased susceptibility to

needle-inoculated L.braziliensis infection21. Some early
studies with L.major have suggested that the effects of
neutrophil depletion are mouse strain dependent 22,
but these studies often used a monoclonal antibody,
RB68C5, that is now known to deplete inflammatory
monocytes as well as neutrophils. Contradictory roles
for neutrophils are also evident from studies of another
innate neutrophil function, the extrusion of neutrophil extracellular traps (NETs), which are composed of
filamentous DNA that is decorated with antimicrobial
peptides. In human neutrophils, NET extrusion was
stimulated by L.donovani promastigotes by a pathway
that was independent of lipophosphoglycan (LPG)
(BOX2). However, whereas wild-type parasites survived
this onslaught, LPG-deficient L.donovani did not23, suggesting a parasite-protective role for this major surface
glycoconjugate. By contrast, wild-type L.amazonensis
was susceptible to killing by NETs, and LPG that was
isolated from these parasites triggered NET release24.
Given the many diverse parts played by neutrophils in
the innate and adaptive immune response (as further
discussed below), it will be technically challenging
to directly confirm the importance of parasite transit
through neutrophils and the role of NETs in parasite
establishment and disease progression invivo.
Macrophages, monocytes and dendritic cells. Although
parasites can readily be found in neutrophils, it is within
mononuclear phagocytes that there is the best evidence
for their replication and long-term survival. Two-photon
intravital imaging of mouse skin following needle injection of L.major has provided direct evidence that dermal DCs take up parasites within the first few hours
of infection. The process of uptake is highly dynamic,
with dermal DCs discriminating between parasites and
inert beads and capturing their prey in a process that
involves pseudopodium extension25. Resident dermal

macrophages are also rapidly infected, and they become
the dominant infected population after 24 hours 12.
Heterogeneity in the mechanism of phagocytic uptake
(for example, coiling versus conventional zipper phagocytosis) has been reported for different types of macro
phages invitro26, but the mechanism (or mechanisms)
that are used invivo are not known. It is unclear whether
dermal DCs or macrophages are capable of transporting
parasites from the initial site of infection to the lymph
node that drains that site and where acquired immune
responses are initiated, but both questions are important
for future study.
As the numbers of resident macrophages and DCs
in the skin are too limited to sustain parasite multiplication, the progression of infection may require the
recruitment of the immediate precursor of these cells,
the monocyte. Importantly, this process is regulated by
neutrophils27. After cutaneous infection with L.major
in mice, it seems that many of the monocytes that are
recruited to the infection site become monocyte-derived
DCs (moDCs28), which subsequently have apparently
contradictory roles during the infection. On the one
hand, moDCs are permissive host cells for the parasite,
thus expanding the developing lesion9. Indeed, they may
facilitate further monocyte recruitment by increasing the
blood supply to the site of infection29. On the other hand,
moDCs upregulate expression of major histocompatibility complex class II (MHC class II) molecules, which are
critical for the ability of DCs to act as antigen-presenting
cells. These cells also secrete IL12, which is important
for the induction of a host-protective T helper 1 (TH1)type response9,28. Indeed, in mice lacking the chemokine
receptor CCR2 (and hence the ability to recruit monocytes to the lesions), a non-protective TH2 response is
induced by the infection30. Interestingly, whereas moDCs
may be critical for the induction of a TH1 response, the
non-infected (bystander) DCs could be the key mediators
of this response. This is supported by the fact that DCs
that are infected invitro with L.braziliensis promastigotes
do not upregulate MHC class II or secrete IL12, whereas
uninfected bystander DCs in the same culture do31. Thus,
some of the most important functions of DCs in promoting protective immunity are inhibited in infected
cells. Bystander activation of DCs (measured by upregulation of MHC class II) was also found to occur in the
spleenof mice that had been infected with L.donovani
amastigotes, but this study showed no impediment of
function in infected DCs32. Bystander DC activation and
consequently bystander Tcell activation may provide a
means for facilitating a rapid Tcell response at multiple
systemicsites.
In mouse models of visceral leishmaniasis that use
intravenous inoculation of amastigotes to establish visceral infection, a further degree of subtlety in host cell
preference is observed. Amastigotes of L.donovani are
preferentially taken up by resident tissue macrophages
(BOX1) that lack the CD11b and CD11c markers, such
as marginal zone macrophages and marginal metallo
phils in the spleen, stromal macrophages in the bone
marrow and Kupffer cells in the liver 33. Resident splenic
REVIEWS
Tissue-resident
macrophage or DC
Sandfly
Dermis
Phagolysosome
Neutrophil
Metacyclic
promastigote
Non-leishmanicidal
vacuole
Blood vessel
moDC
To the lymph node?
Figure 2 | Multiple cell types are involved in the uptake of Leishmania parasites. Metacyclic
promastigotes
are
Nature Reviews
| Microbiology
deposited in the dermis in a mixture of immunomodulatory salivary secretions and parasite-derived proteophosphoglycans.
The impact of these factors on local phagocyte function is poorly defined. Metacyclic promastigotes from the initial
inoculum (or those that have been released from infected neutrophils) are phagocytosed by tissue-resident macrophages
and dermal dendritic cells (DCs). Capillary and other tissue damage resulting from the mechanical trauma of the bite may
result in the release of endothelial alarmins, such as interleukin33 (IL33), which facilitates the recruitment of neutrophils. The
neutrophils swarm around the extracellular metacyclic promastigotes, engulfing many in non-leishmanicidal vacuoles.
The death of neutrophils releases metacyclic promastigotes that may be pre-conditioned for survival in other myeloid
cells. Alarmins (such as high mobility group protein B1 (HMGB1) and IL1), which are released from ruptured neutrophils,
possibly aid in attracting inflammatory monocyte-derived DCs (moDCs) to the local site. Infected inflammatory moDCs
may facilitate parasite traffic to the draining lymph node. Long-term replication and perpetuation of the pathogen
principally involves either macrophages or moDCs, depending on the parasite species. It is not known whether neutrophils
are involved in amastigote uptake after the initial infection.
macrophages that express epidermal growth factor-like

module-containing mucin-like hormone receptor-like 1
(EMR1) and are experimentally defined by the monoclonal antibody F4/80, and resident DCs in spleen and
liver are infected to a far lesser extent. Furthermore, in
contrast to the dominance of moDCs in both early and
late stages of cutaneous leishmaniasis, moDCs appear to
have a lesser role as hosts for L.donovani 8. However, in
tissues that contain multiple populations of potential host
cells, apparent host cell preference may reflect both differing levels of host cell permissiveness to infection and
anatomical constraints to infection.
Stromal cells as host cells for Leishmania parasites. The
presence of L.major in skin and lymph node fibroblasts
was first highlighted over a decade ago34, and since that
time it has become apparent that infection of stromal
cells can also occur in other forms of leishmaniasis. It
was initially proposed that the residence of L.major in
these cells provided a niche for survival in the face of
immune attack, but recent studies also suggest that the
infection of stromal cells can contribute to immune evasion. For example, splenic stromal cells that are infected
with L.donovani express high levels of the chemokine
CCL8. Together with CXCL12, this chemokine attracts
haematopoietic stem cells into a niche that favours development of DCs that can reduce the effectiveness of TH1
immunity 35.
The intracellular fate of Leishmania parasites

The realization that Leishmania parasites can survive
in diverse populations of phagocytes, which contain
phagosomes with differing microbicidal properties,
raises an important question: do Leishmania parasites
rely on constitutive broad-acting countermeasures for
protection against the phagosomal environment, or do
they employ inducible virulence factors that are selectively expressed in differing intracellular environments?
As yet, there are few answers to this question, probably
for a number of reasons. First, post-genomic analysis of
leishmanial virulence factors is still in its infancy. Second,
although it is the amastigote that ultimately inhabits and
replicates within the phagolysosomal niche, most studies
on intracellular survival have focused on the early establishment of promastigotes, hence modelling only the first
wave of intracellular infection. Third, the historical use
of easily accessible macrophage populations (for example,
those derived from peritoneum or bone marrow) ignores
the tissue-specific heterogeneity of the host cells36.
Nevertheless, despite these limitations in studies to date,
the complexity to come is already becomingevident.
Phagosome biogenesis. In mouse neutrophils, L.donovani
metacyclic promastigotes survive undamaged in the
phagosome an intracellular membrane-bound compartment that is related to the endoplasmic reticulum
(ER)37 providing a mechanistic basis for the Trojan

REVIEWS
Box 1 | Monocyte and macrophage diversity
Monocytes, as well as neutrophils, originate in the bone marrow from a common
myeloid precursor cell. Monocytes have a critical role in leishmanial infections as they
differentiate into macrophages, which provide a home for parasite replication, but
can also differentiate into dendritic cells (DCs), which are crucial in priming a
protective immune response. The macrophages and DCs that arise from monocytes
exhibit many different phenotypes, which are thought to be determined by cues
within the infected tissues114. In addition, monocytes are a heterogeneous population
of cells, which may also contribute to the generation of distinct macrophage and DC
subsets115. In humans, the best described subsets are classic monocytes, which are
defined by their expression of CD14, and pro-inflammatory monocytes, which in
addition to CD14 also express the low-affinity Fc receptor CD16. Different markers
define monocyte subsets in mice. One monocyte subset expresses CCR2 (a
chemokine receptor that is critical for release of cells from the bone marrow) and
LY6C (the function of which is unknown) and is recruited into inflammatory sites.
Another subset is potentially derived from LY6Chi monocytes and expresses the
fractalkine receptor, CX3CR1. The LY6Chi monocytes that migrate into leishmanial
lesions are the source of monocyte-derived DCs. Our understanding of how these
diverse monocyte subsets contribute to disease is still limited.
Macrophages also display considerable tissue-specific heterogeneity, reflected both
in function and phenotype. For example, in the spleen there are distinct populations
of macrophages in the red pulp (where they express F4/80) and the marginal zone
(where macrophages at the outer border express SIGNR1 (also known as CD209
antigen-like protein B) and macrophages at the inner border, which are known as
metallophilic macrophages, express CD169). In lymph nodes, macrophages in the
subcapsular sinus have a defined role in antigen capture. In liver, resident tissue
macrophages are called Kupffer cells, but even these may be heterogeneous. Resident
tissue macrophages may have conventional roles for example, as phagocytes but
some may also have a supportive role in maintaining tissue structure or forming part of
the stem cell niche. As some of these macrophages have functions that are reminiscent
of fibroblasts, they may be referred to as stromal macrophages. Our understanding of
how these different types of macrophages contribute to the various forms of
leishmaniasis is very rudimentary8,33,72.
Granules
Cytosolic particles within
neutrophils that are referred to
as primary, tertiary or specific,
based on their staining
characteristics and their
content. Primary granules (also
called azurophilic granules)
contain the enzyme
myeloperoxidase, which is
responsible for the green
colour of pus.
RAB GTPases
A large family of monomeric
guanine nucleotide binding
proteins that act as important
regulators of vesicle transport
and docking in eukaryotic cells.
Fc receptors
Cell surface receptors that
recognize the Fc tails of
antibody molecules. The
binding of particles that are
coated with antibody by the
Fcreceptors on phagocytic
cells triggers internalisation
and potent antimicrobial
effector responses.
Horse model referred to earlier. Maintenance of this

ERlike compartment requires LPG-dependent inhibition of lysosomal fusion (a function for LPG that was first
described when studying the infection of macrophages38).
Thus, LPG acts as a virulence factor to allow safe passage of metacyclic promastigotes through neutrophils,
in addition to its other numerous roles. However, a rather
different picture has emerged from studies of human
neutrophils that were infected with L.major or L.donovani,
in which no evidence for the involvement of the ER in
phagosome formation was found39. In these neutrophils,
primary granules could fuse with parasite-containing
phagosomes, but parasite survival was ultimately determined by whether or not fusion of the phagosome with
tertiary and specific granules (which are responsible for
acidification and superoxide generation, respectively)
had occurred (FIG.3a).
In macrophages, it is generally accepted that parasitecontaining phagosomes undergo maturation to acquire
lysosomal properties, and promastigotes inhibit this
process. However, early events in phagosome biogenesis are less clear. In support of an ERmediated model
of phagocytosis, one study found that most phagosomes
that are formed around L.donovani and Leishmania
pifanoi promastigotes in bone marrow-derived macro
phages contain the ER chaperone calnexin as well as
SEC22b (a vesicle protein that is involved in ERGolgi
transport). Using the toxin ricin as a tool to monitor
ERphagosome communication, this study further suggested that the ER and the phagosome were in continuous communication40. Delayed phagosomal maturation,
first demonstrated with L.donovani 38, has also been
observed using bone marrow-derived macrophages that
were infected with L.mexicana. In this elegant study,
many of the technical challenges of analysing asynchronous processes such as phagocytosis were overcome by
using real-time imaging of infection in macrophages that
were derived from transgenic mice expressing RAB5
(which is one of several RAB GTPases and a key orchestrator of endosome and phagosome maturation) fused to
GFP41. Surprisingly, RAB5 was detected in L.mexicanacontaining phagosomes for only 12min, indicating the
rapid maturation of these organelles. Phagosome maturation was delayed (measured by an increase in the time
that the parasite spent in a RAB5+ compartment) when
LPG1deficient promastigotes (which do not undergo
complement receptor-mediated phagocytosis) were used,
or when wild-type parasites were opsonized with antibody to target them for uptake by Fc receptors. However,
in contrast to earlier reports38, LPG-dependent inhibition of phagosome maturation in this model did not
ultimately affect parasite intracellular survival41.
Various studies have demonstrated that the acidification of phagosomes that typically occurs during their
transformation into phagolysosomes is transiently inhibited in parasite-containing phagosomes. For L.donovani,
this has been reported to be due to the integration of LPG
into lipid microdomains of the phagosome membrane that
contain the ganglioside GM1. This process leads to exclusion or loss of synaptotagmin V, which is an essential
player in the recruitment of the vesicular proton ATPase
(V-ATPase) that drives phagosome acidification42. Hence,
LPG-deficient parasites were assumed to die as a result of
the acidification that occurred before they became fully
adapted to an intracellular lifestyle. However, the observation that LPG-deficient L.major is also rapidly killed in
macrophages that lack signal transducer and activator of
transcription 1 (STAT1), in which phagosome acidification fails owing to defective chloride channel function,
suggests that the death of LPG-deficient L.major is independent of acidification. Indeed, in these latter studies, a
host-protective effect for STAT1 dependent phagosome
acidification was observed to operate only on amastigotes43. Related to this observation, a recent study has suggested that the shift in temperature that is associated with
the move from an invertebrate vector to a mammalian
host is the major determinant of amastigote-specific gene
expression44, rather than phagosome acidification.
In addition to the parasite- and cell type-specific differences noted above, host cell maturation status can
also influence the intracellular fate of Leishmania parasites. For example, the maturation of parasite-containing
phagosomes in immature bone marrow DCs is arrested
at the stage of the late endosome, whereas in mature
bone marrow DCs the parasite-containing phagosomes
acquire the small GTPase RAB7 and fuse with lysosomes
(FIG.3b). This might provide a mechanism for ensuring
that the immature DCs that are infected at local sites can
transport live parasites to systemic tissue. Unfortunately,
REVIEWS
Box 2 | Surface coat of leishmanial promastigotes
Leishmania promastigotes are covered by a dense glycocalyx, which is composed of
several types of molecules that are attached to the plasma membrane using a glycophospoinositol (GPI) anchor. The most abundant molecule is lipophosphoglycan (LPG),
which has an important role in the interactions between the parasite and the sandfly
and, once in the mammalian host, promotes the infectivity of the parasites. LPG is a long
phosphoglycan polymer with multiple repeating sugar residues, glycan side chains and
a capping oligosaccharide. Importantly, there is considerable diversity in LPG structure
among Leishmania spp., which explains their vector specificity116 and may also affect
their immunological properties. A series of LPG mutants have been developed in
Leishmania spp. that have been extensively used to define the function of LPG both
within the sandfly and within the mammalian host117. Changes in LPG structure as the
parasites transform from a procyclic form to an infective metacyclic form are critical for
releasing the parasites from the sandfly midgut, as well as protecting the promastigotes
in the mammalian host from a variety of immune responses. The surface of
promastigotes also contains a variety of other phosphoglycans and GPI-anchored
glycoproteins. The most abundant surface glycoprotein is the zinc metalloproteinase
MSP (also known as GP63)55, which seems to have a significant role in leishmanial
virulence. Perhaps unsurprisingly, the expression levels of MSP, LPG, glycoinositol
phospholipids and other molecules that are associated with the hostparasite
interaction may vary between Leishmania species, strain and life cycle stage.
Broad-ranging, comprehensive analysis is therefore required to ascertain the biological
significance of this and other leishmanial virulence factors.
similar studies examining phagosome biology in

other host cells under various conditions of activation
arelacking.
In infections with some Leishmania parasites from
the New World, the parasite-containing phagosomes are
strikingly enlarged, and it has recently been suggested
that this may help dilute the leishmanicidal effects of
nitric oxide. Lysosome size in cells is regulated by lysosomal trafficking regulator (LYST; also known as Beige
protein). Mice with mutations in Lyst and humans with
ChdiakHigashi syndrome (who carry mutations in
the human homologue, LYST) have large lysosomes and
lysosome-related organelles, including phagosomes.
When LYST was overexpressed in mouse macrophages
and fibroblasts, phagosomes were reduced in size and the
parasites contained within them were more susceptible to
killing by nitric oxide. As LYST is induced during infection with Leishmania parasites, it therefore behaves as an
inducible innate responsegene45.
Lipid microdomains
Regions of a biological
membrane that are enriched
in a particular protein or
lipid and can vary in size,
composition and function.
For example, lipid rafts are
highly dynamic microdomains,
10200nm in size, that are
enriched in cholesterol and
sphingolipids and serve to
compartmentalize different
membrane functions.
Iron regulation in the phagosome. Although many

factors contribute to the survival of Leishmania parasites in the phagosome, access to iron has a central role
(reviewed in REF.46) (FIG.4). Amastigotes can use ferrous
iron (Fe2+) as well as hemin (the Fe3+ oxidation product
of haem) and haemoglobin, and a high-affinity hemin
receptor has recently been described in L.infantum47. In
mice, Slc11a1 (also known as Nramp1 and Lsh) encodes
a phagosomal efflux pump that translocates Fe2+ and
Mn2+ into the cytosol48 and thus limits iron availability
to the parasite. As a countermeasure, L.amazonensis
upregulates the expression of its own iron transporter,
LIT1, after its entry into macrophages46,49. Recent studies with L.donovani suggest that intra-phagosomal
competition for iron may, by depleting the macrophage
labile-iron pool, activate the cytosolic iron sensors
IRP1 and IRP2, which leads indirectly to increased
production of the iron-binding protein transferrin and

thus transferrin-mediated iron uptake50.
Subverting intracellular signalling

As Leishmania parasites inhabit an intracellular niche,
it is perhaps not surprising that they have evolved various means to attenuate and/or subvert how their host cell
integrates signals from the external immune environment. Indeed the literature has a rich history of reports of
Leishmania spp. affecting a range of diverse macrophage
functions, including chemotaxis, cytokine production
and immune synapse formation. However, until recently
many of these studies have been overshadowed at a
mechanistic level by the vexed issue of spatial segregationthat is, how do intra-phagosomal parasites affect
the cytosolic signalling pathways of their host cell? In this
section we review recent studies that are beginning to
provide some clarity to thisissue.
Cellular phosphotyrosine phosphatases. The role of a host
protein phosphatase, SRC homology 2 domain phosphotyrosine phosphatase 1 (SHP1; also known as PTPN6), in
regulating anti-leishmanial immunity has long been recognized (reviewed in REF.51). SHP1 has a central role in
the regulation of inducible nitric oxide synthase (iNOS)
and hence nitric oxide production, and it was recently
shown that SHP1 binds to a conserved KTIM motif that
is found in multiple kinases that act downstream of SHP1
and are associated with innate immunity (these kinases
include extracellular signal-related kinase1 (ERK1),
ERK2 and IL1 receptor-associated kinase 1 (IRAK1)).
L.donovani increases SHP1 activity and expression in
host macrophages, a process thought to contribute to
parasite survival. But how is this achieved? New evidence
points to a well-known leishmanial virulence factor,
major surface protease (MSP; also known as GP63 and
leishmanolysin)5254. MSP enters the host cell cytosol in a
process that is dependent on the presence of cholesterolrich lipid microdomains or lipid rafts in the host cell
membrane55, and appears to have an ability to selectively
cleave intra-cytosolic protein tyrosine phosphatases such
as SHP1, protein tyrosine phosphatase 1B (PTP1B) and
T cell protein tyrosine phosphatase (TCPTP; also known
as PTPN2), leading to their activation55,56. The kinetics of
protein tyrosine phosphatase cleavage after exposure to
parasites or to recombinant MSP suggests that the raftdependent entry of MSP into the host cell cytosol may
precede internalization, but it is unclear whether this
continues while the parasite is within the phagosome.
Leishmania spp. contain multiple MSP genes, and species
differences in expression of these genes are well known;
for example, in L.chagasi MSPs originate from three gene
classes and, in this species at least, there are important
differences in glycosylation and cellular localization
between MSPs in promastigotes and amastigotes54. It will
be important to determine whether all MSPs cleave intracytosolic protein tyrosine phosphatases. In L.donovani,
MSP can be found on the promastigote surface as well as
in the parasite cytoplasm, and it has been proposed that
these pools of MSP are functionally distinct, with the surface MSP being involved in parasite development within

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a Neutrophil
b DC
Promastigote
Phagosome
Phagosome
Immature DCs
Mature DCs
RAB7
MPO-containing
primary granule
Parasite
survival
Tertiary
granule
CD68
Specific
granule
Parasite
degradation
LAMP1
and LAMP2
Parasite
survival
Lysosome
Parasite
degradation
Figure 3 | Phagosome fate is determined by factors from

bothReviews
the host
and
Nature
| Microbiology
Leishmania spp. a | In human neutrophils, all phagosomes containing promastigotes
fuse with myeloperoxidase (MPO)-containing primary granules. However, destruction
of the parasites requires the additional fusion of tertiary and specific granules. Fusionof
tertiary and specific granules induces a decrease in luminal pH and also results in an
increase in the concentration of reactive oxygen radicals. In mouse neutrophils, it has
been suggested that lipophosphoglycan (LPG) from the parasite has a role in regulating
phagosome fate, but the fusion of specific granules has not been determined. b | Late
endosomal markers such as lysosome-associated membrane protein 1 (LAMP1) and
LAMP2 are found in phagosomes containing Leishmania major promastigotes in
both immature dendritic cells (DCs) and mature DCs from mouse bone marrow. By
contrast, recruitment of the small GTPase RAB7, which facilitates lysosomal fusion,
was not observed in immature DCs; this suggests that inhibition of RAB7 recruitment
could be a mechanism that is used by Leishmania spp. to ensure the transport of live
parasites to lymph nodes118.
Signalosome
A high-molecular-mass
cytosolic or membrane-bound
complex that contains many of
the individual proteins that are
associated with a signalling
pathway, often together with
various scaffold proteins.
the sandfly and the cytoplasmic MSP being a pre-formed

store that is ready for rapid use in the mammalian host 57,
in a manner analogous to the various effectors that are
used during typeIII secretion in bacteria58.
MSP is not alone in targeting SHP1, as the L.donovani promastigote fructose1,6bisphosphate aldolase
immunoprecipitates with SHP1 from macrophage cytosol. Likewise, MSP is somewhat promiscuous in its action;
in fibroblasts, transforming growth factor--activated
kinase 1 (an upstream activator of p38 mitogen-activated
protein kinase (p38 MAPK; also known as MAPK14)) is
a target of enzymatic cleavage by MSP, providing a mechanism for inactivating p38 MAPK56. Similarly, MSP also
affects peri-phagosomal actin accumulation, an essential feature of phagosome maturation, by cleaving the
120kDa scaffold protein tyrosine phosphatase PTPPEST,
which is a key regulator of WiskottAldrich syndrome
protein (WASP) and actin remodelling56.
Host cellular protein tyrosine phosphatases may also
have broader roles in anti-leishmanial immunity. Of
note, SHP2 (also known as PTPN11), which shares many
downstream targets with SHP1, is coupled to signalregulatory protein 1 (SIRP1; also known as PTPNS1),
which is a myeloid-restricted inhibitory receptor 59,60 that
binds the membrane glycoprotein CD47 when macro
phages encounter invariant natural killer Tcells during
early L.donovani infection61. Intriguingly, sodium stibogluconate, the first-line anti-leishmanial drug in most
parts of the world, also targets SHP1 at concentrations

that are used for chemotherapy in humans62. Finally,
and perhaps not surprisingly, the targeting of cellular
phosphatases may not be a ubiquitous virulence mechanism, and the disparate results for parasite survival
and lesion development that are seen in SHP1deficient
macrophages and mice may reflect host genotype,
the macrophages used (peritoneal versus a cell line),the
use of complement opsonization in vitro and even
the route of inoculation63,64.
Protein kinase C and nuclear factor-B. Interference with
host cell signalling at the level of macrophage protein
kinase C (PKC) has also long been known65. An enzyme
with PKC-like activity that is found in the infective promastigotes of L.mexicana has been recently reported to
be upregulated during early contact with macrophages
and to be involved in macrophage invasion66. Similarly, a
role has been proposed for phosphatidylinositol kinases
in a variety of leishmanial signalling responses that are
linked to invasion. Hyporesponsiveness of host MAPK
and nuclear factor-B (NFB) leads to cross-tolerance
to activation by bacterial lipopolysaccharide (LPS) and
L.major 67,68 but does not appear to be due to the induction of cellular protein tyrosine phosphatases, suggesting
alternative means for parasites to inhibit host responsiveness. L.amazonensis promotes the activity of the NFB
p50p50 transcriptional-repressor complex, which negatively regulates iNOS gene expression. Furthermore, in
L.amazonensis-infected macrophages that had been previously stimulated with LPS, the NFB p50p50 dimer
replaced the NFB p65p50 dimer (which is normally
produced in LPS-stimulated macrophages). In addition,
MSP cleaves the NFB p65 subunit 51. These results
suggest an active process of immune deviation69.
Lipid microdomains. Lipid microdomains, including
rafts and caveolae, have an important role in the organization of membrane proteins, in cellcell contact and in
numerous signalling processes. Not surprisingly, they are
increasingly being implicated in the interactions between
macrophages and Leishmania parasites (FIG.5). As noted
above, host cell lipid rafts may have a role in the entry of
leishmanial virulence factors such as MSP into the host
cell cytosol. However, rafts and other lipid microdomains
may also serve as targets for disrupting host cell function
and, indeed, as a portal of parasite entry 70. Microarray
analysis indicates that macrophage lipid metabolic
pathways are perturbed by Leishmania infection71,72.
Depletion of cholesterol, which is the major lipid component of lipid rafts, is observed in a variety of experimental and clinical settings and has been associated
with defective antigen presentation following L.donovani infection73. Strikingly, this defect can be improved
by cholesterol replenishment, with dramatic effects on
disease progression invivo. Cholesterol depletion has
also been implicated in immune modulation by L.major.
In L.major-infected macrophages, CD40 is preferentially associated with a signalosome containing TRAF6
(tumour necrosis factor (TNF) receptor-associated factor 6) and spleen tyrosine kinase (SYK), which results
REVIEWS
virulence factors into the host cytoplasm, through fusion
with the mammalian cell plasma membrane or with the
phagolysosome membrane. Although exosomes from
L.donovani and L.major have some influence on disease outcome when administered before experimental
infection80, the precise role of exosomes in pathogenesis
remains unclear, as there are no known means through
which their production by parasites can be manipulated
invivo.
Fe3+
TF
Fe3+
TFR
Macrophage
cytoplasm
TF
Phagolysosome
Fe2+
SLC11A1
Amastigote
Fe2+
LIT1
TF
Fe3+
Fe2+
SLC11A2
Fe2+
Fe2+
Figure 4 | Iron wars within macrophages infected with Leishmania parasites. Fe2+
Nature Reviews | Microbiology
transporters from both the host (SLC11A1) and Leishmania spp. (LIT1) compete for
phagosomal free iron. Studies in mouse macrophages that were infected with Leishmania
donovani suggest that the resulting depletion of cytosolic Fe2+ may lead to activation of
the host iron-responsive element binding proteins IRP1 and IRP2 (not shown)50. These
proteins enhance the stability of the transferrin (TF) receptor (TFR) mRNA, which in turn
leads to increased TFR-dependent uptake of extracellular Fe3+. Reduction of Fe3+ to Fe2+
within the early endosome is followed by iron transport into the cytosol, which is
dependent upon the host transporter SLC11A2.
in ERK1- and/or ERK2dependent secretion of IL10.

This contrasts with the normal association of CD40 in
uninfected cells with a signalosome that contains TRAF2,
TRAF3, TRAF5 and the SRC kinase LYN and that leads
to p38 MAPK-dependent IL12 production74. In addition, L.major infection of macrophages has also been
shown to induce MAPK phosphatase 1 (MKP1), which
dephosphorylates p38 MAPK and reciprocally decreases
expression of MKP3, a phosphatase with specificity
for ERK1 and ERK2 (REF. 75). Thus, parasite-mediated
perturbation of membrane and cytosolic components
of the CD40 signalling pathway may influence the
immunoregulatory function of macrophages.
Lipid microdomains may also underlie the promiscuous functions of LPG. Following L.donovani infection,
LPG associates with the phagolysosome membrane,
regulating the accumulation of periphagosomal filamentous actin (Factin) and thereby transiently inhibiting phagosomelysosome fusion (see earlier). A recent
study indicates that LPG is associated with rafts on the
phagolysosome membrane and that, after raft disruption,
this and other functions of LPG are lost76. Raft-associated
LPG may also be responsible for the alteration in the susceptibility of L.infantum-infected macrophages to HIV
infection77.
A role for exosomes. Exosomes are vesicles that bud from
the plasma membrane, and have been found in cell-free
supernatants from a variety of cultured mammalian cells
and pathogens, including Leishmania spp. (reviewed
in REF.78). Recent proteomic analysis of leishmanial
exosomes suggests that they contain many if not all of
the molecules that have functionally been described as
leishmanial virulence factors79. Hence, it is possible that
exosomes represent vehicles that allow the entry of these
TypeI interferons. TypeI IFN responses are usually

associated with viral infections; however, both typeI
IFNs themselves and the signature genes they induce are
increasingly becoming seen as important in leishmaniasis.
One example of such a response being beneficial to the
parasite is seen during infection with L.amazonensis,
which induces the expression in macrophages of PKR,
a protein kinase that is activated by double-stranded
RNA. PKR appears to promote parasite survival through
induction of the macrophage-deactivating cytokine
IL10 (REF.81). By contrast, there are other examples for
which typeI IFN-induced proteins appear detrimental rather than beneficial to intracellular survival. For
example, interferon regulatory factor 7 (IRF7), which is
a master regulator of the typeI IFN response, acts as an
upstream regulator of leishmanicidal activity in L.donovani-infected stromal macrophages 72. But perhaps the
most elegant example is that of Leishmania guyanensis,
which is associated with mucocutaneous leishmaniasis
and can carry its own virus (Leishmania RNA virus1;
LRV1)82. The metastatic potential of different L. guyanensis isolates correlates with the LRV1 viral load.
Importantly, the presence of LRV1 was associated with
increased Toll-like receptor 3 (TLR3)-dependent secretion of IFN and other pro-inflammatory cytokines from
macrophages. Furthermore, cutaneous lesion development was reduced in Tlr3/ mice compared with wildtype mice when both were infected with L.guyanensis
strains that had high levels of LRV1, but no difference
was observed when both were infected with L.guyanensis strains that had low levels of or lacked LRV1. Hence,
the inflammatory potential of L. guyanensis is dependent
upon the virus that it carries83.
Adaptive immunity
Host cells for Leishmania spp. also have a pivotal role in
bridging the gap between innate and adaptive immunity.
However, although many of the survival strategies noted
above may indirectly affect the three signals that are
required for inducing Tcell activation and differentiation
(antigen processing and presentation, the expression of
co-stimulatory molecules and the production of host cell
cytokines), there have been surprisingly few studies over
the past few years that directly address these pathways in
an invivo context and/or in relation to defined virulence
factors or vaccine candidate antigens. Notably, few examples have been found of bona fide virulence factors that
selectively target antigen presentation, although these are
abundant in other intracellular pathogens. The tools of
insitu analysis hold great promise for addressing some
of these questions in coming years. By contrast, there has

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Altered antigen presentation
Promastigote
Plasma membrane
Virulence factors
Lipid microdomain
Lysosome
MHCII CD40
Phagosome
Actin
remodelling
LPG-modified
lipid microdomain
Figure 5 | Lipid microdomains during Leishmania infection of macrophages.

Nature membrane
Reviews | Microbiology
During the initial encounter, lipid microdomains on the plasma
of the
macrophage have a role in directing parasite uptake and the entry of specific
virulence factors such as major surface protein (MSP, also known as GP63). Virulence
factors can also be transferred to the macrophage by parasite-produced exosomes.
Once the promastigote has entered the phagosome, lipophosphoglycan (LPG) inserts
into lipid rafts and inhibits phagosomelysosome fusion. Additional metacyclic promastigote-derived virulence factors may cross the phagosome membrane using lipid
microdomains or by exosomes, and thereby reach their cytosolic targets. Similar roles
for lipid microdomains could be postulated for phagosomes containing amastigotes,
although little data exist to directly support this. Altered lipid rafts may also be
responsible for defective antigen presentation and CD40 signalling. MHC class II,
major histocompatibility complex class II.
been, and continues to be, much interest in defining the

cellular mediators of acquired resistance. We describe
in this section some of the more recent nuances of the
acquired immune response to Leishmaniaspp.
Host resistance and adaptive immunity. CD4+ TH1 cells
are critical for the control of Leishmania infections,
owing to their ability to make IFN, which activates
macrophages and DCs, leading to parasite death (FIG.6).
The role of CD8+ Tcells in cutaneous leishmaniasis has
been less well appreciated. Although early studies indicated that CD8+ Tcells were important to control visceral
leishmaniasis84, the initial studies with L.major indicated
that CD8+ Tcells were not important for control of a primary infection but they participated in the resistance to
reinfection85. However, when mice were infected with low
doses of parasites, CD8+ Tcells appeared to be essential for resolution of primary infection86, owing in part
to the ability of IFN to promote a TH1-type response87.
Nevertheless, CD8+ Tcells are not always associated
with disease resolution. For example, the recruitment of
CD8+ Tcells that express the granule-associated serine
protease granzymeB is correlated with lesion progression
in patients infected with L.braziliensis 88. The factors that
determine when CD8+ Tcells are protective and when
they promote disease remain to be elucidated. Moreover,
it appears that CD8+ Tcell exhaustion following infection with L.donovani may contribute to the chronicity
of infection89.
As noted above, moDCs that infiltrate the lesions
appear to be particularly important in the induction
of a CD4+ TH1-type response following L.major infection. Interestingly, it was recently found that CD8+ Tcell
activation following L.major infection appears to instead

depend upon dermal DCs (defined by expression of the
Ctype lectin langerin (also known as CD207)). Thus,
when dermal DCs were specifically depleted in mice (by
administering diphtheria toxin to mice that expressed
the simian diphtheria toxin receptor under control of the
langerin promoter), CD8+ Tcell responses were significantly diminished, but CD4+ Tcell responses were not
affected90. Importantly, CD8+ Tcells that are activated
during Leishmania infections may not all be specific, as
uninfected DCs that have matured during inflammation can stimulate CD8+ Tcells to proliferate without the
expression of their cognate ligands32. The role of these
non-leishmanial-specific CD8+ Tcells in the infection is
not clear, but when previously activated CD8+ Tcells are
expanded during infection, they can provide increased
resistance to previously encountered pathogens91.
Parasite persistence. In spite of the development of a
robust immune response in resistant mice, as well as in
many patients, a small number of parasites persist following disease resolution. The production of IL10 has a
large role in dampening the immune response and thus
allowing some parasites to escape destruction. This was
shown by depleting IL10 from mice that were infected
with low doses of L.major, which led to sterile cure (that
is, no living parasites remained)92. Recent studies have
shown that IL10 can come from a variety of sources
following leishmanial infections, including regulatory T
(TReg) cells93, TH1 cells9496, CD8+ Tcells92, Bcells97, natural
killer cells98, regulatory DCs35, macrophages99 and neutro
phils100. Which of these is most important as a source
of IL10 is less clear, but may depend upon differences
in the parasites and the stages of the infection. On one
hand, IL10transgenic mice (in which IL10 is only produced in cells that express MHC class II molecules) are
extremely susceptible to infection with L.major 101. On
the other hand, a recent study in mice expressing human
IL10 (from a transgene encoded on a bacterial artificial
chromosome) suggested that IL10 production by Tcells,
rather than macrophages, may be more critical for parasite clearance102. In L.donovani infection, CD8+CD40+
Tcells may act as contra-TReg cells by limiting the production of IL10 during the early phase of infection, but
themselves become susceptible to IL10induced apop
tosis as the disease progresses103. Thus, the question of
how immunoregulatory mechanisms limit immune
responses, and as a consequence lead to the persistence
of parasites following disease resolution, remains an
area of active investigation.
When leishmaniasis involves infection of lymphoid
tissues, such as the spleen and lymph nodes, these
undergo dramatic remodelling 33,104. Although erosion of
stromal cells and vascular remodelling represent the most
likely underlying mechanism behind the loss of architectural integrity, the main functional consequence may
be to develop a state of immune suppression dependent
upon spatial segregation (REF. 105). Of note, interventions
that restore the tissue microarchitecture can have important immune restorative functions104,106. Interestingly,
recent studies suggest another instance for which the
REVIEWS
DC
Antigen presentation
CD4+ CD8+
TReg
TH1
CD8+
DC
IL-10
NK cell
Monocyte
B cell
Macrophage
Macrophage
IFN
Effector cells
Central memory
DC
Figure 6 | Cellular components of the anti-leishmanial immune response. Monocytes infiltrate the site of
Natureactivated,
Reviews | Microbiology
infection and differentiate into dendritic cells (DCs). DCs become infected but fail to become
whereas
local uninfected DCs upregulate major histocompatibility complex class II (MHC class II). Macrophages are also
infected by the parasites. Uninfected DCs may pick up dead parasites or leishmanial antigen and become the critical
antigen-presenting cells (APCs). CD4+ Tcells are then activated and differentiate into T helper (TH1) cells, which
produce interferon (IFN), and this promotes parasite killing by infected cells and also further promotes the
development of TH1 cells. Some CD4+ Tcells fail to become TH1 cells, and adopt a central memory Tcell phenotype.
CD8+ Tcells recognizing leishmanial antigens are also activated and also produce IFN. Control of the response is
largely mediated by the production of interleukin10 (IL-10), which can come from several different cell types,
including regulatory T (TReg) cells, TH1 cells, CD8+ cells, natural killer (NK) cells, Bcells, macrophages and DCs.
Concomitant immunity
A situation in which
immunological resistance to
reinfection co-exists at the
same time as persistence of
the original infection.
mechanism behind an ineffective immune response

and, hence, enhanced parasite persistence could only
have been uncovered by insitu approaches. The interactions between CD4+ Tcells and L.major-infected host
cells have been visualized using two-photon imaging in
established dermal lesions. Although many of the specific
Tcells were found to colocalize with parasite-infected
cells, there were areas of tissue where accumulations of
parasites were ignored by Tcells107. Why this is the case
remains to be determined. However, avoidance of detection at this level does not seem to occur in the case of
hepatic L.donovani infections, in which parasites are
found in defined granulomas and infiltrating effector
CD8+ Tcells appear to be readily able to seek out their
targets8.
As mentioned earlier, there have been many mechanisms described by which parasites attempt to modulate
the ability of their host cells to respond to the signals
that lead to induction of leishmanicidal activity. From
these observations one might conclude that completely
eliminating parasites may not be possible regardless of
the magnitude of the immune response. However, earlier
studies in which IL10 was eliminated have suggested that
sterile cure could be achieved in certain situations92. More
recently, in micelacking BCL-2interacting mediator of
cell death (BIM), a pro-apoptotic BCL2 family member,
not only did L.major infections resolve, but also this resolution was associated with the clearance of all detectable
parasites108. Hence, given a sufficient immune response,
sterile cure can be achieved in leishmaniasis.
Memory and vaccination. As parasites generally persist, even after apparent clinical cure, the type of immunity that is induced by Leishmania infections is akin to
concomitant immunity. The Tcell subsets that contribute
to such immunity have been characterized over the past
several years, and include CD4+ Tcells with a phenotype
of central memory Tcells109, effector TH1cells and resting
effector TH1cells110. In addition, CD8+ Tcells can have a
critical role in resistance to reinfection85. The question of
how to generate these cells by vaccination remains a challenge, as does the question of which Tcells may be most
likely to survive and provide the best protection. Recent
studies suggest that the most protective CD4+ Tcells are
those that are multifunctional, capable of producing not
only IFN, but also IL2 and TNF111. Consistent with the
findings that elimination of IL10 can promote resistance,
IL10 appears to limit the generation of these protective
Tcells during vaccination112. Unfortunately, although
several approaches have been taken to develop a vaccine
for leishmaniasis, to date none have been successful in
humans (reviewed in REFS1,113).
Concluding remarks
Challenges remain in understanding leishmanial biology, the host responses to the parasites and how to use
such knowledge to develop new ways of combating the
infection. However, advances over the past several years
provide a roadmap for future discovery. The sequencing of several leishmanial genomes provided a wealth
of information that will be used to define new drug

REVIEWS
targets, mechanisms responsible for drug resistance
and virulence factors. Species diversity within the genus
Leishmania has a major role in the manifestations of the
disease. Thus, the application of genomic approaches,
such as the rapid sequencing of parasite genomes as well
as omics analyses of the parasite and the host cell during
infection, will certainly lead to a better understanding of
the pathogenesis of all forms of leishmaniasis.
A fresh look at the monocyte, macrophage and
DC subsets that have central roles in the aetiology
of Leishmania infections, is likely to yield important
advances that will lead to new ideas for treatment. The
quest for a prophylactic vaccine continues, although
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Acknowledgments
Work in the P.K. laboratory is funded by grants from the UK

Medical Research Council and the Wellcome Trust. Work in the
P.S. laboratory is funded by grants from the National Institute
of Allergy and Infectious Diseases, US National Institutes of
Health.
Competing interests statement
The authors declare no competing financial interests.
FURTHER INFORMATION
Paul Kayes homepage:
http://www.york.ac.uk/cii/staff/academic/kaye/
Philip Scotts homepage: http://www.med.upenn.edu/apps/
faculty/index.php/g20001882/p4382139
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REVIEWS

Leishmaniasis: complexity at the

*Centre for Immunology and

Penn Institute for

Leishmaniasis is one of the most significant of the

Mycobacterium leprae, the same microorganism can cause

604 | AUGUST 2011 | VOLUME 9

Figure 1 | The life cycle of Leishmania parasites. Leishmania

Host cells for Leishmania parasites

NATURE REVIEWS | MICROBIOLOGY

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Old World, subgenus Leishmania

Leishmania donovani and Leishmania

Leishmania major, Leishmania tropica and

Diffuse cutaneous leishmaniasis

New World, subgenus Leishmania

L.infantum, Leishmania mexicana, Leishmania

Diffuse cutaneous leishmaniasis

L.mexicana and L.amazonensis

New World, subgenus Viannia

Leishmania braziliensis, Leishmania

L.braziliensis and L.panamensis

*Adapted from REF. 119.

neutrophil depletion in mice increased susceptibility to

involves pseudopodium extension25. Resident dermal

606 | AUGUST 2011 | VOLUME 9

To the lymph node?

macrophages that express epidermal growth factor-like

The intracellular fate of Leishmania parasites

NATURE REVIEWS | MICROBIOLOGY

VOLUME 9 | AUGUST 2011 | 607

Horse model referred to earlier. Maintenance of this

608 | AUGUST 2011 | VOLUME 9

similar studies examining phagosome biology in

Iron regulation in the phagosome. Although many

production of the iron-binding protein transferrin and

Subverting intracellular signalling

NATURE REVIEWS | MICROBIOLOGY

VOLUME 9 | AUGUST 2011 | 609

Figure 3 | Phagosome fate is determined by factors from

the sandfly and the cytoplasmic MSP being a pre-formed

parts of the world, also targets SHP1 at concentrations

610 | AUGUST 2011 | VOLUME 9

in ERK1- and/or ERK2dependent secretion of IL10.

TypeI interferons. TypeI IFN responses are usually

NATURE REVIEWS | MICROBIOLOGY

VOLUME 9 | AUGUST 2011 | 611

Figure 5 | Lipid microdomains during Leishmania infection of macrophages.

been, and continues to be, much interest in defining the

activation following L.major infection appears to instead

612 | AUGUST 2011 | VOLUME 9

mechanism behind an ineffective immune response

NATURE REVIEWS | MICROBIOLOGY

VOLUME 9 | AUGUST 2011 | 613

Kedzierski, L. Leishmaniasis vaccine: where are we

by Phlebotomine sandflies in Europe: a review. Euro.

614 | AUGUST 2011 | VOLUME 9

36. Gorgani, N.N., Ma, Y. & Clark, H.F. Gene signatures

NATURE REVIEWS | MICROBIOLOGY

100. Charmoy, M. etal. Leishmania major induces distinct

Work in the P.K. laboratory is funded by grants from the UK

Competing interests statement

The authors declare no competing financial interests.

VOLUME 9 | AUGUST 2011 | 615