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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.
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Proliferation in the midgut
Procyclic
promastigotes
Amastigotes
Metacyclic
promastigotes
Sandfly bite
Sandfly bite
Attachment
Reinvasion
Lysis
Phagocyte
Uptake
Proliferation
Phagolysosome
Intracellular amastigote
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.
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,
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Table 1 | The main species of Leishmania that affect humans*
Main disease manifestation
Species
Cutaneous leishmaniasis
L.aethiopica
L.infantum
Cutaneous leishmaniasis
Mucocutaneous leishmaniasis
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Tissue-resident
macrophage or DC
Sandfly
Dermis
Phagolysosome
Neutrophil
Metacyclic
promastigote
Non-leishmanicidal
vacuole
Blood vessel
moDC
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.
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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.
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,
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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.
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.
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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
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.
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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.
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
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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.
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
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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
1.
2.
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4.
5.
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7.
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whether it is possible to develop a vaccine that provides long-term protection without constant boosting
remains unknown. Nevertheless, harnessing the immune
response to control infection will require a better understanding of the various types of Tcells that promote
protection as well as pathology and that regulate
immunity to the parasite. Finally, Leishmania spp. will
continue to provide powerful tools to interrogate the
immune system, in exploring the function of myeloidlineage cells, understanding the role of innate immune
responses in both protection and pathology and defining the development and interactions between effector,
regulatory and memory Tcells.
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Acknowledgments
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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