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IMMUNITY TO FUNGAL INFECTIONS


Luigina Romani
The topic of immunity to fungal infections is of interest to a wide range of disciplines, from
microbiology to immunology. It is of particular interest in terms of therapy of HIV-infected
individuals, and patients with cancer or individuals who have received transplants.
Understanding the nature and function of the immune response to fungi is an exciting
challenge that might set the stage for new approaches to the treatment of fungal diseases,
from immunotherapy to vaccines. The past decade has witnessed the development of a wide
range of new approaches to elucidate events that occur at the hostfungus interface.

COMMENSALS The kingdom of Fungi comprises many species that are prominent features are also important: the highly
Two organisms that live in a close associated with a wide spectrum of diseases in effective strategies of immune evasion they must have
relationship, in which one benefits humans1 (BOX 1). The clinical relevance of fungal evolved to survive in the host environment and the
by the relationship and the other
diseases has increased enormously in the second half of prolonged antigenic stimulation of the host that can
neither benefits nor is harmed.
the twentieth century, mainly because of an increasing have marked immunoregulatory consequences. So, in
population of immunocompromised hosts, including the context of the antagonistic relationships that char-
individuals infected with HIV, transplant recipients acterize hostpathogen interactions, the strategies used
and patients with cancer24. The fungal threat will con- by the host to limit fungal infectivity are necessarily
tinue to increase, as shown by the occurrence of distinct and, in retaliation, fungi have developed their
aspergillosis in severe acute respiratory syndrome own elaborate tactics to sidestep these defences1. This
(SARS)5 and by the inclusion of Coccidiodes immitis as highlights the complexity of the relative contributions
a potential agent of bioterrorism6. The crude mortality of individual aspects of host defences in limiting fungal
from opportunistic fungal infections still exceeds 50% infectivity. However, as immune restoration after com-
in most human studies, and has been reported to be as bination antiretroviral chemotherapy has been shown
high as 95% in bone-marrow transplant recipients to limit fungal infections in HIV-positive individuals4,
infected with Aspergillus species. Therefore, the study manipulation of the immune system could be a candi-
of fungi is a research priority. Because fungal date for future strategies aimed at preventing or treating
pathogens are eukaryotes, and therefore share many of fungal infections in susceptible patients. In this review,
their biological processes with humans, many antifungal I outline cellular and molecular pathways of immune
drugs can cause toxicity when used therapeutically7. defence mechanisms that have greatly contributed to
No standardized vaccines exist for preventing any of our present understanding of the host response to
the human infections caused by fungi a situation fungi from a regulatory perspective, and have been
that is attributable to both the complexity of the most helpful in accommodating the clinical findings in
pathogens and their sophisticated strategies for surviv- a conceptual framework that is amenable to strategies
Department of
Experimental Medicine ing in the host and evading immune responses (BOX 2). of immunointervention.
and Biochemical Sciences, Although not unique among infectious agents, fungi
Microbiology Section, have complex and unusual relationships with the verte- Immunity to fungi
University of Perugia, brate immune system, partly due to some prominent It is known that host defence mechanisms influence
Via del Giochetto,
06122 Perugia, Italy.
features. Among these are their ability to exist in differ- the manifestation and severity of fungal infections,
e-mail: lromani@unipg.it ent forms and to reversibly switch from one to the such that the clinical forms of the disease depend on a
doi:10.1038/nri1255 other during infection (BOX 2). For COMMENSALS, two patients immune response. For example, the host

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Innate immunity
Box 1 | The pathogenesis of typical fungal infections
Traditionally considered only as a first line of defence,
Most fungal infections are accidental and originate from an exogenous source by innate immunity has recently received renewed atten-
inhalation (Aspergillus spp., Cryptococcus neoformans or endemic mycoses), the gastro- tion because, despite a certain lack of specificity, it
intestinal tract for commensals (Candida spp.) or reactivation of a latent infection. effectively distinguishes self from non-self and acti-
Aspergillus fumigatus vates adaptive immune mechanisms by the provision
Alveolar macrophages ingest and destroy inhaled conidia and prevent germination of specific signals15. The constitutive mechanisms
to branching and septate hyphae, which is the invasive form that is associated with of innate defence are present at sites of continuous
fatal infection. Fungal proteases might enable conidia to evade phagocytosis and interaction with fungi and include the barrier function
killing. of body surfaces and the mucosal epithelial surfaces of
As a second line of defence, neutrophils attack hyphae through the release of oxidants the respiratory, gastrointestinal and genito-urinary
and degranulation. tracts (reviewed in REF. 16). Microbial antagonism
Pulmonary dendritic cells (DCs) ingest conidia and hyphae, migrate to draining lymph (lactobacilli and bifidobacteria have shown efficacy in
nodes and instruct local disparate T helper (TH)-cell responses. the biotherapy of candidiasis), DEFENSINS and COLLECTINS
indicate the marked pathogen specificity of the consti-
Cryptococcus neoformans tutive mechanisms1719. Most host defence mecha-
The monomorphic yeast typically causes primary pulmonary infections, from where nisms, however, are inducible after infection and,
haematogenous spread to the meninges might occur together with defective TH1-cell- therefore, their activation requires that invariant mole-
mediated immunity. cular structures shared by large groups of pathogens
The most distinctive feature of this fungus is the presence of an acidic mucopolysaccharide (also known as pathogen-associated molecular
capsule, which is required for virulence and is important diagnostically. patterns, PAMPs) are recognized by a set of pattern
Endemic mycoses recognition receptors (PRRs), including Toll-like
Primary pulmonary infection occurs as a result of inhalation of conidia, which then receptors (TLRs), as discussed later.
convert to the pathogenic yeast form or to spherules (in the case of Coccidiodes immitis). Mammalian innate antifungal defences are mediated
by cells, cellular receptors and several humoral factors.
Yeasts survive and replicate in host macrophages through several evasion strategies
Professional phagocytes, consisting of neutrophils,
that include defective phagosomelysosome fusion, regulation of phagosomal pH, iron
restriction, suppression of the respiratory burst and dysregulated production of pro- mononuclear leukocytes (monocytes and macrophages)
inflammatory cytokines. and dendritic cells (DCs) have an essential role. Natural
killer (NK) cells, T CELLS and non-haematopoietic cells,
Patients with defective TH1-cell-mediated immunity might suffer life-threatening
such as epithelial and endothelial cells, are also impor-
progression or reactivation of latent foci of infection.
tant16. However, their relative contributions largely
Candida albicans depend on the site of infection. The innate response to
The clinical spectrum of C. albicans infections ranges from mucocutaneous to fungi serves two main purposes: a direct antifungal effec-
systemic life-threatening infections. The main risk factors that predispose to severe tor activity by carrying out pathogen destruction through
candidal infections are congenital or acquired defects of cell-mediated immunity, either a phagocytic process, which provides an immediate
including quantitative and qualitative defects in neutrophils and dysregulated innate cellular immune response against fungi residing
TH-cell reactivity. intracellularly, or through the secretion of microbicidal
In histopathological sections, budding yeast cells, PSEUDOHYPHAE and HYPHAE can be compounds against uningestible fungal elements; and an
seen. In mice, both yeasts and hyphae translocate across the gastrointestinal tract and instructive role on cells of the adaptive immune system,
might eventually gain access to blood vessels. through the production of pro-inflammatory mediators,
Gut DCs phagocytose both fungal morphotypes and instruct local and systemic TH-cell including chemokines and cytokines, the induction of
responses. In the presence of protective opsonizing IgM, gut DCs produce interleukin-10 co-stimulatory activity by phagocytic cells, and antigen
and activate regulatory T (TReg) cells that negatively regulate antifungal TH1-cell uptake and presentation. Although a division of labour
reactivity. By providing signals to different T-cell subsets, including TH and TReg cells, exists among the cellular mediators of the innate system,
DCs coordinate the overall immune response at the sites of colonization/infection. the perception is that they might share the ability to
serve both functions of the innate immune response.
This might allow for full use of redundancy and com-
PSEUDOHYPHAE immune system is a major determinant of which par- pensatory mechanisms under specific conditions of
An exaggerated form of budding ticular form of disease will develop after exposure to infection and disease.
in which the newly formed cells the ubiquitous organism Aspergillus fumigatus8 or
do not take on an oval shape and
whether transition from commensalism to infection The TLRPAMP recognition system. Mammalian
pinch off from the parent, but
instead remain attached and will occur with Candida albicans9,10. The host defence TLRs are a family of conserved cellular receptors that
continue to elongate. mechanisms against fungi are numerous, and range mediate cellular responses to PAMPs and other lig-
from protective mechanisms that were present early in ands20. Toll was originally defined as a Drosophila gene
HYPHAE
the evolution of multicellular organisms (innate that was important for ontogenesis and antimicrobial
In moulds, spores germinate
to produce branching filaments
immunity) to sophisticated adaptive mechanisms, resistance21. The sequence similarity of the cytoplas-
known as hyphae (singular which are specifically induced during infection and mic portion of Drosophila Toll and the intracellular
hypha), ~2 to 10 m in disease (adaptive immunity). The T HELPER 1 (TH1)/TH2 domains of mammalian interleukin-1 receptor
diameter, which might form dichotomy has shed light on the general principle that (IL-1R) indicated similarities in Toll and IL-1R sig-
a mass of intertwining strands
diverse effector functions are required for eradication nalling and illustrated the evolutionary conservation
known as mycelia.
of different fungal infections1114. of both cell-signalling systems22.

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All TLRs activate a core set of stereotyped Several cell-wall components of fungi might act as
responses, including inflammation. However, individ- PAMPs that are recognized by TLRs expressed by phago-
ual TLRs can also induce specific programmes in a cytes and DCs (FIG. 1). TLR2 signalling leads to the preva-
myeloid differentiation primary response gene 88 lent production of inflammatory cytokines, such as
(MYD88)-dependent22 or -independent manner23 tumour-necrosis factor (TNF) and IL-1, although IL-10
in cells of the innate immune system that are tailored is also produced occasionally2428. Signalling through
for a particular pathogen. It is recognized that the TLR2 by zymosan occurs together with the -glucan
intricacies of how TLRs signal will ultimately provide receptor dectin-1 (REF. 26), which indicates collaborative
an explanation for the molecular basis of how cells recognition of distinct microbial components by differ-
involved in innate immunity dictate the processes of ent classes of innate immune receptors. Although not
host defence that are specific to the provoking formally proven, dectin-1 also seems to mediate the
pathogen22. recognition of Pneumocystis carinii -glucan, which is

Box 2 | Fungal infections: morphogenesis and virulence

Dimorphic fungi Opportunistic fungi

25C 37C Budding yeast


Blastomyces Candida
T HELPER 1 (TH1)/TH2 CELLS dermatitidis albicans
Functional subsets of CD4+ Pseudohypha
T cells that express -T-cell
receptors. They produce either Parent
type-1 cytokines (such as IL-2 yeast cell Germ-tube
and IFN-) that support Coccidiodes
macrophage activation, the immitis
Hypha
generation of cytotoxic T cells
and the production of
opsonizing antibodies or type-2 Cryptococcus
cytokines (such as IL-4, IL-5 neoformans Capsule
and IL-13) that support B-cell
Histoplasma
activation, the production of capsulatum
non-opsonizing antibodies,
allergic reactions and the Conidia
expulsion of extracellular
parasites.
Paracoccidioides Aspergillus
brasiliensis umigatus
DEFENSINS
Small basic peptides produced
by immune cells that are
microbicidal and work by
damaging bacterial membranes.
Humans are constantly exposed to fungi, but only a limited number of fungi cause severe infections. So, pathogenicity is
not a stable characteristic of most fungi. The pathogenesis of fungal infections involves several virulence factors that allow
COLLECTINS fungal survival and persistence in the host, eventually leading to tissue damage. Some virulence factors are of obvious
A family of proteins so named importance, such as: various complementary structures through which fungi adhere to host tissues and the extracellular
because they contain both matrix; the production of phospholipases, proteases and elastases that cause tissue damage and impairment of host
collagen-like sequences and defences; the ability to switch to metabolic pathways that are required for intracellular survival; thermotolerance
calcium-dependent lectin
domains. The collectins bind
(the ability to grow at 37C), which is a prerequisite for dissemination to visceral organs; and the ability to exist in
to various carbohydrates different forms and to reversibly switch from one to the other during infection122124.
present on the surfaces of Examples of the latter are the dimorphic fungi, which transform from saprobic filamentous moulds to unicellular yeasts
microorganisms through their in the host. Also, some species of Candida can grow in different forms, such as yeasts, blastospores, pseudohyphae and
lectin domains and also interact hyphae, depending on infection sites. Cryptococcus neoformans yeasts become coated with a capsule, and the filamentous
with cell-surface receptors on fungi (for example, Aspergillus spp., Fusarium spp. and Zygomycota), which are inhaled as unicellular conidia, can
phagocytic cells to promote
the uptake of bound particles.
transform into branching hyphae in the lungs. Although such morphogenesis is an example of a developmental change,
it is distinct from the life cycles that are displayed by other organisms, as there is no evidence that cycling between different
T CELLS morphotypes is obligatory for fungi. Instead, morphological transition, often connected with metabolic flexibility, is a
T cells express a T-cell receptor mechanism that some fungi have evolved to adapt to different environments.
(TCR) composed of either - Associations between morphogenesis and virulence have long been presumed for dimorphic fungi that are human
and -subunits (-TCR) or of pathogens, as one morphotype exists in the environment or during commensalism, and others in the host during
- and -subunits (-TCR).
Most (>90%) T cells have an
the disease process125. However, although morphological flexibility could be a key contributor to fungal invasion,
-TCR that recognizes no molecular data unambiguously establish a role for fungal morphogenesis as a virulence factor126. In addition, as
conventional MHC class I or II virulence genes are co-regulated with cell morphogenesis, the ability to switch from yeast to hyphal growth in response
molecules. T cells that express to various environmental signals is considered to be inherent to Candida virulence. Both yeast and hyphal forms
-TCRs are less frequent and of fungi clearly have a wide range of attributes that contribute actively to fungal infectivity. Undoubtedly, fungal
the ligands of this type of morphogenesis, through antigenic variability, phenotypic switching and dimorphic transition, implicates the existence
receptor are less well
characterized.
of many recognition and effector mechanisms to oppose fungal infectivity at the different body sites.

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resistance to C. albicans and A. fumigatus34. The


PLM GXM
C. albicans yeasts C. albicans hyphae MYD88-dependent pathway is also essential for innate
A. fumigatus conidia A. fumigatus hyphae resistance to C. albicans, but not to A. fumigatus, which
A. fumigatus hyphae Mannan
is in line with the unaltered handling of the fungus by
C. albicans
Zymosan -glucan C. albicans MYD88-deficient macrophages35. Intriguingly,
C. albicans -glucan
yeasts and P. carinii A. fumigatus
C. albicans
Drosophila Myd88, although required for antifungal
hyphae defence, is unable to induce expression of the anti-
fungal peptide drosomycin in the absence of other
dectin-1
IL-1RI TLR2 ? CD14 TLR4 TLR9 adaptors36. The contribution of individual TLRs to the
MD2 immune response might vary depending on fungal
Cell surface
species, fungal morphotypes and route of infection.
Cytoplasm For example, signalling by C. albicans essentially occurs
through IL-1R (a finding that is consistent with the
occurrence of IL-1 in infection16) and by A. fumigatus
through TLR4, and TLR2 and TLR4 are both impli-
MYD88-dependent signal transduction cated in different ways in the control of disseminated
or mucosal infections with C. albicans34.
Individual TLRs and IL-1R also activate specialized
Production of pro-inflammatory cytokines antifungal effector functions of neutrophils that corre-
Production of IL-12 by dendritic cells late with susceptibility to infection34. TLR expression
Induction of respiratory burst and degranulation
T helper 1 (TH1)-cell differentiation by neutrophils exposed to C. albicans and A. fumigatus
is induced in a morphotype-specific manner. Although
Figure 1 | Role of TLRs as activators of innate and adaptive immunity to fungi. they do not affect phagocytosis, TLRs affect specific
The recognition of fungi and fungal pathogen-associated molecular patterns (PAMPs), mainly
antifungal programmes of neutrophils, such as the
associated with fungal cell walls, leads to the activation of antifungal effector functions in
phagocytes, such as respiratory burst and degranulation, and production of interleukin-12p70 respiratory burst and degranulation34. As the quantity
(IL-12p70) by dendritic cells (see text). This leads to inflammatory and protective antifungal and specificity of delivery of toxic neutrophil products
T helper 1 (TH1)-cell responses. The canonical signalling pathway for mammalian Toll-like ultimately determine the relative efficiency of fungi-
receptors (TLRs) and IL-1 receptor (IL-1R) after ligation of PAMPs involves interaction with the cidal activity versus inflammatory cytotoxicity to host
adaptor molecule MYD88 (myeloid differentiation primary response gene 88) located in the cells, this indicates that TLRs might govern protection
cytosol. The activation of the MYD88 adaptor culminates in the activation and nuclear
and immunopathology at the level of the innate
translocation of nuclear factor-B (NF-B) and subsequent gene activation. Additional
pathways, including the MYD88-independent pathway, are yet to be explored in response to
immune response.
fungi. GXM, glucoronoxylomannan from Cryptococcus neoformans; PLM, phospholipomannan The emerging picture indicates an essential require-
from Candida albicans; Aspergillus fumigatus; Pneumocystis carinii. ment for the IL-1R1MYD88-dependent pathway in
innate and TH1-cell-mediated resistance to C. albicans,
and the crucial, although not obligatory, involvement of
CONIDIA known to signal through the MYD88-dependent path- the TLR4MYD88 pathway in resistance to A. fumigatus.
Externally borne asexual spores way29. It is of interest that Aspergillus hyphae, unlike TLR signalling occurs in a morphotype-specific manner,
produced by filamentous fungi. CONIDIA, seem to be sensed by human monocytes although the simultaneous ligation of many TLRs, as well
Conidia of different shape and
through TLR4 and CD14 (REF. 30), which indicates that as TLR cooperativity in vivo, make it difficult to gauge the
size easily disseminate into the
environment. TLRs discriminate between distinct fungal morpho- relative contributions of individual fungal morphotypes
types. However, as Aspergillus hyphae might also evade in TLR activation and functioning. Also, TLRs have
DIMORPHISM TLR recognition31, this indicates that TLR recognition different effects on the occurrence of innate and adaptive
The ability of some fungi to cycle of only selected fungal morphotypes might contribute TH1-cell immunity to each fungus, which is consistent
reversibly between yeast and
hyphal forms.
to the survival of fungi in vivo. TLR4 and CD14 also with the ability of individual TLRs to activate specialized
mediate the recognition of Saccharomyces cerevisiae- antifungal effector functions in neutrophils and DCs34.
OPSONINS and C. albicans-derived mannan32 and of glucoronoxy-
Substances, usually antibodies lomannan33 (a major component of the capsule of Antifungal effector activity. The antifungal effector
or complement components,
Cryptococcus neoformans). The finding that glucoro- functions of phagocytes include killing and growth
that coat a particle such as a
microorganism and enhance noxylomannan only partially activates TLR-dependent inhibition of fungi, as well as pathways to oppose fungal
phagocytosis by phagocytic signal transduction pathways might account for its infectivity, including effects on DIMORPHISM and pheno-
cells. immunosuppressive and immunodysregulatory effects typic switching16. Although, in general, phagocytes have
on the host. Although TNF and IL-1 production in intrinsic antifungal activity, this activity can be
OXIDATIVE
The production of oxidizing
response to C. albicans might also occur in a TLR4- increased by OPSONINS and T-cell-derived cytokines,
agents, such as reactive oxygen independent manner, resistance to infection is which indicates that the innate and adaptive immune
and nitrogen intermediates, by decreased in TLR4-deficient mice, together with the systems do not work independently, but are reciprocally
effector phagocytes. release of chemokines25. Therefore, TLR2 and TLR4 regulated14,16. The optimal restriction of fungal growth
are both involved in inducing host defences to the occurs through a combination of OXIDATIVE and comple-
fungus, a finding that exemplifies the recruitment of mentary non-oxidative mechanisms, the latter consist-
different TLRs by one microbial species. Our own ing of degranulation and intracellular or extracellular
studies indicate that the MYD88-dependent pathway release of effector molecules, defensins and neutrophil
in DCs is required for adaptive TH1-cell-mediated cationic peptides, and iron sequestration16. Enzymes

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CHRONIC GRANULOMATOUS such as the nicotinamide adenine dinucleotide regulation of T-cell function44. Myeloid suppressor cells
DISEASE phosphate (NADPH) oxidase and inducible nitric are responsible for the immunosuppression observed in
A primary immunodeficiency oxide synthase initiate the oxidative pathways known as pathologies as varied as tumour growth, overwhelming
that affects phagocytes. It is
respiratory burst. The respiratory burst produces toxic infections, graft-versus-host disease and pregnancy44. A
characterized by a greatly
increased susceptibility to severe reactive oxygen intermediates (ROIs), the nature of population of neutrophils that suppress TH1-cell activa-
bacterial and fungal infections. which varies depending on the nature of pathogens and tion is present in bone-marrow-transplanted mice with
the type of phagocytic cell. ROIs damage fungi by pro- candidiasis45, which indicates that myeloid suppressor
YEASTS
ducing protein modifications, nucleic-acid breaks and cells might prevent functional immunoreconstitution in
Unicellular oval or spherical
cells, usually about 3 to 5 m
lipid peroxidations37. The production of ROIs is initi- transplantation. The reciprocal influence between neu-
in diameter, that reproduce ated by microbial products, such as lipopolysaccharide trophils and T cells further implies that immunity to
asexually by processes known (LPS), and is potentiated by opsonins and cytokines16. fungi is a highly coordinate and unitary process.
as blastoconidia formation In retaliation, fungi have evolved strategies to selectively Macrophages are a heterogeneous population of
(budding) or fission.
inhibit the respiratory burst through the production of tissue-resident cells that express the machinery for anti-
specific scavengers of oxidative killing by phagocytes, gen presentation; however, their main contribution to
such as catalase, mannitol and melanin38. Patients with antifungal defence is phagocytosis and killing of fungi37,46.
inherited X-linked CHRONIC GRANULOMATOUS DISEASE, result- Not surprisingly, therefore, fungi have various mecha-
ing from a deficiency in oxidant formation due to nisms or putative virulence factors to evade phagocytosis,
mutations in any of the four genes that encode the sub- escape destruction and survive inside macrophages38,4751.
units of NADPH oxidase39, have increased susceptibility Macrophages serve as a protected environment in which
to aspergillosis, but could benefit from interferon- the dimorphic fungi multiply and disseminate from the
(IFN-) therapy40. Moreover, transplantation of bone- lungs to other organs. Histoplasma capsulatum is
marrow cells transfected with the gene encoding an example of a successful intracellular pathogen of
NADPH oxidase restored fungicidal activity of mice with mammalian macrophages50.
chronic granulomatous disease a finding that opens Complement, collectins and antibodies promote
up the possibility for gene therapy in fungal infections41. binding (opsonization) and recognition of fungi by
The fact that not only quantitative42, but also qualita- various receptors16. A member of the collectin family,
tive43 defects in neutrophils are important predisposing pentraxin 3, is required for prompt handling of
factors to certain disseminated fungal infections points Aspergillus conidia by alveolar macrophages, such that
to a functional versatility of neutrophils in fungal dis- its deficiency is linked to the susceptibility to infection
eases. Their functions might well go beyond microbici- of otherwise immunocompetent mice18. The specific
dal activity, to include an immunoregulatory action on biological activities of the complement system and
TH cells. Accumulating evidence indicates that cells of antibodies that contribute to host resistance are multi-
the myeloid lineage are capable of positive and negative faceted and interdependent52,53. For example, antibodies
contribute to the activation of the complement system
Box 3 | Antibodies in immunity to fungi
by fungi52 and complement is essential for antibody-
mediated protection54. Studies with C. neoformans have
The main recognized functions of antibodies in fungal infections include: prevention shown that the high levels of carbon dioxide in the
of adherence, toxin neutralization, opsonization and antibody-dependent cellular lungs favour capsule formation, which impairs phago-
cytotoxicity53. However, the absence of an association between deficiencies in cytosis in the absence of anticapsular antibodies55 that
antibodies and susceptibility to fungal infections and the presence of specific antibodies can alter the conformation of the capsule and so favour
in patients with progressive fungal infections53 have provided evidence against a direct binding and phagocytosis of YEASTS56,57. However,
protective role of antibodies in fungal infections. Recent advances in the field show that: antibodies have shown disparate biological effects in
both protective and non-protective antibodies against fungi can be shown, the relative fungal infections a finding that is consistent with the
composition and proportion of which might vary greatly53,58,127; evidence that both protective and non-protective anti-
the amount, specificity, isotype and idiotype of antibodies have marked effects on bodies are induced during infection53,58. For this reason,
protective efficacy53; interest in antibodies has recently seen a resurgence to
antibodies specific for heat-shock protein 90 are associated with recovery from identify those that positively modulate infection (BOX 3).
infections with Candida albicans and protection against disseminated disease in Complement, antibodies and collectins not only fulfil
patients with AIDS, and they synergize with antifungal chemotherapy128; the requirement of a first line of defence against fungi,
antibodies specific for a mannan adhesin fraction passively transfer protection against but also have an impact on the inflammatory and
candidiasis in mice129; adaptive immune responses, through several mecha-
idiotype-specific antibody or single chains thereof have broad fungicidal activity and nisms, including regulation of cytokine secretion and
therapeutic efficacy in experimental infections130,131. co-stimulatory molecule expression by phagocytes59,60.
Each receptor on phagocytes not only mediates
Research is now in progress to identify antibodies that are protective, the peptide
distinct downstream intracellular events related to
mimetics that specifically elicit them and putative candidate vaccines that elicit
clearance of fungi, but it also participates in complex
protective immunity. Nevertheless, given the interdependency between humoral and
cellular immunity in infections, a division of labour might be conceptually inconsistent
and disparate functions related to immunomodula-
with the experimental observations that an intact T-cell function is required for tion and activation of immunity, depending on the
antibody-mediated protection and that antibodies might have an influence over the cell type. The receptors for different complement
TH1/TH2-type cytokine balance and the induction of regulatory T cells. breakdown products (complement receptors, CRs),
mannosylfucosyl glycoconjugate ligands (mannose

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receptors, MRs) and -glucan (dectin-1) act as early fungi. IL-10 is readily produced by neutrophils,
warning systems and, not surprisingly, their ability to macrophages, DCs and REGULATORY T (T ) CELLS, and it has
REG

activate, in isolation, various effector functions is lim- a crucial role in determining susceptibility to fungal
ited. With a few exceptions61, internalization through infections. IL-10 is produced in a morphotype-specific
constitutively competent MRs does not lead to effec- manner and acts by impairing the antifungal effector
tive clearance of fungi in the absence of opsonins. functions of phagocytes, the secretion of pro-
However, MRs expressed by DCs activate specific pro- inflammatory cytokines, such as TNF, IL-1, IL-6 and
grammes that are relevant to the development of anti- IL-12, and protective cell-mediated immunity. The
fungal immune responses (see later). Ligation of CR3 finding that fungal pneumonia can occur after TNF-
(also known as CD11b/CD18) is one of the most effi- ablation therapy underscores the pivotal role of pro-
cient means of engulfing opsonized fungi, but it also inflammatory cytokines in the control of infection66,67.
has broad recognition capacity for diverse fungal lig- However, later in the course of an infection, high-level
ands. The multiplicity of binding sites and the exis- production of IL-10 might be beneficial by contribut-
tence of different activation states enable CR3 to ing to resolution of the inflammatory response.
engage in disparate (positive and negative) effector Circumstantial evidence indicates that IL-10 produced
activities against fungi. So, because signalling through by cells of the innate immune system is responsible for
CR3 might not lead to phagocyte activation without the prevention of excessive activation of innate effector
the concomitant ligation of receptors for the Fc portion functions, whereas IL-10 secreted by TReg cells is mainly
of immunoglobulins (FcRs), this might contribute to responsible for the establishment of commensalism
intracellular fungal parasitism. It is of interest, there- and, perhaps, fungal latency and persistence68.
fore, that H. capsulatum uses this receptor to gain entry Virtually all fungi that infect humans induce the
into macrophages, where it survives62, and not into production of IL-12 by phagocytes and DCs69. Similar to
DCs63, where it is rapidly degraded. Similarly, Candida IL-10, IL-12 is produced in a morphotype-dependent
enters through CR3 to survive inside DCs (discussed manner, through the use of different recognition recep-
later). By contrast, ligation of FcRs is usually sufficient tors and TLRs34. For example, its production is inhibited
to trigger phagocytosis, a vigorous oxidative burst and by CR3 ligation on macrophages by H. capsulatum70 and
the generation of pro-inflammatory signals. Ultimately, on DCs by C. albicans (see later). IL-12, together with
the recognition of antibody-opsonized particles is a IL-18, induces IFN- a key cytokine in the innate con-
high-level threat. It is of interest that FcR-mediated trol of fungal infections in mice and humans69. IFN-,
phagocytosis might rescue suppression of the respira- produced by T and NK cells, stimulates migration, adher-
tory burst, which indicates one possible mechanism ence, phagocytosis and oxidative killing of neutrophils
by which T and B cells enhance the antifungal activity and macrophages, and sustains TH1-cell reactivity by its
of macrophages and might explain the failure of ability to maintain IL-12 responsiveness in CD4+ T cells.
macrophages from HIV-infected subjects to oppose IFN- restores resistance to fungi in patients with chronic
fungal infectivity efficiently (reviewed in REF. 16). granulomatous disease40 and, as an adjunctive therapy,
potentiates the efficacy of antifungal chemotherapy71.
The instructive role of innate immunity. The instructive Deficient IFN- receptor-mediated signalling occurs in
role of the innate immune system in the adaptive neonates and might predispose to fungal infections72.
immune responses to fungi occurs through fungal However, experimental evidence indicates that IFN-
growth restriction as CD4+ TH-cell differentiation might not work in a TH2 setting12 a finding that under-
in vivo is affected by antigen load expression of co- scores the requirement for critical interpretation of the
stimulatory molecules by phagocytic cells, and levels of IFN- production in clinical settings.
chemokine and cytokine production (reviewed in REF. 64).
The local release of these effector molecules regulates cell DCs as an interface between host and fungi
trafficking by various types of leukocyte, therefore initiat- DCs acquire antigens in peripheral tissues and, as they
ing an inflammatory response, activating phagocytic cells mature, migrate to the T-cell areas of lymphoid
to a microbicidal state and directing TH-cell development. organs, providing T cells with the appropriate signals.
The inflammatory response to fungi might serve to As DCs express several TLRs, they are the main con-
limit infection, but might also contribute to patho- nectors of the innate and adaptive immune systems. DCs
genicity, as documented by the occurrence of severe are uniquely adept at decoding the fungus-associated
fungal infections in patients with immuno- information and translating it into qualitatively differ-
reconstitution disease65. These patients might experi- ent adaptive TH-cell immune responses73. TLRs and
ence intractable fungal infections despite recovery other PRRs determine the functional plasticity of DCs in
from neutropaenia and the occurrence of adaptive response to fungi and contribute to the discriminative
immune responses. Therefore, recovery from infec- recognition of different fungal morphotypes. DCs
tion might not only depend on effector-cell function, (both human and mouse) are now known to recognize
but also on resolution of the inflammatory process. and internalize several fungi, including A. fumigatus,
REGULATORY T (TREG) CELLS Transforming growth factor- (TGF-) and IL-10 are C. albicans, C. neoformans, H. capsulatum and
TReg cells are CD4+CD25+
cells that regulate the balance
potent immunosuppressive cytokines, with beneficial Malassezia furfur14,37,73. C. albicans proved to be a use-
between immunity and and detrimental effects on host responses to fungi. ful pathogen model to dissect events that occur at the
immunopathology. IL-10 is a double-edged sword in the fight against fungusDC interface74,75. A unique feature of DCs is

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Candida yeasts Candida hyphae Aspergillus conidia Aspergillus hyphae

Mouse immature
dendritic cells
phagocytose the
different fungal
morphotypes

Coiling phagocytosis Zipper-type phagocytosis Coiling phagocytosis Zipper-type phagocytosis

...through different
phagocytic modalities

MHC class II molecules MHC class II molecules MHC class II molecules MHC class II molecules
...undergo Co-stimulation Co-stimulation Co-stimulation Co-stimulation
functional maturation... IL-12 production IL-4/IL-10 production IL-12 production IL-4/IL-10 production

...and instruct
protective TH1- and
non-protective
TH2-cell responses.

Frequency of IFN--producing TH1 cells Frequency of IL-4-producing TH2 cells

Figure 2 | The interaction of dendritic cells with fungi: a host perspective of fungal virulence. Dendritic cells (DCs) are
unique phagocytic cells as they can phagocytose different fungal morphotypes of Candida albicans and Aspergillus fumigatus,
as shown by the confocal microscopy (top panels). Candida images reproduced from REF. 74 with permission The Rockefeller
University Press (2003). Aspergillus images reproduced, with permission, from REF. 114 The American Association of
Immunologists, Inc. (2002). Transmission electronic microscopy indicates that the uptake of the different fungal elements occurs
through different forms of phagocytosis. Internalization of yeasts and conidia occurs mainly by coiling phagocytosis, which is
characterized by the presence of overlapping bilateral pseudopods, that leads to a pseudopodal stack before transforming into
a phagosome wall. By contrast, entry of hyphae occurs by a more conventional, zipper-type phagocytosis, characterized by the
presence of symmetrical pseudopods, which strictly follows the contour of the hyphae before fusion. As DCs are equipped with
pattern-recognition receptors such as Toll-like receptors, they can decode the fungus-associated information and translate it into
qualitatively different adaptive T helper (TH)-cell immune responses. The ligation of distinct receptors by yeasts/condida and hyphae
translates into downstream signalling events, ultimately regulating co-stimulation, cytokine production and the development of
TH and regulatory T cells an event that is greatly influenced by fungal opsonins (see text). The functional plasticity of DCs at the
pathogenimmune system interface might offer new clues to fungal virulence. IFN-, interferon-; IL, interleukin.

their ability to internalize different fungal morphotypes. entry of fungus through CR3. Co-ligation of CR3 with
For example, DCs internalize Candida yeasts, Aspergillus FcR, as in the phagocytosis of hyphae or opsonized
conidia and hyphae of both (FIG. 2). Phagocytosis occurs yeasts, results in the production of IL-4 and/or IL-10,
in distinct ways and involves different recognition upregulation of co-stimulatory molecules and MHC
receptors. Recognition and internalization of yeasts and class II molecules, and activation of TH2/TReg cells68.
conidia occurs mainly by COILING PHAGOCYTOSIS, through Signalling through the MYD88 pathway is required for
the ligation of MRs of different sugar specificity, the production of IL-12 by DCs in response to Candida
COILING PHAGOCYTOSIS
A mechanism for the uptake DC-SIGN and, partly, CR3. By contrast, entry of hyphae yeasts and Aspergillus conidia with the implication of
of eukaryotic microorganisms occurs by a more conventional, ZIPPER-TYPE PHAGOCYTOSIS, distinct TLRs (IL-1RI and TLR9 for Candida and TLR4
by phagocytic cells, in which and involves the cooperative action of FcR and CR3 and TLR9 for Aspergillus); however, TLR2, but not
unilateral pseudopods of the (REF. 68). Phagocytosis of either fungal form does not MYD88, signalling is required for IL-10 production34.
phagocytes wrap around
microorganisms in multiple
require TLR2, TLR4, TLR9 or MYD88 (REF. 34). Opsonins greatly modify receptor usage on DCs by
turns, giving rise to largely self- The ligation of distinct receptors by yeasts and the different fungal morphotypes and qualitatively
apposed pseudopodal surfaces. hyphae translates into downstream signalling events, affect DC activation. Mannose-binding lectin (MBL)
ultimately regulating cytokine production and co- opsonization, for example, increases the uptake of
ZIPPER-TYPE PHAGOCYTOSIS
stimulation an event that is greatly influenced by yeasts through CR3 and prevents DC activation and
A mechanism of phagocytosis
of pathogens, which occurs by fungal opsonins68. Entry through MRs results in the the production of IL-12 (REF. 68). It is of interest that
sequential interactions between production of pro-inflammatory cytokines, including collectins seem to favour phagocytosis of fungus with-
receptors and ligands on the IL-12, upregulation of co-stimulatory molecules and out inducing the production of cytokines an activ-
surfaces of the phagocytes and MHC class II molecules, and activation of protective ity that is compatible with a primitive mechanism of
pathogens. Consequently, the
engulfing pseudopods strictly
TH1-cell responses. MRs are also required for the entry of host defence and in line with their ability to down-
follow the contour C. neoformans into DCs and the activation of antifungal regulate the inflammatory response to fungi59. These
of the particle. TH1-cell responses76,77. These events are suppressed after results might explain the increased susceptibility to

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fungal infections of patients with defective MBL78 or or results in mild infection that confers protective
MBL gene polymorphisms79. Antibodies can also subvert immunity. For C. neoformans, the high prevalence of
the entry of yeasts and hyphae68,80. A notable and impor- antibodies specific for cryptococcal antigens in normal
tant feature of Peyers patch DCs is the production of individuals indicates that primary infection is followed
IL-10 in response to Candida an event that occurs by by fungal growth restriction and lifelong immunity.
signalling through CR3 and that requires the presence of Underlying acquired immunity to C. albicans, such as
opsonizing antibodies80. These IL-10-producing DCs the presence of a positive DELAYED-TYPE HYPERSENSITIVITY
activate CD4+CD25+ TReg cells that negatively affect anti- (DTH) response, is demonstrable in adult immuno-
fungal TH1-cell reactivity (see later). So, by subverting competent individuals, and is presumed to prevent
the morphotype-specific programme of activation of progression from mucosal colonization to sympto-
DCs, opsonins might qualitatively affect DC function and matic infection. Lymphocytes from healthy individuals
TH-cell differentiation in vivo, ultimately impacting on show proliferative responses after stimulation with
fungal virulence. It is conceivable that tissue-dependent fungal antigens and produce several different
factors, opsonins and antibodies modulate receptor cytokines8486.
usage by DCs at different body sites, and might con- There is marked plasticity in the T-cell response to
tribute to the functional plasticity of DCs at the fungi. The heterogeneity of the CD4+ and CD8+ T-cell
pathogenimmune system interface. repertoire might account for the multiplicity and
In this scenario, the qualitative development of the redundancy of effector mechanisms through which
TH-cell response to a fungus might not mainly depend T cells participate in the control of fungal infections.
on the nature of the fungal form being phagocytosed These include direct antifungal activity87, release of
and presented. Instead, the nature of the cell response antimicrobial peptides from CD8+ T cells88, lysis
is strongly affected by the type of cell signalling that is of fungus-containing phagocytes89, and effector func-
initiated by the ligandreceptor interaction in DCs. tions resulting from dynamic interactions with T cells
For Candida, this model would predict that dimor- that express selected members of the V families of
phism per se can no longer be considered as the single the T-cell receptor90. This functional plasticity indicates
most important factor in determining commensalism the potential of vaccines in conditions of immuno-
versus infection, nor can specific forms of the fungus deficiency, as highlighted by the ability of CD8+ T cells to
be regarded as absolutely indicative of saprophytism compensate for CD4+ T-cell deficiency in experimental
or infection at a given site. The selective use of receptor- models of vaccine-induced resistance to endemic
mediated entry into DCs could explain the full range fungi91,92. The flexible programme of T cells leads to the
of host immune relationships with the fungus, including production of many mediators, including cytokines. Due
saprophytism and infection. Usage of CR3, and the to their action on circulating leukocytes, the cytokines
consequent attenuation of IL-12 production, might produced by fungus-specific T cells are instrumental in
favour commensalism of the fungus at human mobilizing and activating antifungal effectors, so provid-
mucosal surfaces, including gut and vagina, where ing prompt and effective control of infectivity after the
immune tolerance is desirable to the host. Averting fungus has established itself in tissues or spread to internal
cellular activation through interaction with CR3 organs. Therefore, host resistance to fungi seems to
might be an important evasive strategy for fungi. depend on the induction of cellular immunity, mediated
Finally, as both fungal morphotypes, but particularly by T cells, cytokines and effector phagocytes (FIG. 3).
hyphae, activate gut DCs for the local induction of The clinical circumstances in which fungal infections
TReg-cell responses68, and because the morphogenesis occur are associated with impaired cell-mediated immu-
of C. albicans is activated in vivo by a wide range of nity. AIDS and severe haematological malignancies are
signals81, it seems that the discriminative response examples of acquired defects in T-cell function that
towards TReg-cell function represents a successful strategy predispose to severe fungal infections. Furthermore, the
of adaptation to the mammalian host. It could indeed occurrence of severe disseminated infections by filamen-
DELAYED-TYPE
HYPERSENSITIVITY
allow for fungal persistence in the absence of the tous fungi in non-granulocytopaenic patients24, as well
(DTH). A T-cell-mediated pathological consequences of exaggerated immunity as with the onset of graft-versus-host disease in bone-
immune response characterized and possible autoimmunity. Therefore, in addition to marrow-transplant recipients93, provides compelling
by monocyte/macrophage the induction of phase-specific products that enhance evidence of the pathogenic role of T-cell dysreactivity in
infiltration and activation.
DTH skin tests have classically
fungal survival in the host, transition to the hyphal infection. In endemic mycosis, the severity of the disease
been used for the diagnosis of phase of the fungus could induce immunoregulatory correlates with the degree of impairment of cell-
infection with intracellular events that will benefit the host82. mediated immunity, and is associated with increased lev-
pathogens such as els of antibodies94. Generation of a dominant TH1-cell
Mycobacterium tuberculosis,
Adaptive immunity response mediated by IL-12 is required for the expression
and as a measure of the vigour
of the cellular immune system. Serological and skin reactivity assays indicate that fungal of protective immunity to fungi. Experimental data have
Classical DTH responses to infections are common, but clinical disease is rare, shown the deleterious effects of IL-12 or IFN- ablation
intracellular pathogens are consistent with the development of acquired immu- on the course and outcome of fungal infections69.
thought to depend on CD4+ nity83. For many fungal pathogens, the effective tissue Through production of the signature cytokine IFN- and
T cells that produce a T helper
1-type profile of cytokines
response to invasion is granulomatous inflammation providing help for opsonizing antibodies, the activation
(interferon- and tumour- a hallmark of cell-mediated immunity. For dimor- of TH1 cells is instrumental in the optimal activation of
necrosis factor). phic fungi, the initial exposure is either asymptomatic phagocytes at sites of infection. Therefore, the failure to

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Innate immunity Fungus

Mucosal surface

PRR Immature
dendritic cell

Maturation
Macrophage
Opsonin Neutrophil
Draining lymph node
Innate immune functions
such as phagocytosis and
neutrophil degranulation Mature
IL-10 dendritic cell
Inflammatory Antigen
response IL-12
IL-18 presentation

TCR
MHC

B cell T cell
T cell
B cell
Antibody
production

IFN- TH1 IL-12


TNF

Lymphocyte activation
IL-4 TH2 and cytokine release
IL-4
IL-5

TGF- TReg
IL-10
IL-10 Adaptive immunity

Figure 3 | Balancing protection and immunopathology in fungal infections: a cooperative effort of the innate and adaptive
immune systems. Most fungi are detected and destroyed within hours by innate defence mechanisms mediated by phagocytes and
opsonins through the involvement of distinct pattern-recognition receptors (PRRs). These mechanisms act immediately and are
followed some hours later by an early induced inflammatory response, which must be activated by infection but does not generate
lasting protective immunity. These early phases help to keep infection under control. In vertebrates, however, if the infectious organism
can breach these early lines of defence, an adaptive immune response will ensue, with the generation of antigen-specific T helper (TH)
effector cells, regulatory T (TReg) cells and B cells that specifically target the pathogen and induce memory cells that prevent subsequent
infection with the same microorganism. Dendritic cells sample fungi at the site of colonization/infection, transport them to the draining
lymph nodes and activate disparate TH and TReg cells in a morphotype- and tissue-dependent manner. As the different TH-cell subsets
release a distinct panel of cytokines, capable of delivering activating and inhibitory feedback signals to effector phagocytes, the
activation of the appropriate TH-cell subset is instrumental in the generation of a successful immune response to fungi. Counter-
regulatory TReg cells might serve to dampen the excessive inflammatory reactions and contribute to the development of memory
antifungal immunity. Solid and broken lines refer to positive and negative signals, respectively. IFN-, interferon-; IL, interleukin; TCR,
T-cell receptor; TGF-, transforming growth factor-; TNF, tumour-necrosis factor.

deliver activating signals to effector phagocytes might defective production of IFN- and DTH anergy, associ-
predispose patients to overwhelming infections, limit ated with increased levels of type 2 cytokines (IL-4 and
the therapeutic efficacy of antifungals and antibodies, IL-5), IgE, IgG4 and IgA, and eosinophilia, which is a
and favour persistency and/or commensalism. marker of poor prognosis in endemic mycoses96. In
Immunological studies in patients with polarized forms patients with a defective IL-12/IFN- pathway, such as
of paracoccidioidomycosis show an association between those with hyperimmunoglobulinaemia E syndrome,
TH1-biased reactivity and asymptomatic or mild forms fungal infections and allergy are both observed97.
of the infection, in contrast to the correlation between IL-4 is an important determinant of susceptibility
TH2-cell responses and severe disease95. Not surprisingly, and resistance in most fungal infections11. Ablation of
therefore, patients with disseminated infection have IL-4 enhances immunity to fungi in experimental

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models of infection11. IL-4 can both deactivate and alteration in receptor-mediated signalling in response
activate phagocytes and DCs for certain specialized to fungal polysaccharide might predispose patients
functions; for example, it can inhibit the antifungal with CMC to a dysfunctional induction of TReg-cell
effector activities of phagocytes, yet can promote the activity, negatively affecting TH1-cell-dependent
production of IL-12 by DCs12. So, the most important clearance of the fungus, without implicating the
mechanism underlying the inhibitory activity of IL-4 activation of TH2 cells. Because both the recovery of
in infections is its ability to act as the most potent fungus from the gastrointestinal tract and the detec-
proximal signal for commitment to TH2-cell reactivity, tion of underlying TH1-cell reactivity, such as DTH
which dampens protective TH1-cell responses and and lymphoproliferation, can fluctuate in healthy
favours fungal allergy. In atopic individuals, the sup- subjects, it is tempting to speculate that T Reg cells
pressed DTH response to fungi is associated with mediate tolerance to the fungus at the site of colonization.
increased levels of antifungal IgE, IgA and IgG98,99. The ligation of distinct TLRs on DCs and the ensuing
However, susceptibility to fungal infections might not production of IL-6 are crucial events that mediate the
always be associated with marked production of IL-4. inhibition of TReg-cell function20. This is in agreement
For example, although an association between chronic with the failure of IL-6-deficient mice to activate anti-
disseminated candidiasis and genetic variants of IL-4 fungal TH1-cell responses concomitantly with
has been described recently100, levels of IL-4 or IL-5 increased IL-10 production11. It is also interesting that
are not always increased in patients with chronic pro-inflammatory cytokines, but not IL-6, are
mucocutaneous candidiasis (CMC), despite defective produced by oral and/or vaginal epithelial cells in
production of type 1 cytokines101. response to the fungus a finding that might explain
Several clinical observations indicate an inverse the downregulation of IFN- production in some
relationship between IFN- and IL-10 production in patients with recurrent vaginal candidiasis108.
patients with fungal infections. High levels of IL-10,
negatively affecting IFN- production, are detected in Therapeutic prospects
chronic candidal diseases 102, in the severe form of One strategy to prevent antifungal drug resistance is
endemic mycoses 103 and in neutropaenic patients to improve the immune functions of immuno-
with aspergillosis 104. Fungal polysaccharides are compromised hosts. The therapeutic efficacy of anti-
known to negatively modulate CMC through the fungals is limited without the help of host immune
production of IL-10, which indicates that IL-10 reactivity109. Various cytokines, including chemokines
production might be a consequence of infection 11. and growth factors, have proved to be beneficial in
However, tolerance to fungi can also be achieved experimental and human fungal infections 11. The
through the induction of TReg cells that can finely tune T H1/T H2-cell balance itself can be the target of
antifungal TH-cell reactivity. Therefore, suppressor immunotherapy. The inhibition of T H2-type
T cells have recently regained their reputation as key cytokines, or the addition of TH1-type cytokines, can
controllers of antifungal immunity 83. Naturally increase the efficacy of antifungals, such as polyenes
occurring downregulatory mechanisms that occur in and azoles, in experimental mycoses. The discovery of
the respiratory mucosa might account for the lack TLRs, which are now targets of antifungal drugs110,
of pathology in P. carinii-infected mice 105. DCs and their functional plasticity68 and new roles
Administration of CD4+CD25+ TReg cells prevents the for antibodies 57 have been major breakthroughs in
inflammatory pathology that is associated with the field of fungal immunology, which might offer
pathogen clearance. In mice with candidiasis, new grounds for a better comprehension of the cells
CD4+CD25+ TReg cells, producing IL-10 and TGF-, and immune pathways that are amenable to manipu-
prevent complete elimination of the fungus from the lation in patients with or at risk of fungal infections.
gastrointestinal tract; fungal persistence allows the Further understanding of the cooperation of various
development of memory immunity68. innate immune receptors in fungal recognition
It has long been presumed that the ability of potentially provides a basis for new therapeutic
C. albicans to persist in host tissues mainly involves strategies for immunomodulation. Notwithstanding
the immunosuppressive property of cell-wall glyco- the redundancy and overlapping repertoire of anti-
proteins. Mannan and its oligosaccharide fragments fungal effector mechanisms, the deliberate targeting
could be potent inhibitors of cell-mediated immunity of cells and pathways of antifungal cell-mediated
and seem to reproduce the immune deficit of patients immunity might be a useful strategy in developing
with CMC106. CMC, although encompassing various fungal vaccines capable of both sterilizing immunity
clinical entities, has been associated with autoimmune and protection against fungal reactivation111. A great
polyendocrinopathycandidiasisectodermal dystrophy deal of attention is being focused on antigens that
a condition in which the mutated gene has been activate DCs to trigger these responses112. The ulti-
shown to be involved in the ontogeny of CD25+ mate challenge will be to design fungal vaccines that
TReg cells107. In CMC, the defective production of type 1 can induce optimal immune responses by targeting
cytokines does not occur concomitantly with the specific receptors on DCs in vivo. This will require,
increase in type 2 cytokine production (that is, IL-4 or however, further studies aimed at elucidating the
IL-5) but, more often, with IL-10 (REF. 101). This convergence and divergence of pathways of immune
finding has led to the speculation that an inherent protection elicited in infections or after vaccination.

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Studies in vivo confirm that DCs sample fungi at sites More recently, research on fungi has entered the era
of infection, transport them to the draining lymph of genomics119. Sequencing of the genomes of most
nodes and initiate disparate TH-cell responses to the fungal pathogens is almost complete. The emerging
different fungal morphotypes80,113115. Furthermore, genomic sequence from many fungal species has already
adoptive transfer of DCs transfected with fungal RNA allowed the application of genomic technologies, such as
restores protective antifungal immunity in a mouse DNA microarray analysis and signature-tagged mutage-
model of allogeneic bone-marrow transplantation116. nesis, to the study of fungal pathogenesis, virulence and
These results, together with the finding that fungus- antifungal discovery120,121. It will be exciting to
pulsed DCs can reverse the T-cell anergy of patients witness the revolution built on the combination of
with fungal diseases117,118, indicate the use of DCs for genomics with more traditional approaches in our
fungal vaccines. understanding of fungi and fungal diseases.

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