Immunity Against Fungal Infections

Shuai Jiang
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

ABSTR ACT: Fungal diseases are major causes of morbidity and mortality among the immunocompromised, including HIV-infected individuals and
patients with cancer. Individuals without a weakened immune system can also suffer from these infections. Not surprisingly, fungi are a major target for
the immune system, rendered visible to it by expression of pathogen-associated molecular patterns/signatures. We now appreciate the roles of both innate
and adaptive immunity in eliminating fungal infections, and how a disproportionate or inadequate immune response can diminish the hosts capacity to
eliminate fungi. This review focuses on our current understanding of the roles of innate and adaptive immunity in clearing common and emergent fungal
pathogens. A clearer understanding of how the hosts immune response tackles fungal infection may provide useful clues as to how we might develop new
agents to treat those diseases in the future.
KEY WORDS: innate immunity, adaptive immunity, fungal infection
CITATION: Jiang. Immunity Against Fungal Infections. Immunology and Immunogenetics
Insights 2016:8 36 doi:10.4137/III.S38707.

CORRESPONDENCE: luckysjiang@caltech.edu

PEER REVIEW: Four peer reviewers contributed to the peer review report. Reviewers
reports totaled 820 words, excluding any confidential comments to the academic editor.

Paper subject to independent expert single-blind peer review. All editorial decisions
made by independent academic editor. Upon submission manuscript was subject to
anti-plagiarism scanning. Prior to publication all authors have given signed confirmation
of agreement to article publication and compliance with all applicable ethical and legal
requirements, including the accuracy of author and contributor information, disclosure
of competing interests and funding sources, compliance with ethical requirements
relating to human and animal study participants, and compliance with any copyright
requirements of third parties. This journal is a member of the Committee on Publication
Ethics (COPE).

FUNDING: Author discloses no external funding sources.

Provenance: the author was invited to submit this paper.

COMPETING INTERESTS: Author discloses no potential conflicts of interest.

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TYPE: Review
RECEIVED: April 27, 2016. RESUBMITTED: June 11, 2016. ACCEPTED FOR
PUBLICATION: June 24, 2016.
ACADEMIC EDITOR: Jennifer Nyland, Editor in Chief

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This is an open-access article distributed under the terms of the Creative Commons
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Introduction

Emerging evidence indicates that fungi are an increasingly

important class of pathogens in plants and mammals.1 The
correlate between the incidence of fungal infection and
clinical fungal-related disease has risen dramatically in the
last two decades, which would suggest an increasing pool of
susceptible, immunocompromised individuals. These could
conceivably include individuals infected with human immunodeficiency virus (HIV), patients with a hematologic or solid
cancer, and transplant recipients.2
Multiple species of fungal pathogen have come to be
associated with various human diseases,3 against which the
innate and adaptive immune responses are considered to
be the principal defenses.4 The mechanistic aspects of these
immuneresponses (innate or adaptive) vary depending on the
fungal species encountered,5 the target organism, and the site
of infection. Countering these, pathogenic fungi have developed multiple mechanisms to evade host immune defenses.
Survival within phagocytes from where fungi can later disperse
throughout their host is one particular elegant strategy.1,6 To
maintain a stable hostfungi interaction, the immune response
is segregated into an innate first-line defense, which is latterly
strengthened by a second tier, adaptive response.
This review summarizes the two major types of host
immune response to fungi, inclusive of the major cellular players
including macrophages, neutrophils, dendritic cells (DCs), and
T- and B-cells. It also addresses our current knowledge of the
mechanistic aspects of each cell types antifungal action. Finally,

I briefly discuss insights gained from studies of immune cell

function and how these may inform future vaccine strategies.

Innate Immunity and Fungal Infection

Neutrophils, macrophages, and DCs are all critical to the

antifungal response.7 Upon infection, these innate immune
cells are rapidly recruited to sites of infection by virtue of their
production of inflammatory cytokines, chemokines, and/or
complement units.810 The release of inflammatory cytokines,
as well as reactive oxygen intermediates and antimicrobial
peptides, can then clear the fungi in target organs.
Neutrophils, a class of professional phagocyte, can also
engulf and/or kill invading fungi.11 One of its more recently discovered antifungal mechanisms is the neutrophil extracellular
trap, which, together with an oxidative burst and the release of
antimicrobials, constitutes a potent antifungal response.12 Activated neutrophils release the cytokines IL-12 and IL-18 (Fig. 1)
and mediate antifungal responses via their expression of receptors such as Toll-like receptor 4 (TLR4) and/or the complement
receptors (eg, CR1).13 For example, Candida albicans can induce
reactive oxidative intermediates via their cell wall components
although the necessity of the oxidative burst for Aspergillus
conidia killing remains controversial.14,15 Clearly, there are gaps
in our knowledge of how neutrophils and fungal pathogens
interact; filling these may require new investigative methods.
Macrophages have long been appreciated for their role in
balancing the effector cytokine species required for neutrophil
recruitment and activation, as well as enhancing or inhibiting
Immunology and Immunogenetics Insights 2016:8

Jiang

Figure 1. Immunity against fungal pathogens. Fungi usually infect their host via epithelial or endothelial cells, invading both the mucosal and endothelial
surfaces. Cells in both the innate and adaptive wings of the immune system are activated by fungal infection, which subsequently generate different
antifungal effectors. Upon initial fungal infection, innate immune cells (including macrophages, neutrophils, and DCs) release cytokines such as IL-12,
IL-10, and IL-18. Cellular players in the adaptive immune response then secrete various cytokines against fungal infection: Th1 cells produce IFN- and
TNF-; Th2 cells produce IL-4 and IL-5; Th17 cells generate IL-17 and IL-22; and TReg cells produce TGF- and IL-10. B-cells also secrete antibodies to
target fungal pathogens.

innate immunity.16 For example, following infection by A. conidia,

macrophages can produce pro-inflammatory cytokines, including TNF- and IL-1.17 However, they can also stimulate
IL-10 production, which is a typical anti-inflammatory cytokine
(Fig. 1).18 The strength of either response may be dialed up by
TLR signaling, inclusive of TLR4 and TLR2,19 which would
suggest that different TLR signaling pathways contribute to
dissimilar biological responses upon fungal infection. A. conidia
can also induce NF-kB translocation in both the TLR2 and
TLR4 signaling cascades.20 Additionally, it was reported that
human macrophage anti-C. albicans activity and the inhibition
of phagolysosomal fusion in macrophages are both nonoxidative
mechanisms.21 It is worth noting that C. albicans may attempt to
mitigate these effects by preventing macrophage proliferation.22
The administration of corticosteroids suppresses the production
of IL-1, TNF-, and MIP-1 in macrophages, all of which
are protective against aspergillosis.23
DCs are particularly potent players in the immune response
as they initiate both innate and adaptive immune responses
to various fungi including Cryptococcus neoformans, Aspergillus
fumigatus, and C. albicans.24 The signaling pathways triggered by
DCs largely depend on the infectious agent.25 DCs also capture
and process antigens, express lymphocyte costimulatory molecules, and migrate to lymphoid organs and secrete cytokines to
initiate immune responses including IL-12 and IL-10 (Fig. 1).
Similar to macrophages, DCs can access the TLR system for antifungal host defense.26 However, DCs largely mediate antifungal
4

Immunology and Immunogenetics Insights 2016:8

immunity by initiating and buffering T-cell responses.27 Future

research on DC targeting may prove to be fruitful in terms of
generating potent vaccines against fungal pathogens.
NK cells show capacity against multiple types of fungi,
including C. albicans and A. fumigatus in vitro.28,29 NK cells
produce interferon gamma (IFN-) and play a fungicidal role
in fighting against C. neoformans.30 Furthermore, other innate
immune cells including mast cells, basophils, and eosinophils
contribute to the fungal protection as well.
Epithelial cells are also very important to the antifungal role. For instance, mucosal epithelial surface is the initial site of C. albicans for contacting with host, and epithelial
cells upregulate TLR4 and subsequently protect against tissue
damage caused by C. albicans.31 Furthermore, endothelial
cells can also interact with fungi, and the interaction between
C. albicans and endothelial cells has been reported, 32 such as in
blood vessels; however, its mechanism might involve complex
processes, which would be potentially great for both bench
work and clinical research in future.
Clearly, the innate immune response to fungi is important, but remains poorly understood. In particular, the regulatory mechanism at play may prove to be useful in improving
our understanding of treatment options.

Adaptive Immunity and Fungal Infection

The role of adaptive immunity in the antifungal immune

response is also well appreciated.33 Immune-regulatory CD4+

Immunity against fungal infections

T helper cells are of key importance, which can be functionally

categorized as one of the five groups: Th1, Th2, Th9, Th17,
andTReg cells.
Th1 cells can be activated by DCs via TLR signaling,
activated in response to the recognition of immutable fungal
molecules.34 Th1 cells can then help to optimize the activation of phagocytes at sites of infection. 35 Th1 cells can also
secrete signature pro-inflammatory cytokines such as IFN-
and TNF- (Fig. 1). Any diminished ability of Th1 cells to
mediate inflammatory signaling to phagocytes (such as macrophages) may lead to the decline of the infected patient. Thus,
modulating Th1 cells can boost the therapeutic efficacy of
antifungal agents.
Th2 cells, activated by IL-4 and IL-13, generate cytokines including IL-5 (Fig. 1) that can limit the Th1 response,
as well as activating M2 macrophages, which are harmful
to patients with severe fungal infections and fungal-related
allergic responses.36 Hyperactivated Th2 cells have also been
linked to cystic fibrosis.37 As an indication of the complexity of these issues, Th2-associated antibody responses can also
partially increase the Th1 cell response.38
Th17 cells act principally at mucosal surfaces, including
the lungs, where these cells play important roles in protective antifungal immunity.39 Th17 cells produce IL-17 and
IL-22 (Fig. 1) largely following their activation by signals
transduced by the myeloid differentiation primary response
88 (MYD88) pathway (including the key signaling effector
SYK-CARD9) and the mannose receptor pathways in DCs
and macrophages.40 Defective Th17 cells render patients susceptible to mucosal fungal infections, such as hyperimmunoglobulin E syndrome, which results from mutations in the stat1
gene in autosomal dominant mucocutaneous candidiasis.41
Moreover, TReg cells generating anti-inflammatory cytokines
including TGF- and IL-10 (Fig. 1) have been described in
fungal infections of both mice and humans.42 In experimental
fungal infections, TReg cells have been shown to regulate both
inflammation and immune tolerance in the respiratory and/or
gastrointestinal mucosa. Collectively, Th1, Th2, Th17, and
TReg cells are essential to the hosts susceptibility or resistance
to invasive fungal infections. Future research efforts will be
required to determine whether other T-cell subsets (eg, Th9)
also operate within this framework.
CD8+ T-cells can also block the fungal growth such as
C. albicans in vitro. The observation that CD8+ T-cells can
provide protection even without the presence of CD4+ T-cells
against fungi infection such as Histoplasma capsulatum. Furthermore, CD8+ T-cells can produce IFN against Pneumocystis carinii infection and induce the clearance of the fungal
infection.43
Antibody generation by B-cells is critical for fungal clearance, such as clearing pneumocystis from the lung (Fig. 1).
Moreover, titers for antibodies against pneumocystis have
been measured in young individuals, similar to other pathogenic fungi such as C. albicans.44 Emerging evidence also

indicates that this organism is widely experienced in nature

with antibody production, particularly IgGs and IgM, constituting part of the natural host response.45 Many different
analytic techniques have been used to examine pneumocystis
preparations or antigens and identify pneumocystis-specific
antibodies. The fine-tuning of adaptive immune responses
during fungal infections would also be a useful tool for treating fungal-related human diseases.

Conclusion and Outlook

Given that the pool of immunocompromised individuals is

rapidly expanding, there would appear to be an urgent need
to develop novel, more potent antifungal drugs. Aspects of
the innate and acquired immune response to fungi have been
intensely investigated. Furthermore, novel analytic techniques
capable of detecting immune responses elicited by fungi have
proven to be a promising area of scientific research.
Future clinical therapies for invasive fungal infections
may include drugs that enhance the antifungal activity of
immune effectors. This option would be especially relevant
for immunocompromised hosts in clinical trials, although
the safety and efficacy of novel antifungals remains questionable. Another potential approach is the modulation of
key signaling regulators. For example, findings that the
innate and adaptive immune response to common fungal pathogens can be mediated by TLRs, MYD88, and/or
noncoding RNAs, such as microRNAs, suggest that their
manipulation might be a useful tool for the enhancement of
antifungal resistance.
Clearly an improved understanding of the roles and
mechanisms of the hostpathogen interaction may pay dividends in terms of our development of novel antifungal therapies, with more investment in this research area now needed
to stimulate interest in solving current and future challenges
posed by fungal disease.

Author Contributions

The author conceived, organized, drafted, reviewed, and

approved the manuscript.
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