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The immune response to fungal infections

The immune response to fungal infections


Shmuel Shoham1 and Stuart M. Levitz

 

"With the increasing number of immune compromised patients, fungi have emerged as major causes of human disease. Risk factors for systemic candidiasis include presence of intravascular catheters, receipt of broad-spectrum antibiotics, injury to the gastrointestinal mucosa and neutropenia. Within a species, the fungal morphotype (e.g. yeast, pseudohyphae and hyphae of Candida albicans) may be an important determinant of the host response. Whereas yeasts and spores are often effectively phagocytosed, the larger size of hyphae precludes effective ingestion.

Differentiation of CD4+ T cells along a T-helper (Th) cell type 1 (Th1) or type 2 (Th2) pathway and development of specific Th responses, is an essential determinant of the hostís susceptibility or resistance to invasive fungal infections. Development of Th1 responses is influenced by the concerted action of cytokines, such as interferon (INF)-c, interleukin (IL)-6, tumour necrosis factor (TNF)-a, and IL-12, in the relative absence of Th2 cytokines, such as IL-4 and IL-10 (Romani, 2002).

Oropharyngeal candidiasis (OPC) is among the most common mycotic infections of immunocompromised patients. Development of infection depends upon both systemic and local determinants. Risk factors for oral candidiasis include extremes in age, diabetes mellitus, particularly when glycemic control is poor, nutritional deficiencies, use of broad spectrum antibiotics and immunosuppression (especially of cell-mediated immunity) (Klein et al, 1984; Guggenheimer et al, 2000). Local factors that promote infection include dentures, salivary abnormalities, treatment with inhaled steroids, and destruction of mucosal barriers with radiotherapy for head and neck cancers or cytotoxic chemotherapy. Human immunodeficiency virus (HIV) is one of the most important predisposing conditions worldwide. AIDS patients have a particularly high incidence of mucosal candidiasis, which is often recurrent and, when it involves the esophagus, can be disabling (Sangeorzan et al, 1994). Local defence mechanisms against mucosal infection include salivary proteins, such as lactoferrin, beta-defensins, histatins, lysozyme, transferrin, lactoperoxidase, mucins, and secretory immunoglobulin A. These impair adhesion and growth of Candida in the oropharyngeal cavity.  Development of OPC has been associated with a salivary Th2-type cytokine profile (Leigh et al, 1998).

Cell-mediated immunity plays the dominant role in prevention of candidiasis at the gastrointestinal surfaces. In AIDS, development of oropharyngeal and oesophageal candidiasis correlates with declining CD4+ lymphocyte counts. OPC is also associated

with T cell immunosuppression from corticosteroid therapy, organ transplantation, cancer chemotherapy and chronic mucocutaneous candidiasis (CMC). Candida species have emerged as an important cause of bloodstream and deep tissue infections. Risk factors for candidaemia include breakdown of mucosal barriers due to cytotoxic chemotherapy and surgical procedures, neutropenia, changes in the gut flora due to antibiotics, and invasive interventions that breach the skin, such as intravenous lines and drains (Wey et al, 1989). Common sites of dissemination include the bloodstream, kidney, liver, spleen, and endovascular structures. Quantitative and qualitative abnormalities of neutrophils and monocytes are associated with systemic candidiasis. Patients with lymphoma, leukaemia, chronic granulomatous disease, and recipients of intensive cancer chemotherapy with resultant neutropenia are at increased risk for disseminated infection. Similar to the situation with Aspergillus hyphae, the large size of Candida hyphae and pseudohyphae may preclude phagocytosis.

Achieving a balance between Th1 and Th2 cytokines may be important for optimal

antifungal protection while minimizing immune-mediated damage. In vivo models indicate that T regulatory cells attenuate Th1 antifungal responses, induce tolerance to the

fungus and participate in the development of long lasting protective immunity after yeast priming (Montagnoli et al, 2002; Romani, 2004).

Dendritic cells play an important role in linking innate with adaptive immunity. Dendritic cells that ingest the yeast form induce differentiation of CD4+ T cells toward a Th1 pathway. In contrast, hyphae induce Th2 responses (díOstiani et al, 2000). Neutrophils, macrophages and natural killer (NK) cells also modulate adaptive responses to the fungus. Neutrophils differentially induce Th1 and Th2 responses depending on whether the exposure is to yeast or hyphae.

The syndrome of chronic disseminated candidiasis (CDC, also known as hepatosplenic candidiasis) predominantly affects patients with haematological malignancies upon recovery from neutropenia. CDC is characterized by increased serum levels of IL-10 and local production of Th2-inducing cytokines by hepatocytes and by infected mononuclear cells (Roilides et al, 1998b; Letterio et al, 2001). Thus, although neutropenia is a major predisposing factor, the propensity for persistence of the fungus in infected tissues may be a consequence of cell-mediated immune dysregulation with suppression of Th1 and overexpression of Th2 responses."


Summary
During the past two decades, invasive fungal infections have
emerged as a major threat to immunocompromised hosts.
Patients with neoplastic diseases are at significant risk for such
infections as a result of their underlying illness and its therapy.
Aspergillus, Candida, Cryptococcus and emerging pathogens,
such as the zygomycetes, dark walled fungi, Trichosporon and
Fusarium, are largely opportunists, causing infection when
host defences are breached. The immune response varies with
respect to the fungal species and morphotype encountered.
The risk for particular infections differs, depending upon
which aspect of immunity is impaired. This article reviews the
current understanding of the role and relative importance of
innate and adaptive immunity to common and emerging
fungal pathogens. An understanding of the host response to
these organisms is important in decisions regarding use of
currently available antifungal therapies and in the design of
new therapeutic modalities.
Keywords: aspergillosis, candida, cryptococcosis, T cells,
dendritic cells.
Overview
With the increasing number of immune compromised
patients, fungi have emerged as major causes of human
disease. These pathogens are largely opportunists, causing
infection when host defences are breached. In this regard,
patients with neoplasms are particularly at risk due to their
immunocompromise, which can be a consequence of either
their underlying malignancy and/or the treatment for their
disease. Of the over 100 000 fungal species in existence, only a
small percentage is known to cause human infection. Risk
factors for systemic candidiasis include presence of intra-
vascular catheters, receipt of broad-spectrum antibiotics,
injury to the gastrointestinal mucosa and neutropenia. Patients
with haematological or solid malignancies and transplant
recipients are especially vulnerable. Mucosal candidiasis also
occurs in such patients and in those with Acquired Immune
Deficiency Syndrome (AIDS). Cryptococcosis predominantly
affects persons with advanced AIDS, lymphoid and haemato-
logical malignancies and transplant recipients. Filamentous
fungi, including species of Aspergillus and Fusarium, the
Zygomycetes, and the dark walled fungi, generally cause
invasive disease in neutropenic hosts and solid organ trans-
plant recipients. At highest risk are patients with prolonged
and profound neutropenia after treatment with highly cyto-
toxic chemotherapy for haematological malignancies and
recipients of haematopoietic stem cell transplantation (HSCT).
In the latter group, infections with filamentous fungi are
increasingly encountered during the post engraftment period.
In this article, we will discuss the host response to the
pathogenic fungi most likely to infect oncology patients.
The immune response varies with respect to the fungal
species encountered. The relative importance of specific innate
and adaptive defence mechanisms differs, depending upon the
organism and anatomical site of infection (Table I). Within a
species, the fungal morphotype (e.g. yeast, pseudohyphae and
hyphae of Candida albicans) may be an important determinant
of the host response. Whereas yeasts and spores are often
effectively phagocytosed, the larger size of hyphae precludes
effective ingestion. Pathogenic fungi have developed mecha-
nisms to elude and subvert host defences. Some fungi have
evolved as intracellular parasites and can survive within
phagocytes by using them to evade fungal killing and to
disseminate throughout the host. Major characteristics of the
immune response are the interdependence of various arms of
the immune system and the interplay between host defences
and fungal pathogenic mechanisms.
Several shared defence mechanisms are operative in response
to a range of fungi. Neutrophils, macrophages and monocytes
are fundamentally important antifungal effector cells. Phago-
cytes already residing in target organs at the time of infection
attempt to kill or damage fungi. Additional effector cells,
including neutrophils and monocytes, are recruited to sites of
infection by the action of inflammatory signals, such as
cytokines, chemokines and complement components. Fungi
are killed or damaged by production and/or release of reactive
oxygen intermediates and antimicrobial peptides et al, 1980; Mambula et al, 2000). Whether the cells use
intracellular or extracellular antifungal mechanisms depends
upon the infecting species, morphotype, and route of exposure

Dendritic cells initiate innate and adaptive immunity to a
range of microorganisms (Huang et al, 2001). These cells
capture and process antigens, express lymphocyte co-stimula-
tory molecules, migrate to lymphoid organs and secrete
cytokines to initiate immune responses (Banchereau & Stein-
man, 1998). Dendritic cells have an instrumental role in
linking innate and adaptive responses to a range of pathogenic
fungi including Aspergillus fumigatus, Cryptococcus neoformans
and C. albicans (Bauman et al, 2000; Braedel et al, 2004).
Signals transmitted by dendritic cells can vary depending upon
the encountered fungus or morphotype with resultant differ-
ences in the nature of adaptive immune responses elicited.
Differentiation of CD4+ T cells along a T-helper (Th) cell
type 1 (Th1) or type 2 (Th2) pathway and development of
specific Th responses, is an essential determinant of the hostís
susceptibility or resistance to invasive fungal infections.
Development of Th1 responses is influenced by the concerted
action of cytokines, such as interferon (INF)-c, interleukin
(IL)-6, tumour necrosis factor (TNF)-a, and IL-12, in the
relative absence of Th2 cytokines, such as IL-4 and IL-10
(Romani, 2002). The predominance of Th1 over Th2 type
cytokines correlates with protection against various mycoses
(Romani et al, 1994; Roilides et al, 1999). Within this frame-
work, however, are subtleties relating to quantitative and
temporal production of cytokines and the ultimate develop-
ment of particular T-cell responses, as well as a role for
modulation of immunity so as to limit autoimmune injury.
Both human and fungal cells are eukaryotic, as opposed to
bacteria, which are prokaryotes. Thus, in addition to anatomic
similarities (such as possessing a nucleus surrounded by a
nuclear membrane, 80S ribosomes, and Golgi apparati), fungal
and human cells have similar mechanisms for DNA, RNA and
protein synthesis. This greatly limits the number of potential
antifungal drug targets because the vast majority of com-
pounds that inhibit fungi also are toxic to human cells.
Therefore, antifungal drugs tend to target the few features of
fungal cells that differ from human cells. Most fungal cell
membranes contain ergosterol, rather than cholesterol, which
is the sterol found in human cell membranes. Amphotericin B
directly binds to ergosterol, whereas the Ďazolesí and terbin-
afine target ergosterol synthesis. However, the major distin-
guishing feature is that fungal cells have a rigid cell wall
containing chitin, mannans and glucans (the target of the
echinocandin class of antifungal drugs).
The fungal cell wall imparts upon the fungus physical
protection, making it resistant to certain host defences, such as
complement-mediated lysis. Innate immune defences, inclu-
ding b-glucan receptors, mannose receptors, and toll-like
receptors (TLRs), have evolved to recognize and respond to
components of fungal cell walls. For example, at the phagocytic
cell surface are TLRs that identify conserved molecular
patterns found on microbial (including fungal) products
(Akira et al, 2001; Mambula et al, 2002; Levitz, 2004). These
receptors are composed of an extracellular domain that
distinguishes microbial products and a cytoplasmic domain
that transmits signals to intracellular adapter proteins. One
such adapter, MyD88, initiates a signalling cascade leading to
the expression of microbicidal molecules and cytokines. The
proportional role of individual receptors, such as TLR2, TLR4,
and TLR9, in MyD88 activation varies depending upon the
infecting fungus and the site of infection. Specific receptors
differentially activate antifungal functions, which may result in
dissimilar responses and susceptibility to infection (Bellocchio
et al, 2004; Braedel et al, 2004).
Aspergillus
Aspergillus species are ubiquitous moulds with worldwide
distribution. Exposure most commonly occurs when airborne
spores are inhaled into the lungs or sinuses. Once inhaled,
spores reach distal areas of the lung by virtue of their small
size. The most common infecting species is A. fumigatus,
followed by A. flavus and A. niger (Marr et al, 2002; Husain
et al, 2003). In normal hosts, isolation of Aspergillus generally
reflects colonization and not infection (Uffredi et al, 2003).
The clinical manifestations of aspergillosis vary depending
upon the nature of the host. In atopic individuals with an
allergic or hypersensitivity response, the fungus triggers
immune phenomena including allergic rhinitis, asthma, hyper-
sensitivity pneumonitis and allergic bronchoplumonary asper-
gillosis (ABPA) (Horner et al, 1995). In patients with cavitary
pulmonary lesions, saprophytic colonization by Aspergillus
leads to aspergillomas. Finally, immunocompromised patients
may develop invasive aspergillosis (IA). This article will focus
on the latter group of patients. The degree of fungal invasion,
response to therapy and clinical outcome of IA depends upon
the type and depth of immune suppression. In susceptible
hosts, Aspergillus conidia germinate to form hyphae, the
Table I. Defects in host defences that predispose patients to infections
with specific fungi.
Fungal pathogen Host factor
Candida (mucosal) Impaired cell mediated immunity
Candida (disseminated) Impaired mucosa or integument,
neutropenia
Aspergillus Neutropenia, high-dose corticosteroids
Cryptococcus Impaired cell mediated immunity,
corticosteroids
Zygomycetes Neutropenia, deferoxamine treatment,
corticosteroids, diabetic ketoacidosis
Fusarium Neutropenia, impaired integument,
corticosteroids
Scedosporium Neutropenia
Trichosporon Neutropenia, impaired integument





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Keywords: immune response fungal infections fungi systemic candidiasis intravascular catheters antibiotics gastrointestinal mucosa neutropenia

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