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ChaPTEr 29 Host Defenses to Fungal Pathogens 415

targets the CNS, causing meningoencephalitis, a life-threatening to withstand diverse environmental conditions but also maintains
condition. plasticity to permit cell growth and division and formation of
different cell types throughout the life cycle of a fungal organism.
HOST DEFENSE AGAINST FUNGI BY Availability of nutrients, stress, hypoxia, and hypercarbia are
EPITHELIAL CELLS environmental cues to the modification of the cell wall. The
major constituents of the fungal cell wall are chitin, glucans,
Given the ubiquity of many fungal organisms, humans inhale and glycoproteins. Chitin is a structurally important component
a diverse species of fungi regularly. Moreover, the microbiota of the fungal cell wall located closest to the plasma membrane.
has a profound influence on human health. Early work on this The composition of the outer layer varies, depending on the
complex collection of microorganisms focused on bacteria, but fungal species, morphotype, and growth stage. Branched β-1,3
increasing evidence indicates that the mycobiome plays an glucan cross-links to chitin and is covalently linked to other
important role in human health. Indeed, sequencing data from polysaccharides (e.g., galactomannan and β-1,6 glucan). The
the respiratory sputum of normal volunteers showed over 40 fungal cell wall composition differs dramatically between conidia
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distinct species of fungi. Interestingly, sputum from patients and hyphae, which leads to differential recognition and response
with allergies demonstrated a distinct mycobiome. Although by the immune system. Many fungal species produce melanin,
there is an association, it remains unclear as to whether specific a natural pigment found on the cell wall and is associated with
species of fungi are causal for allergic responses. Growth of the enhanced virulence of many pathogenic fungi. Melanin
commensal fungi is limited by release of antimicrobial peptides protects the organism from both environmental stressors and
and colonization by other microbial flora that compete for interferes with host defense mechanisms. Specifically, fungal
nutrients. Disruptions to this delicate balance can have serious melanin has been associated with decreased phagocytosis, an
pathological consequences. altered cytokine response, and reduces susceptibility to antifungal
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Skin and the epithelial mucosa of the respiratory, gastro- drugs. In some organisms, such as A. fumigatus, a hydrophobic
intestinal (GI), and genitourinary tracts represent the first line rodlet layer composed of hydrophobins makes the conidia water-
of defense against fungal pathogens, acting as a physical barrier proof and shields underlying carbohydrates that may induce
against infection. There is evidence that epithelial cells provide inflammation.
more than just barrier function by triggering an immune response. Fungal dimorphism is a critical feature of virulence for both
Several groups have demonstrated that oral epithelial cells infected yeast and molds. C. albicans exist in three forms that have distinct
with fungi produce proinflammatory cytokines and chemokines shapes: blastospores (also known as yeast cells), pseudohyphal
in vitro. 11,12 Similarly, stimulation of human corneal epithelial cells, and true hyphal cells. Yeast cells are typically 5 µm in
cells with A. fumigatus hyphae activates Syk signaling and leads diameter with a round to ovoid shape. Pseudohyphae resemble
to production of inflammatory cytokines (interleukin-1β [IL-1β] elongated yeast cells that remain attached to one another. These
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and IL-6) and chemokines (IL-8 and CXCL1). Hyphal formation fungi usually grow in a branching pattern that may facilitate
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is critical for inducing a strong response by epithelial cells. scavenging for nutrients at distal sites. True hyphal cells are long
Recently, a fungal toxin termed candidalysin has been identified and highly polarized, with parallel sides and no obvious constric-
that is a cell permeable peptide that induces a strong inflammatory tions between cells. Similarly, A. fumigatus conidia are waxy
response within epithelial cells. Production of candidalysin by hydrophobic ovoid-shaped cells of approximately 3–5 µm in
C. albicans is required for T-helper 17 (Th17) responses. diameter. A. fumigatus can filament to generate hyphae that are
C. albicans is a commensal fungus in the human GI tract, but >40 µm in length. For both C. albicans and A. fumigatus, this
its abundance is limited by intestinal bacteria. Antibiotics that dimorphism is a virulence factor as organisms that fail to do so
disrupt the balance of bacterial microbiota favor overgrowth of are avirulent.
Candida species. It is thought that patients with fever and
neutropenia who develop invasive candidemia result from THE INNATE IMMUNE RESPONSE TO
translocation of fungi from the GI tract. Emerging data connect FUNGAL PATHOGENS
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gut homeostasis and immune responses to fungi in the lung.
Many questions remain about how epithelial cells discriminate Once a fungal pathogen has invaded the host system, innate
fungal morphology and which proteins mediate epithelial recogni- immune cells, such as macrophages/monocytes, neutrophils,
tion and activation in response to pathogenic fungi. Compared and dendritic cells (DCs), phagocytose and degrade the organ-
with host defense mechanisms exerted by myeloid cells, much ism (Chapter 3). In immunocompetent individuals, physical
less is known about host–pathogen interactions in epithelial barriers (e.g., epithelial cells, mucous, skin) are effective at
mucosa. preventing infection. In the respiratory tract, macrophages
routinely neutralize fungal pathogens that make their way to the
THE FUNGAL CELL WALL alveoli. Understanding the rules that govern the recognition and
response to these fungal pathogens provide important insights
The fungal cell wall contains many of the relevant pathogen- into how these organisms cause disease in immunocompromised
associated molecular patterns (PAMPs) and epitopes for the individuals.
immune response. PAMPs are recognized by cells of the host Recognition of fungal pathogens by innate immune cells is
innate immune system and are often targets for antifungal agents. mediated by pattern recognition receptors (PRRs). Engagement
The ultrastructure of fungal organisms is similar to mammalian of PRRs and PAMPs triggers a cascade of molecular events that
cells. This feature has thwarted the development of a broad coordinates phagocytosis and degradation of the pathogen.
armamentarium of antifungal agents. However, fungi also possess Additionally, release of cytokines, reactive oxygen species (ROS)
a cell wall, a structure not found in mammalian cells. The fungal production, and presentation of fungal antigens to the adaptive
cell wall not only provides the organism with mechanical strength immune system aids in controlling infection.