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416 ParT ThrEE Host Defenses to Infectious Agents

KEY CONCEPTS neutrophils. Macrophages are recruited to the site of infection by
Innate Immunity to Fungal Pathogens chemotaxis. They are also responsible for patrolling interfaces with
the environment, including the lung and the GI tract. In contrast
• Fungi express highly conserved pathogen-associated molecular patterns to neutrophils, macrophages express class II MHC and can activate
(PAMPs) that are recognized by pathogen recognition receptors (PRRs) T cells. Upon activation by fungi through PRRs and PAMPs,
expressed on host phagocytes. macrophages produce potent inflammatory cytokines, including
• Dectin-1 is a C-type lectin receptor (CLR) that acts as a PRR to recognize tumor necrosis factor α (TNF)-α and IL-6. Engagement of the
β-1,3 glucan expressed on the cell walls of Candida, Aspergillus, and inflammasome within these cells leads to copious production
other fungal pathogens.
• Toll-like receptors (TLRs) recognize fungal cell wall components and of IL-1β. Macrophages receive assistance from activated T cells
nucleic acids. that secrete interferon-γ (IFN-γ), which can activate a host of
• Engagement of PRRs and PAMPs initiates signaling that coordinates genes to improve the antifungal response from macrophages.
secretion of cytokines, reactive oxygen species (ROS) production,
and presentation of fungal antigens to the adaptive immune system Role of Dendritic Cells
to facilitate elimination of the pathogen. In contrast to macrophages, DCs can stimulate naïve T cells.
Moreover, DCs are capable of taking up both yeast and conidia.
DC subsets are characterized by expression of specific surface
Recently engulfed pathogens become enclosed in membrane markers. Plasmacytoid DCs (pDCs) expressing specific surface
delineated compartments called phagosomes, which traffic toward markers phagocytose A. fumigatus conidia and spread over hyphae.
the lysosome, as directed by modifications to the phagosomal pDCs incite an immune response by release of proinflammatory
membrane proteins and changes to the intraphagosomal environ- cytokines, including IFN-α and TNF-α. pDCs are typically found
ment. Proteins recruited to the phagosomal membrane are specific in the spleen but will migrate to the lungs following challenge
to its contents. Phagolysosomes intersect with class II major by A. fumigatus conidia. Depletion of pDCs has been shown to
histocompatibility complex (MHC) molecules and permit loading result in increased mortality, indicating a nonredundant role for
of pathogen-specific peptides. T cells are then activated in an pDCs in host defense against A. fumigatus.
antigen-specific manner to augment the immune response and C. albicans epithelial infections appear to recruit pDCs. These
generate long-term immunity. cells reorganize and become more concentrated in the T-cell
zones of lymph nodes. Draining lymph nodes of mice infected
Role of Neutrophils with Candida versus control mice showed that pDCs were the
Neutrophils are the most critical cell in the host defense against predominant DC subset after vaginal infection. pDCs are involved
fungal pathogens. Patients with neutropenia or acquired defects in the induction of Th1 responses to C. albicans vaginal infection.
in neutrophil-mediated killing are at higher risk of developing
IFIs, including IA. Although phagocytosis is a critical feature in PATTERN RECOGNITION RECEPTORS
controlling infection, other mechanisms also limit the spread of
infection and serve to kill invading organisms. Neutrophils rely Recognition of fungal pathogens is mediated by PRRs expressed
on multiple mechanisms for killing, including granule-dependent by innate immune cells, including DCs and myeloid cells (e.g.,
killing, nicotinamide adenine dinucleotide phosphate (NADPH) macrophages, monocytes, and neutrophils). The interaction
oxidase–dependent killing, and neutrophil extracellular trap between PRRs and PAMPs expressed on the fungal cell wall
(NET) formation (Chapter 22). triggers downstream signaling, which elaborates the host immune
Phagocytosis of fungal organisms by neutrophils triggers response and facilitates elimination of the pathogen. The major
production of antimicrobial ROS. Generation of ROS by the PRRs involved in antifungal immunity are Toll-like receptors
NADPH oxidase complex is a result of engagement of surface (TLRs) and C-type lectin receptors (CLRs). Other relevant PRRs
receptors, including dectin-1, and signaling adaptors, including include nucleotide-binding oligomerization domain (NOD)–like
caspase recruitment domain family member 9 (CARD9) and receptors (NLRs), and retinoic acid-inducible gene I (RIG-I)–like
Syk. Loss of ROS production has a clear phenotype in Aspergillus receptors (RLRs).
infections. Patients with chronic granulomatous disease (CGD)
fail to control Aspergillus hyphae, which leads to invasion and Toll-Like Receptor
metastatic spread of disease. In contrast, conidial forms of Toll-like receptors (TLRs) are transmembrane receptors that
Aspergillus do not require ROS. The data for Candida infections recognize a broad range of microbial ligands, including fungal and
are less compelling. There appears to be modest reduction in bacterial cell wall components, bacterial and viral nucleic acids,
killing of serum-opsonized C. albicans, but killing of unopsonized and bacterial lipoproteins (Fig. 29.2) (Chapter 3). TLR1, -2, -4, -5,
organisms is unimpaired. -6, and -10 are expressed on the cell surface, whereas TLR3, -7,
In addition to cytotoxic granules and ROS production, -8, and -9 are expressed on intracellular membranes. Intracellular
neutrophils are capable of NET formation. This relatively newly TLRs recognize nucleic acids derived from fungi, bacteria, and
discovered cytotoxic mechanism delivers a web-like structure viruses and signal through MyD88 or TRIF. MyD88 signaling
composed of chromatin and histones. For Candida, it appears triggered by TLRs is essential for host fungal defense; mice lacking
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that NET formation contributes to fungal killing. However, in MyD88 are more susceptible to IFIs. However, humans with
Aspergillus, data from studies do not support a clear role for MyD88 signaling defects do not have increased incidence of fungal
NETs. infections. To date, several TLRs have been implicated in fungal
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immunity in mice, including TLR2, TLR4, TLR7, and TLR9. The
Role of Macrophages importance of TLRs has been demonstrated in human biology.
Macrophages also play a critical role in neutralizing fungal In humans, polymorphisms in TLR1, TLR3, TLR4, and TLR6 are
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organisms. These phagocytic cells are much longer lived than associated with increased susceptibility to IFIs (especially IA).