Page 439 - Clinical Immunology_ Principles and Practice ( PDFDrive )

ChaPTEr 29 Host Defenses to Fungal Pathogens 419

Fungus

Dectin-1 Dectin-1
Neutrophil
recruitment

Plasma membrane
IL-17A
IL-17F
IL-2 2

Syk
Th17

CARD9
Raf-1 NFAT NADPH IL-6, TGFβ
BCl-10 MALT1 oxidase
LC3 Th2
ROS recruitment
to phagosome
NF-κβ IL-4
IL-4
NRLP3 IL-5
IL-13
etc.
caspase1
pro-IL1β IL1β

NFKβ IL-1β IL-10 IL-12
Cytokines IL-23 IL-12 Th1
IL-6 TNFα
NFAT IL-2
Cytokines IL-10 IFNδ
etc.
Nucleus
Macrophage
activation
FIG 29.4 Dectin-1 Signaling in Response to Fungal Pathogens. Upon recognition of fungal
pathogens, dectin-1 signaling triggers secretion of cytokines, production of reactive oxygen species
(ROS), and activation of the adaptive immune system to facilitate elimination of the pathogen.

CARD9 THE INFLAMMASOME
Mutations in the CARD9 adaptor molecule, downstream of IL-1β activation occurs when its precursor pro–IL-1β is cleaved
dectin-1, are associated with increased susceptibility to invasive by caspase-1. IL-1β is critical for neutrophil recruitment and
Candida infections. Patients with CARD9 deficiencies have for induction of the Th17 response. Activation of the inflam-
decreased Th17 cells, reduced chemokine/cytokine production, masome regulates IL-1β, IL-18, IL-17, and IFN-γ. NLR family
26
and impaired neutrophil activation. Numerous patients have domain containing protein 3 (NLRP3) is required for activation
been identified to have mutations in CARD9 that lead to fungal of caspase 1. Caspase 8 may also play a role in regulating activation
26
infections. The vast majority of inborn errors in immunity that of IL-1β. Syk-dependent production of ROS activates the NLRP3
predispose to fungal disease typically also lead to development inflammasome, which coordinates with NF-κB to promote
27
of nonfungal infections. Patients with gain-of-function (GOF) production of IL-1β. Mice lacking the inflammasome or IL-1β
28
signal transducer and activator of transcription 1 (STAT1) are highly susceptible to disseminated candidiasis. In addition
or autosomal dominant STAT3 also suffer from mycobacte- to ROS, lysosomal rupture, release of cathepsins, and efflux of
rial and other bacterial infections. In contrast, mutations of potassium can lead to activation of the inflammasome. Many
CARD9 appear to affect susceptibility to fungal infections components of the fungal cell wall can trigger inflammasome
exclusively. This observation makes CARD9 a key regulator in activation in vitro. However, in these experiments, cells were
antifungal immunity. Other genes associated with increased risk pretreated with adenosine triphosphate (ATP) or lipopolysac-
of fungal infections typically predispose patients to increased charide (LPS) to provide an extra signal. When whole live fungal
mucocutaneous or invasive disease. In contrast, CARD9 organisms are used, pretreatment with ATP or LPS is not required.
deficiency predisposes to both mucosal and systemic fungal Mice lacking NLRP3, apoptosis-associated speck-like protein
diseases. containing a C-terminal caspase recruitment domain (ASC), or