New advances in invasive aspergillosis immunobiology leading the way towards personalized therapeutic approaches

Abstract

Invasive aspergillosis (IA) remains a devastating disease in immune compromised patients despite significant advances in our understanding of fungal virulence and host defense mechanisms. In this review, we summarize important research advances in the fight against IA with particular focus on early events in the interactions between Aspergillus fumigatus and the host that occur in the respiratory tract. Advances in understanding mechanisms of immune effector cell recruitment, antifungal effector mechanisms, and how the dynamic host-fungal interaction alters the local microenvironment to effect outcomes are highlighted. These advances illustrate exciting new therapeutic opportunities, but also emphasize the importance of understanding each unique fungus-host interaction for improving patient outcomes.

Keywords: Antifungal effector; Aspergillus fumigatus; Fungal virulence; Invasive aspergillosis; Phagocytes.

Figure 1. Model of fungus-induced signaling and activation of effector systems in myeloid cells

Germinating A. fumigatus conidia (SC, swollen conidia) expose primarily surface β-glucan as well as other ligands that can activate Syk via CLRs (i.e., Dectin-1 with a hemi-ITAM in the receptor tail), FcRγ-coupled (i.e., Dectin-2 that complexes with Dectin-3), and integrin receptors, i.e. Mac-1 (CD11b/CD18). Downstream PKCδ and CARD9 activation is critical for caspase-1 and -8 activity, NF-κB activation, and cytokine production. Syk-dependent PLCγ2 activation is linked to NADPH oxidase assembly in neutrophils. Following phagocytosis, A. fumigatus triggers macrophage TLR9-Btk signaling that is transduced into calcineurin-dependent NFAT activation. HIF-1α cooperates with NF-κB and NFAT to regulate inflammatory cytokine production (e.g., CXCL1) in myeloid cells. Macrophage phagosomes that contain swollen conidia recruit Rubicon-, Beclin-1, UVRAG-, and VPS34-containing complexes that result in phosphatidylinositol-3-phosphate (PIP₃) deposition and the assembly of functional NADPH oxidase. PIP₃ and ROS mediate the assembly of ATG12/ATG5/ATG16L-dependent conjugation systems that facilitate ATG3- and ATG7-dependent lipidation of LC3. Lipidated LC3 inserts into phagosomal membrane and regulates the phagolysosomal fusion. The relative contribution of NADPH oxidase versus LC3-associated autophagy to fungal killing in myeloid cells has not been clearly defined in vivo. Rubicon not only associates with the class III phosphatidylinositol-3-kinase (i.e. VPS34 complex), but also stabilizes the NADPH oxidase complex, and negatively regulates CARD9-dependent NF-κB signal transduction. Please see text for additional detail.

Figure 2. Biphashic neutrophil recruitment to the lungs in response to Aspergillus fumigatus

(1) Upon entry into the airway resting Aspergillus conidia (RC) rapidly begin germination. Upon swelling and germtube emergence (G) tissue resident monocytes and macrophages recognize Aspergillus exposed carbohydrate cell wall components through an array of pattern-recognition receptors. These activated monocytes and macrophage secrete numerous inflammatory cytokines, including IL-1α, IL-1β, GM-CSF, and TNF-α into the surrounding tissue to initiateneutrophil recruitment. TNF-α may directly enhance neutrophil recruitment to the lung, while (2) IL-1α and IL-1b will mediate cross-talk with airway epithelial cells that express the IL-1RI. Through IL-1RI/MyD88-dependent signaling events airway epithelial cells produce CXCL1, CXCL5, and G-CSF. (3) These pro-inflammatory mediators drive the first wave of CXCR2-dependent neutrophil recruitment to the lungs. (4) Upon entry into the lungs neutrophil interact with the Aspergillus germtubes, which results in Card9-dependent, but Dectin-1 and Dectine-2 independent, signaling which results in the expression of CXCL2 by neutrophils. (5) Finally, CXCL2 drives the accumulation of a second wave of neutrophils to the lungs through a CXCR2-dependent mechanism. Neutrophils found in the lungs at later time-point also express higher levels of the CXCR2 receptor and Dectin-1.