Aspergillus fumigatus and Aspergillosis in 2019

Abstract

Aspergillus fumigatus is a saprotrophic fungus; its primary habitat is the soil. In its ecological niche, the fungus has learned how to adapt and proliferate in hostile environments. This capacity has helped the fungus to resist and survive against human host defenses and, further, to be responsible for one of the most devastating lung infections in terms of morbidity and mortality. In this review, we will provide (i) a description of the biological cycle of A. fumigatus; (ii) a historical perspective of the spectrum of aspergillus disease and the current epidemiological status of these infections; (iii) an analysis of the modes of immune response against Aspergillus in immunocompetent and immunocompromised patients; (iv) an understanding of the pathways responsible for fungal virulence and their host molecular targets, with a specific focus on the cell wall; (v) the current status of the diagnosis of different clinical syndromes; and (vi) an overview of the available antifungal armamentarium and the therapeutic strategies in the clinical context. In addition, the emergence of new concepts, such as nutritional immunity and the integration and rewiring of multiple fungal metabolic activities occurring during lung invasion, has helped us to redefine the opportunistic pathogenesis of A. fumigatus.

Keywords: Aspergillus; antifungal agents; aspergillosis; cell wall; diagnosis; glycans; immunity; microbiota; receptors.

Copyright © 2019 American Society for Microbiology.

Figures

FIG 1

Aspergillus fumigatus, a trimorphic filamentous fungus with vegetative mycelium in nature and in patients, the asexual conidia produced after mycelial starvation, and the resting ascospores produced from two heterothallic strains of opposite sex.

FIG 2

(A) MAT loci from the heterothallic species Aspergillus fumigatus (based on data from reference 13). Blue arrows indicate a MATα-domain gene, red arrows indicate a MAT high-mobility group gene, black bars indicate intronic sequences, and gray bars indicate homologous sequences. (B) Conidiation regulators in A. fumigatus (adapted from reference 428).

FIG 3

Syndromes associated with aspergillosis patients with different immune statuses include the following: SAFS, severe asthma with fungal sensitization; ABPA, allergic bronchial pulmonary aspergillosis; CPA, chronic pulmonary aspergillosis; IPA, invasive pulmonary aspergillosis; and IBA, invasive bronchial aspergillosis.

FIG 4

Direct health care cost of fungal diseases in the United States, showing the higher inpatient cost of invasive aspergillosis than all other fungal diseases (total inpatient cost of $4.6 billion per year, based on data from reference 75).

FIG 5

Epidemiological trends of IA. Evolving groups of nonneutropenic patients at risk for IA in the era of (i) targeted “precision-medicine” therapies for the management of malignant, inflammatory, and autoimmune diseases that impact the immune system and (ii) complex metabolic and immunological abnormalities in a large proportion of critically ill patients who survive severe infections in the intensive care unit. ICU, intensive care unit; SMKI, small-molecule kinase inhibitor; CAR T cells, chimeric antigen receptor T cells.

FIG 6

Standardized diagnostic criteria for invasive aspergillosis in hematological malignancy and in HSCT patients, based on data from reference . The concepts of proven, probable, and possible IA are introduced, depending on the presence of clinical and microbiological criteria (e.g., positive GM Ag). Adaptations of these criteria have been made for IA in nonneutropenic patients with ICU-related aspergillosis.

FIG 7

Crossing of the epithelial barrier by A. fumigatus germ tubes through an actin tunnel without disturbing the pulmonary lung epithelium. Note the actin sheath (see arrows) in response to the penetration of the germ tube, which occurs without perturbing epithelium integrity (adapted from reference with permission from Oxford University Press).

FIG 8

Phagocytosis of A. fumigatus conidia and intracellular fate of the conidia in the alveolar macrophage of an immunocompetent or immunocompromised host. Note the half-moon shape of the dead conidia inside the phagocyte (the middle and bottom panels are reprinted from reference 203).

FIG 9

Major immune effector pathways in alveolar macrophages activated during phagocytosis of A. fumigatus conidia. Alveolar macrophages are the first immune cells that encounter Aspergillus conidia. Killing of conidia inside AMs occurs via NADPH oxidase-mediated activation of LC3-associated phagocytosis (LAP). Activation of Dectin-1 and other C-type lectin receptor signaling occurs during exposure to β-glucans and other immunostimulatory molecules on the cell wall surface of swollen conidia. This activation triggers Syk-dependent responses regulating (i) NADPH oxidase/ROS-dependent activation of LAP, (ii) the inflammasome, and (iii) CARD-9-, NF-κB-, and IRF1/5-dependent cytokine and chemokine induction. In parallel, (iv) Dectin-1/Raf-1 signaling activates NF-κB and (v) TLR/MyD88-dependent activation of BTK/calcineurin/NFAT signaling regulates TNF production and neutrophil chemotaxis, both via LAP-independent pathways. Certain cytokines (e.g., IFN-γ) modulate LAP and other macrophage responses via JAK/STAT-dependent or independent (e.g., DAPK1) pathways. A significant gap of knowledge exists regarding regulation of other antifungal effector mechanisms (e.g., antimicrobial peptides, iron homeostasis, and other nutritional immunity responses) independently of LAP, cytokines, and chemokines. Furthermore, the mechanisms of cross talk between macrophages and other myeloid cells in the physiological setting of granuloma formation is critical for infection control but remain completely uncharacterized.

FIG 10

Neutrophils and their different anti-A. fumigatus activities. Neutrophil chemotaxis occurs in two waves and is regulated by (a) epithelium-dependent IL1R/MyD88 signaling and (b) inflammatory monocyte-mediated CARD9 signaling pathways. PTX-3 production by myeloid cells facilitates the anti-A. fumigatus killing by neutrophils. Neutrophils employ mainly ROS-dependent mechanisms of killing against intracellular (conidia) and extracellular (hyphae) fungal morphotypes. Intracellular killing of conidia is mediated by induction of apoptotic-type fungal cell death induced by ROS. Type I IFN and type III interferon signaling occuring via IFNLR1 in neutrophils is a pathway critical for optimal ROS production. IL-17A autocrine production via IL-6/IL-23 and Dectin-2 signaling is required for optimal ROS production. ROS-independent mechanisms of conidia leading to intracellular inhibition are mediated by Zn and Fe starvation by lactoferrin and other effectors. ROS-induced NETosis is another mechanism of inhibition of Aspergillus hyphae without a clear role in immunity in vivo.

FIG 11

Iron metabolism as an example of the complex interactions occurring between multiple metabolic pathways.

FIG 12

Schematic representation of the conidium and hyphal cell walls. Note that even though the major core polysaccharide components of the cell wall are the same in both morphotypes, the surface composition is different between the conidium and the mycelium, with rodlets and melanin on the conidium cell wall, whereas the mycelium is covered by galactosaminogalactan (GAG).

FIG 13

Galactosaminogalactan present on the surface of the mycelium (A and B) is responsible for adhesion to an inert surface (B) or to host cells. (C) Note the glabrous mycelium in a GAG-minus mutant.

FIG 14

Galactose-containing molecules and their synthesis, an understudied pathway that is essential for in vivo fungal growth. GM, galactomannan; GAG, galactosaminogalactan; Ugm1, UDP galactospyranose mutase; Uge3/5, UDP glucose epimerase; GfsA, galactofuranosyltransferase; Gt4C, Scl1/2, and Adg3 are members of the biosynthetic cluster for galactosaminogalactan; Dfg, orthologs of the DCW5/DFG1 pathway of yeast involved in the binding of the GM to β1,3 glucans; m, mycelium; c, conidium; ManPol, a complex of 11 mannosyltransferases involved in the synthesis of the conidial mannan (based on data from references , , , , and 493), indicates the unknown members of this biosynthetic pathway.

FIG 15

Trehalose biosynthesis, a key pathway for survival of A. fumigatus. In red are the regulators (transcription factors) controlling trehalose biosynthesis (Glc, glucose). Note that trehalose biosynthesis has not been shown biochemically but is deduced from gene deletion or from in silico analysis (based on data from references , , , , and 510).

FIG 16

Schematic representation of key biological characteristics of A. fumigatus essential for the survival of the species. (A) Quiescence of resting conidia and dormancy of ascospores; role of extracellular polysaccharides (α1,3 glucans in yellow and galactosaminogalactan in red) in the formation of a fungal multihyphal biofilm. (B) Colony heterogeneity of nuclear organization, schematized by different colors of the nuclei, leading to the absence of synchrony in this organism that may result from genetic and/or epigenetic changes occurring during nucleus divisions within the expanding mycelium.

FIG 17

Binding of Pseudomonas aeruginosa to the mycelium of Aspergillus fumigatus (adapted from reference 572).

FIG 18

New hypothetical scheme showing the nutritional immunity governed by LAP responsible for the persistence and the infective propagules in nonneutropenic patients. In neutropenic patients, the lack of host response is associated with rapid growth, which induces necrosis of host tissues and facilitates fungal nutrition.

FIG 19

Integration of all potential fungal virulence determinants and pathways in A. fumigatus. Favorable and unfavorable environmental and physiological conditions framing the development of A. fumigatusin vivo show the extreme nutritional flexibility and the multiple compensatory reactions of the stress response characterizing this opportunistic pathogen. Toxic immunosuppressors can be GAG and secondary metabolites.

FIG 20

Current antifungal targets and drugs (in green) and issues associated with drug therapy (in red). New drug targets are indicated in black and their target localization by red and white arrows.