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  • Review Article
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Aspergillus fumigatus morphology and dynamic host interactions

Nature Reviews Microbiology volume 15, pages 661–674 (2017)Cite this article

Subjects

Key Points

  • The interaction between Aspergillus fumigatus and the host immune system is highly complex, owing to the capacity of the fungus to adapt to its environment.

  • The different morphological forms of A. fumigatus result in the exposure of different pathogen-associated molecular patterns that trigger distinct sets of pattern recognition receptors, which, in turn, will generate various immune responses that are not always beneficial.

  • Within the host, during infection, environments will change over time, such as the development of a hypoxic environment in the lungs or altered nutritional supply, making it important to realize that additional immunomodulatory treatment has to be tailored for a certain stage of infection.

  • A. fumigatus can adapt and become resistant to antifungal drugs, highlighting the importance of designing novel antifungal drugs and strategies, such as immunotherapy.

Abstract

Aspergillus fumigatus is an environmental filamentous fungus that can cause life-threatening disease in immunocompromised individuals. The interactions between A. fumigatus and the host environment are dynamic and complex. The host immune system needs to recognize the distinct morphological forms of A. fumigatus to control fungal growth and prevent tissue invasion, whereas the fungus requires nutrients and needs to adapt to the hostile environment by escaping immune recognition and counteracting host responses. Understanding these highly dynamic interactions is necessary to fully understand the pathogenesis of aspergillosis and to facilitate the design of new therapeutics to overcome the morbidity and mortality caused by A. fumigatus. In this Review, we describe how A. fumigatus adapts to environmental change, the mechanisms of host defence, and our current knowledge of the interplay between the host immune response and the fungus.

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Figure 1: Aspergillus fumigatus life cycle and its dynamic cell wall.
Figure 2: Innate host defence and T cell responses to Aspergillus fumigatus infection.
Figure 3: NADPH oxidase complex in Aspergillus fumigatus host defence.
Figure 4: Evasion and adaptation strategies of Aspergillus fumigatus.

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Acknowledgements

M.G.N. was supported by an European Research Council (ERC) Consolidator Grant (#310372) and a Spinoza Grant of the Netherlands Organization for Scientific Research. F.L.v.d.V. was supported by the E-rare project EURO-CMC. L.R. was funded by a Specific Targeted Research Project FunMeta (ERC-2011-AdG-293714). J.-P.L. was supported by grants from Aviesan Fungi grant Aspergillus, Labex IBEID, ANR grant ASP2R2 and ANR-DST grant ANR-13-ISV3-0004-01. The authors thank P. Verweij for helpful discussions.

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Authors and Affiliations

  1. Department of Internal Medicine, Radboud University Medical Center,

    Frank L. van de Veerdonk, Mark S. Gresnigt & Mihai G. Netea

  2. Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands

    Frank L. van de Veerdonk, Mark S. Gresnigt & Mihai G. Netea

  3. Department of Experimental Medicine, Pathology Section, University of Perugia, Perugia, 06132, Italy

    Luigina Romani

  4. Unité des Aspergillus, Institut Pasteur, 25–28 Rue du Dr Roux, Paris, 75015, France

    Jean-Paul Latgé

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  1. Frank L. van de Veerdonk
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  4. Mihai G. Netea
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Contributions

F.L.v.d.V, M.S.G, L.R., M.G.N and J-.P.L. researched the data for the article. F.L.v.d.V, M.S.G, L.R., M.G.N and J-.P.L. provided a substantial contribution to discussions of the content. F.L.v.d.V, M.S.G, L.R., M.G.N and J.-P.L. contributed equally to writing the article and to review and/or editing of the manuscript before submission.

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Correspondence to Frank L. van de Veerdonk.

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PowerPoint slides

Glossary

Saprotrophic fungi

Fungi that obtain their nutrition by decomposing organic matter, such as dead plants or animals.

NADPH oxidase complex

A membrane-bound protein complex that produces reactive oxygen species in the form of O2− through the reduction of NADPH.

Conidia

Asexual fungal spores of filamentous fungi.

Conidiophores

Highly organized structures of fungi that successively produce conidia on characteristic conidial heads.

Ascospores

Sexual spores that are produced in cleistothecia when two strains of opposite mating types of Aspergillus fumigatus are grown together.

Aspergilloma

A clump of fungus in a body cavity, such as the lungs.

Siderophore

A high-affinity iron-chelating molecule that is secreted by many bacterial and fungal species.

Galactosaminogalactan

(GAG). A specific carbohydrate polymer that consists of galactose, galactosamine (GalNH2) and N-acetylgalactosamine (GalNAc). GAG is exclusively expressed by hyphae and is also secreted into the environment as an extracellular polysaccharide.

Hydrophobins

Hydrophobic proteins that are present on the surface of Aspergillus fumigatus conidia and are responsible for the typical rodlet configuration of the outer conidial layer.

Pathogen-associated molecular patterns

(PAMPs). Pathogen molecular structures that are recognized by pattern recognition receptors (PRRs) and activate host immune responses.

Pattern recognition receptors

(PRRs). Receptors expressed in host cells that bind to and recognize pathogen-associated molecular patterns (PAMPs), which causes the activation of signalling cascades for the induction of cytokine secretion and activation of the immune response.

Cytokines

Molecules, such as interleukins, chemokines and interferons, that are released mostly, but not exclusively, by immune cells to mediate communication between cells to either activate or suppress the host response directed against an invading pathogen. Chemokines are cytokines that regulate the migration of immune cells.

Pentraxin 3

(PTX3). A soluble pattern recognition receptor that is released by immune cells, including phagocytic cells.

Chronic granulomatous disease

(CGD). A disease caused by genetic defects in the NADPH oxidase complex, resulting in an inability to produce NADPH-dependent reactive oxygen species and an extreme susceptibility to specific infectious diseases, such as infection with Staphylococcus aureus and aspergillosis.

LC3-associated phagocytosis

(LAP). A process in which the autophagy machinery is used to insert lipidated microtubule-associated protein 1 light chain 3 (LC3) molecules into the membrane of phagosomes for the efficient targeting of their contents for degradation.

Interleukin-1 receptor antagonist

(IL-1Ra). An anti-inflammatory cytokine that competitively antagonizes the function of the pro-inflammatory cytokine IL-1 by occupying the IL-1 receptor without activating the downstream signalling pathway.

Neutrophil extracellular traps

(NETs). A network of DNA that is covered with antimicrobial peptides and is released by dying neutrophils to trap and damage particles that are too large to be phagocytosed.

Type 1 T helper cells

(TH1 cells). A lineage of T helper cells that express the surface molecule CD4 and are characterized by the transcription factor TBET and the production of interferon-γ. The primary function of TH1 cells is to augment phagocytosis and kill pathogens.

TH2 cells

(Type 2 T helper cells). A lineage of T cells that express the surface molecule CD4 and are characterized by the transcription factor GATA3 and the production of interleukin-4 (IL-4), IL-5 and IL-13, which induces the production of immunoglobulin E (IgE) and stimulates mucous production by airway epithelial cells.

TH17 cells

(Type 17 T helper cells). A lineage of T cells that express the surface molecule CD4 and are characterized by the transcription factor RAR-related orphan receptor C (RORC) and the production of interleukin-17 (IL-17) and IL-22. TH17 cells induce neutrophil chemotactic activity (IL-17) and have the potential to induce the release of antimicrobial peptides by epithelial cells (IL-17 and IL-22).

TH9 cells

(Type 9 T helper cells). A lineage of T cells that express the surface molecule CD4 and are characterized by the expression of the transcription factor PU.1, and the production of iinterleukin-9 (IL-9) and transforming growth factor-β (TGFβ).

Dendritic cells

(DCs). Antigen-presenting cells that regulate the induction of the adaptive immune response by activating T cell differentiation through antigen presentation and specific cytokine signalling pathways.

Regulatory T cells

(Treg cells). A lineage of T cells that express the surface molecule CD4 and the transcription factor forkhead box P3 (FOXP3), and that regulate pro-inflammatory immune cells.

Type 1 regulatory T cells

(Tr1 cells). A lineage of T cells that express the surface molecule CD4 and regulate the inflammatory response through the secretion of the anti-inflammatory cytokines interleukin-10 (IL-10) and transforming growth factor β1 (TGFβ1).

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van de Veerdonk, F., Gresnigt, M., Romani, L. et al. Aspergillus fumigatus morphology and dynamic host interactions. Nat Rev Microbiol 15, 661–674 (2017). https://doi.org/10.1038/nrmicro.2017.90

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