Requisite role for the dectin-1 β-glucan receptor in pulmonary defense against Aspergillus fumigatus

Jessica L Werner, Allison E Metz, Dawn Horn, Trenton R Schoeb, Matthew M Hewitt, Lisa M Schwiebert, Ines Faro-Trindade, Gordon D Brown, Chad Steele

Research output: Contribution to journalArticle

280 Citations (Scopus)

Abstract

Immune suppression increases the incidence of invasive fungal infections, particularly those caused by the opportunistic mold Aspergillus fumigatus. Previous investigations revealed that members of the TLR family are not absolutely required for host defense against A. fumigatus in nonimmunosuppressed hosts, suggesting that other pattern recognition receptors are involved. We show in this study that naive mice (i.e., not pharmacologically immunosuppressed) lacking the beta-glucan receptor Dectin-1 (Dectin-1(-/-)) are more sensitive to intratracheal challenge with A. fumigatus than control mice, exhibiting >80% mortality within 5 days, ultimately attributed to a compromise in respiratory mechanics. In response to A. fumigatus challenge, Dectin-1(-/-) mice demonstrated impaired IL-1alpha, IL-1beta, TNF-alpha, CCL3/MIP-1alpha, CCL4/MIP-1beta, and CXCL1/KC production, which resulted in insufficient lung neutrophil recruitment and uncontrolled A. fumigatus lung growth. Alveolar macrophages from Dectin-1(-/-) mice failed to produce proinflammatory mediators in response to A. fumigatus, whereas neutrophils from Dectin-1(-/-) mice had impaired reactive oxygen species production and impaired killing of A. fumigatus. We further show that IL-17 production in the lung after A. fumigatus challenge was Dectin-1 dependent, and that neutralization of IL-17 significantly impaired A. fumigatus clearance. Collectively, these results support a requisite role for Dectin-1 in in vivo defense against A. fumigatus.
Original languageEnglish
Pages (from-to)4938-4946
Number of pages9
JournalThe Journal of Immunology
Volume182
Issue number8
DOIs
Publication statusPublished - 15 Apr 2009

Fingerprint

Aspergillus fumigatus
Glucans
Lung
Interleukin-17
dectin 1
Chemokine CCL4
Chemokine CCL3
Respiratory Mechanics
Pattern Recognition Receptors
Neutrophil Infiltration
Alveolar Macrophages
Reactive Oxygen Species
Neutrophils
Fungi
Tumor Necrosis Factor-alpha

Keywords

  • animals
  • aspergillosis
  • Aspergillus fumigatus
  • disease susceptibility
  • interleukin-17
  • lung diseases, fungal
  • male
  • membrane proteins
  • mice
  • nerve tissue proteins
  • neutrophils
  • receptors, immunologic
  • survival rate
  • time factors

Cite this

Werner, J. L., Metz, A. E., Horn, D., Schoeb, T. R., Hewitt, M. M., Schwiebert, L. M., ... Steele, C. (2009). Requisite role for the dectin-1 β-glucan receptor in pulmonary defense against Aspergillus fumigatus. The Journal of Immunology, 182(8), 4938-4946. https://doi.org/10.4049/jimmunol.0804250

Requisite role for the dectin-1 β-glucan receptor in pulmonary defense against Aspergillus fumigatus. / Werner, Jessica L; Metz, Allison E; Horn, Dawn; Schoeb, Trenton R; Hewitt, Matthew M; Schwiebert, Lisa M; Faro-Trindade, Ines; Brown, Gordon D; Steele, Chad.

In: The Journal of Immunology, Vol. 182, No. 8, 15.04.2009, p. 4938-4946.

Research output: Contribution to journalArticle

Werner, JL, Metz, AE, Horn, D, Schoeb, TR, Hewitt, MM, Schwiebert, LM, Faro-Trindade, I, Brown, GD & Steele, C 2009, 'Requisite role for the dectin-1 β-glucan receptor in pulmonary defense against Aspergillus fumigatus', The Journal of Immunology, vol. 182, no. 8, pp. 4938-4946. https://doi.org/10.4049/jimmunol.0804250
Werner, Jessica L ; Metz, Allison E ; Horn, Dawn ; Schoeb, Trenton R ; Hewitt, Matthew M ; Schwiebert, Lisa M ; Faro-Trindade, Ines ; Brown, Gordon D ; Steele, Chad. / Requisite role for the dectin-1 β-glucan receptor in pulmonary defense against Aspergillus fumigatus. In: The Journal of Immunology. 2009 ; Vol. 182, No. 8. pp. 4938-4946.
@article{a4ddc2d5f6094399a27cd8913d3675f0,
title = "Requisite role for the dectin-1 β-glucan receptor in pulmonary defense against Aspergillus fumigatus",
abstract = "Immune suppression increases the incidence of invasive fungal infections, particularly those caused by the opportunistic mold Aspergillus fumigatus. Previous investigations revealed that members of the TLR family are not absolutely required for host defense against A. fumigatus in nonimmunosuppressed hosts, suggesting that other pattern recognition receptors are involved. We show in this study that naive mice (i.e., not pharmacologically immunosuppressed) lacking the beta-glucan receptor Dectin-1 (Dectin-1(-/-)) are more sensitive to intratracheal challenge with A. fumigatus than control mice, exhibiting >80{\%} mortality within 5 days, ultimately attributed to a compromise in respiratory mechanics. In response to A. fumigatus challenge, Dectin-1(-/-) mice demonstrated impaired IL-1alpha, IL-1beta, TNF-alpha, CCL3/MIP-1alpha, CCL4/MIP-1beta, and CXCL1/KC production, which resulted in insufficient lung neutrophil recruitment and uncontrolled A. fumigatus lung growth. Alveolar macrophages from Dectin-1(-/-) mice failed to produce proinflammatory mediators in response to A. fumigatus, whereas neutrophils from Dectin-1(-/-) mice had impaired reactive oxygen species production and impaired killing of A. fumigatus. We further show that IL-17 production in the lung after A. fumigatus challenge was Dectin-1 dependent, and that neutralization of IL-17 significantly impaired A. fumigatus clearance. Collectively, these results support a requisite role for Dectin-1 in in vivo defense against A. fumigatus.",
keywords = "animals, aspergillosis, Aspergillus fumigatus, disease susceptibility, interleukin-17, lung diseases, fungal, male, membrane proteins, mice, nerve tissue proteins, neutrophils, receptors, immunologic, survival rate, time factors",
author = "Werner, {Jessica L} and Metz, {Allison E} and Dawn Horn and Schoeb, {Trenton R} and Hewitt, {Matthew M} and Schwiebert, {Lisa M} and Ines Faro-Trindade and Brown, {Gordon D} and Chad Steele",
year = "2009",
month = "4",
day = "15",
doi = "10.4049/jimmunol.0804250",
language = "English",
volume = "182",
pages = "4938--4946",
journal = "The Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "8",

}

TY - JOUR

T1 - Requisite role for the dectin-1 β-glucan receptor in pulmonary defense against Aspergillus fumigatus

AU - Werner, Jessica L

AU - Metz, Allison E

AU - Horn, Dawn

AU - Schoeb, Trenton R

AU - Hewitt, Matthew M

AU - Schwiebert, Lisa M

AU - Faro-Trindade, Ines

AU - Brown, Gordon D

AU - Steele, Chad

PY - 2009/4/15

Y1 - 2009/4/15

N2 - Immune suppression increases the incidence of invasive fungal infections, particularly those caused by the opportunistic mold Aspergillus fumigatus. Previous investigations revealed that members of the TLR family are not absolutely required for host defense against A. fumigatus in nonimmunosuppressed hosts, suggesting that other pattern recognition receptors are involved. We show in this study that naive mice (i.e., not pharmacologically immunosuppressed) lacking the beta-glucan receptor Dectin-1 (Dectin-1(-/-)) are more sensitive to intratracheal challenge with A. fumigatus than control mice, exhibiting >80% mortality within 5 days, ultimately attributed to a compromise in respiratory mechanics. In response to A. fumigatus challenge, Dectin-1(-/-) mice demonstrated impaired IL-1alpha, IL-1beta, TNF-alpha, CCL3/MIP-1alpha, CCL4/MIP-1beta, and CXCL1/KC production, which resulted in insufficient lung neutrophil recruitment and uncontrolled A. fumigatus lung growth. Alveolar macrophages from Dectin-1(-/-) mice failed to produce proinflammatory mediators in response to A. fumigatus, whereas neutrophils from Dectin-1(-/-) mice had impaired reactive oxygen species production and impaired killing of A. fumigatus. We further show that IL-17 production in the lung after A. fumigatus challenge was Dectin-1 dependent, and that neutralization of IL-17 significantly impaired A. fumigatus clearance. Collectively, these results support a requisite role for Dectin-1 in in vivo defense against A. fumigatus.

AB - Immune suppression increases the incidence of invasive fungal infections, particularly those caused by the opportunistic mold Aspergillus fumigatus. Previous investigations revealed that members of the TLR family are not absolutely required for host defense against A. fumigatus in nonimmunosuppressed hosts, suggesting that other pattern recognition receptors are involved. We show in this study that naive mice (i.e., not pharmacologically immunosuppressed) lacking the beta-glucan receptor Dectin-1 (Dectin-1(-/-)) are more sensitive to intratracheal challenge with A. fumigatus than control mice, exhibiting >80% mortality within 5 days, ultimately attributed to a compromise in respiratory mechanics. In response to A. fumigatus challenge, Dectin-1(-/-) mice demonstrated impaired IL-1alpha, IL-1beta, TNF-alpha, CCL3/MIP-1alpha, CCL4/MIP-1beta, and CXCL1/KC production, which resulted in insufficient lung neutrophil recruitment and uncontrolled A. fumigatus lung growth. Alveolar macrophages from Dectin-1(-/-) mice failed to produce proinflammatory mediators in response to A. fumigatus, whereas neutrophils from Dectin-1(-/-) mice had impaired reactive oxygen species production and impaired killing of A. fumigatus. We further show that IL-17 production in the lung after A. fumigatus challenge was Dectin-1 dependent, and that neutralization of IL-17 significantly impaired A. fumigatus clearance. Collectively, these results support a requisite role for Dectin-1 in in vivo defense against A. fumigatus.

KW - animals

KW - aspergillosis

KW - Aspergillus fumigatus

KW - disease susceptibility

KW - interleukin-17

KW - lung diseases, fungal

KW - male

KW - membrane proteins

KW - mice

KW - nerve tissue proteins

KW - neutrophils

KW - receptors, immunologic

KW - survival rate

KW - time factors

U2 - 10.4049/jimmunol.0804250

DO - 10.4049/jimmunol.0804250

M3 - Article

C2 - 19342673

VL - 182

SP - 4938

EP - 4946

JO - The Journal of Immunology

JF - The Journal of Immunology

SN - 0022-1767

IS - 8

ER -