MyD88 signaling contributes to early pulmonary responses to Aspergillus fumigatus

Camille Bretz, Geoff Gersuk, Sue Knoblaugh, Neelkamal Chaudhary, Julie Randolph-Habecker, Robert C. Hackman, Janet Staab, Kieren A. Marr

Research output: Contribution to journalArticle

Abstract

Toll-like receptors and the β-glucan receptor, dectin-1, mediate macrophage inflammatory responses to Aspergillus fumigatus through MyD88-dependent and -independent signaling mechanisms; however, pulmonary inflammatory responses in MyD88-deficient mice challenged with A. fumigatus are poorly defined. The role of MyD88 signaling in early pulmonary inflammation and fungal clearance was evaluated in C57BL/6J wild-type (WT) and MyD88-deficient (MyD88-/-) mice. Early (<48 h) after infection, MyD88 -/- mice had higher fungal burdens than those of WT mice, although fungal burdens rapidly declined (>72 h) in both. MyD88-/- mice had less consolidated inflammation, with fewer NK cells, in lung tissue early (24 h) after infection than did WT mice. At the latter time point, MyD88 -/- mouse lungs were characterized by a large amount of necrotic cellular debris and fibrin, while WT lungs had organized inflammation. Although there were equivalent numbers of macrophages in WT and MyD88-/- mouse lung tissues, MyD88-/- cells demonstrated delayed uptake of green fluorescent protein-expressing A. fumigatus (GFP-Af293); histologically, MyD88-/- mouse lungs had more hyphal invasion of terminal airways and vessels, the appearance of bronchiolar epithelial cell necrosis, and necrotizing vasculitis. MyD88-/- lung homogenates contained comparatively decreased amounts of interleukin-1β (IL-1β), IL-6, KC, and gamma interferon and paradoxically increased amounts of tumor necrosis factor alpha and macrophage inflammatory protein 1α. These data indicate that the MyD88-dependent pathway mediates acute pulmonary fungal clearance, inflammation, and tissue injury very early after infection. Resolution of abnormalities within a 3-day window demonstrates the importance of redundant signaling pathways in mediating pulmonary inflammatory responses to fungi.

Original languageEnglish (US)
Pages (from-to)952-958
Number of pages7
JournalInfection and immunity
Volume76
Issue number3
DOIs
StatePublished - Mar 1 2008

    Fingerprint

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

Bretz, C., Gersuk, G., Knoblaugh, S., Chaudhary, N., Randolph-Habecker, J., Hackman, R. C., Staab, J., & Marr, K. A. (2008). MyD88 signaling contributes to early pulmonary responses to Aspergillus fumigatus. Infection and immunity, 76(3), 952-958. https://doi.org/10.1128/IAI.00927-07