Galectin-3 enhances neutrophil motility and extravasation into the airways during Aspergillus fumigatusinfection.

Brendan D Snarr,Donald C Sheppard,Benjamin Ralph,Masahiko S Satoh,Rachel Corsini,Bryan G Yipp,Yukiko Sato,Hiroshi Mukae,Takahiro Takazono,Mélanie Lehoux,Koichi Izumikawa,Irah L King,Guillaume St-Pierre,Shane R Baistrocchi,Lindsey R Baden,Sachiko Sato,Maziar Divangahi,Ann Rancourt,John R Wingard,Matthew P Cheng ,Michele W Sugrue

doi:10.1371/journal.ppat.1008741

Abstract

Aspergillus fumigatus is an opportunistic mold that infects patients who are immunocompromised or have chronic lung disease, causing significant morbidity and mortality in these populations. While the factors governing the host response to A. fumigatus remain poorly defined, neutrophil recruitment to the site of infection is critical to clear the fungus. Galectin-3 is a mammalian β-galactose-binding lectin with both antimicrobial and immunomodulatory activities, however the role of galectin-3 in the defense against molds has not been studied. Here we show that galectin-3 expression is markedly up-regulated in mice and humans with pulmonary aspergillosis. Galectin-3 deficient mice displayed increased fungal burden and higher mortality during pulmonary infection. In contrast to previous reports with pathogenic yeast, galectin-3 exhibited no antifungal activity against A. fumigatus in vitro. Galectin-3 deficient mice exhibited fewer neutrophils in their airways during infection, despite normal numbers of total lung neutrophils. Intravital imaging studies confirmed that galectin-3 was required for normal neutrophil migration to the airspaces during fungal infection. Adoptive transfer experiments demonstrated that stromal rather than neutrophil-intrinsic galectin-3 was necessary for normal neutrophil entry into the airspaces. Live cell imaging studies revealed that extracellular galectin-3 directly increases neutrophil motility. Taken together, these data demonstrate that extracellular galectin-3 facilitates recruitment of neutrophils to the site of A. fumigatus infection, and reveals a novel role for galectin-3 in host defense against fungal infections.

Highlights

Aspergillus fumigatus is an opportunistic fungal pathogen that commonly infects the respiratory tract of both immunocompromised patients and patients with chronic lung diseases such as cystic fibrosis [1,2,3]
We found that both mice and humans produce galectin-3 when infected with A. fumigatus, and mice lacking galectin-3 were more susceptible to infection than normal mice
Our study offers insights into the mechanisms underlying the recruitment of neutrophils to the airways during A. fumigatus infection and reveals a new role for galectin-3 in increasing neutrophil motility

Summary

Introduction

Aspergillus fumigatus is an opportunistic fungal pathogen that commonly infects the respiratory tract of both immunocompromised patients and patients with chronic lung diseases such as cystic fibrosis [1,2,3]. Pulmonary A. fumigatus infection manifests as a necrotizing pneumonia, which can disseminate via the bloodstream to distal organs such as the brain. Both clinical and experimental studies have shown that neutrophils play a vital role in the host defense against A. fumigatus [1,2]. There is an urgent need for novel treatment approaches for invasive fungal A. fumigatus infections. One such approach is to enhance innate immune responses to this filamentous fungus

Results

Discussion

Conclusion