Activation and evasion of innate immunity by Aspergillus fumigatus

Ref ID: 19612

Author:

SGE Braem1*, JJPA de Cock2, HAB Wösten2, JAG van Strijp1, PJA Haas1

Author address:

1Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands
2Microbiology and Kluyver Centre for Genomics of Industrial Fermentation, Utrecht University, Utrecht,
The Netherlands

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Purpose:
Phagocyte recruitment is essential for effective clearance of Aspergillus fumigatus. Once pathogens
invade the human body, they are opsonised by serum components such as activated complement
proteins and antibodies. Complement can be activated via antibody-antigen complexes, via the
recognition of sugars and via spontaneous activation. Activation of the complement system
results in deposition of complement component C3b on the outer cell wall of the pathogen and the
generation of small complement molecules in fluid phase, mediating chemotaxis and inflammation.
In response to inflammatory cytokines, endothelial cells of the blood vessel express P-selectin.
P-selectin glycoprotein ligand 1 (PSGL-1), a cell surface receptor expressed on leukocytes,
interacts with P-selectin leading to leukocyte rolling on endothelial cells. After firm adhesion,
leukocytes transmigrate through the endothelial layer into the tissue and migrate via a gradient of
chemoattractants to the site of infection. Leukocytes recognize the pathogen by sensing deposited
C3b molecules and antibodies on the outer cell wall. This opsonisation process is indispensable for
efficient phagocytosis and subsequent killing and clearance of the invading pathogen.
Methods:
In this study we investigated the processes of extravasation of phagocytes and the opsonisation,
phagocytosis and clearance of A. fumigatus. We demonstrate that complement is essential for
phagocytosis by neutrophils of swollen conidia and germ tubes. Although antibodies bind both
morphotypes, antibodies only are insufficient for opsonisation and phagocytosis. Interestingly,
anti-Aspergillus antibodies are required to activate the complement system. This C3b mediated
opsonisation results in efficient phagocytosis and is essential in the killing of A. fumigatus by
neutrophils.
Results:
Previous studies showed that A. fumigatus possesses strategies to evade the innate immune system.
No factors have previously been identified that interfere with phagocyte extravasation. Therefore,
we focussed on the potential of A. fumigatus to modulate cell rolling, the primary process upon
phagocyte recruitment. Using immunoprecipitation with immobilized PSGL-1 we identified
a previously uncharacterized secreted protein that binds to the phagocyte surface. Antibody
competition experiments reveal that the secreted protein binds to the ligand binding part of PSGL-1.
Moreover, post-translational modifications of PSGL-1, which are crucial for P-selectin binding, are
also essential for the binding of the secreted protein.
Conclusion:
In conclusion, we show that antibody mediated activation of complement is essential for efficient
phagocytosis and killing of A. fumigatus. We identified a previously uncharacterized protein secreted
by A. fumigatus that binds PSGL-1 expressed on the phagocyte surface and potentially functions as a
virulence factor that can hamper recruitment of phagocytes to A. fumigatus infected tissue.

Abstract Number: 137

Conference Year: 2014

Link to conference website: http://www.AAA2014.org

New link: NULL

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