Neutrophil S100A8/A9 (calprotectin ) zinc chelation regulates Aspergillus fumigatus hyphal growth in vitro and in a murine model of corneal infection

Ref ID: 19593

Author:

HL Clark1*, Y Sun1, JP Latgé2, JA Calera3, E Pearlman1

Author address:

1Ophthalmology and Visual Science, Case Western Reserve University, Cleveland, USA
2Laboratoire des Aspergillus, Institut Pasteur, Paris, France
3Departamento de Microbiologí­a y Genética, Universidad de Salamanca, Salamanca, Spain

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Background:
Zinc is required for many cellular processes that are essential for fungal growth and survival. S100A8
and S100A9 are proteins abundant in neutrophils which compete for free Zn2+, thereby limiting
fungal growth. We examined the role of neutrophil S100A8/A9 in killing wild-type Aspergillus
fumigatus and A. fumigatus strains with mutations in the transcription factor ZafA, zinc importers
ZrfA/ZrfB and ZrfC and secreted protein Aspf2, all of which comprise the A. fumigatus zinc uptake
system in zinc limiting environments.
Purpose:
The purpose of this study is to examine the role of neutrophil S100A8/A9 in control of A. fumigatus
growth in vivo and in vitro and to determine whether A. fumigatus zinc uptake allows for fungal
survival in the presence of S100A8/A9.
Methods:
Wild-type or mutant strains of A. fumigatus were incubated with neutrophils from S100A9-/- and
control C57BL/6 mice in low (RPMI 1640) or high Zn2+ (RPMI + ZnSO4) media, and fungal growth
was quantified by total chitin. The role of S100A8/A9 was also examined in a well-established
murine model of corneal disease.
Results:
C57BL/6 neutrophils inhibited the growth of wild-type and all mutant strains of A. fumigatus in
low Zn2+, which was ablated in by adding exogenous Zn2+. In contrast to C57BL/6 neutrophils,
S100A9-/- neutrophils were unable to control the growth of wild-type, 916;ZrfA/B and 916;Aspf2 strains
in low Zn2+, but did limit the growth of 916;ZafA and 916;ZrfC strains. Growth of wild-type A. fumigatus
in the corneal stroma was significantly higher in S100A9-/- mice compared to C57BL/6 mice,
although there was no difference in neutrophil infiltration.
Conclusions:
Neutrophil S100A8/A9 regulates growth of wild-type A. fumigatus in vivo and in vitro by competing
for available Zn2+. The susceptibility of 916;ZrfC and 916;ZafA mutants to killing by S100A9-/-
neutrophils suggests a role for additional mechanisms of zinc control by neutrophils and indicates
that ZafA and ZrfC are essential for A. fumigatus survival in the presence of neutrophils.

Abstract Number: 118

Conference Year: 2014

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

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