The Zrf C alkaline zinc transporter is required for Aspergillus fumigatus virulence and its growth in the presence of the Zn/Mn-chelating protein calprotectin

Ref ID: 19614

Author:

J Amich1,3*, A Ruiz-Carmuega1, E Mellado2, R Vicentefranqueira1, F Leal1, JA Calera1

Author address:

1Instituo de Biologí­a Funcional y Genómica (IBGF) CSIC/Universidadn de Salamanca, Salamanca, Spain
2Centro Nacional de Microbiologí­a. Instituto de Salud Carlos III. Madrid, Spain
3IZKF Forschengruppe für Experimentelle Stammcelltransplantation. Med

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Purpose:
Zinc is an essential micronutrient, required for the proper function of many proteins in which it plays
a catalytic, cocatalytic, and/or structural role. Therefore, to grow within the lungs of a susceptible
host Aspergillus fumigatus must be able to obtain zinc from the tissue. The bioavailability of this
element in the living tissues is, however, very low since most of it is tightly bound to proteins.
Moreover, its availability can be further decreased upon infection by the neutrophil-released protein
calprotectin.We previously demonstrated that the correct regulation of zinc homeostasis by the
transcriptional factor ZafA is essential for A. fumigatus virulence. In this work we investigated the
role of the main zinc permeases – ZrfA, ZrfB and ZrfC – in the pathobiology of A. fumigatus.
Methods:
We investigated the virulence of various single, double and triple A. fumigatus mutant strains in
two different mouse models of invasive aspergillosis: neutropenic (cyclophosphamide-cortisone
treated) and non-neutropenic (cortisone treated) mice. In addition, we analyzed histological sections
of infected lungs and performed immunohistochemistry localization of calprotectin. Furthermore,
we tested the growth capacity of several strains in the presence of recombinant human calprotectin
(rhCP).
Results:
The sole presence of ZrfC is sufficient for full virulence, proving that this is the major transporter
devoted to scavenge and uptake zinc from living tissues. zrfA and zrfB genes are not required in the
presence of ZrfC, but can partially compensate its absence as a result of the upregulation of their
transcription. The ZrfC scavenging capacity is largely dependent on its N-terminus, which is absent
in the ZrfA and ZrfB proteins. Furthermore, we show that zrfC enables A. fumigatus to overcome
the Zn/Mn-chelating capacity of calprotectin, which may explain the higher relevance of ZrfC
for virulence in the non-neutropenic mice. Therefore, we propose that the presence or absence of
calprotectin might be one of the major reasons of the different susceptibility to infection depending
on the immunosuppression regime administered.
Conclusions:
Our results prove that zrfC confers A. fumigatus the capacity to grow in the alkaline zinc-limiting
environment provided by the lung tissue of immunosupressed individuals. This finding extends our
knowledge about the pathobiology of A. fumigatus and might anticipate the development of new
antifungal therapies to treat IPA based on inhibiting fungal zinc uptake.
NOTE: THIS ABSTRACT HAS BEEN SELECTED FOR ORAL PRESENTATION.

Abstract Number: 139

Conference Year: 2014

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

New link: NULL

Conference abstracts, posters & presentations

Showing 10 posts of 17325 posts found.

  • Title

    Author

    Year

    Number

    Poster