The ZrfC alkaline zinc transporter is required for Aspergillus fumigatus virulence and its growth in the presence of the Zn/Mn-chelating protein calprotectin.
Aspergillus fumigatus can invade the lungs of immunocompromised individuals causing a life-threatening disease called invasive pulmonary aspergillosis (IPA). To grow in the lungs, A. fumigatus obtains from the host all nutrients, including zinc. In living tissues, however, most zinc is tightly bound to zinc-binding proteins. Moreover, during infection the bioavailability of zinc can be further decreased by calprotectin, an antimicrobial Zn/Mn-chelating protein that is released by neutrophils in abscesses. Nevertheless, A. fumigatus manages to uptake zinc from and grow within the lungs of susceptible individuals. Thus, in this study we investigated the role of the zrfA, zrfB and zrfC genes, encoding plasma membrane zinc transporters, in A. fumigatus virulence. We showed that zrfC is essential for virulence in the absence of zrfA and zrfB, which contribute to fungal pathogenesis to a lesser extent than zrfC and are dispensable for virulence in the presence of zrfC. The special ability of ZrfC to scavenge and uptake zinc efficiently from lungtissue depended on its N-terminus, which is absent in the ZrfA and ZrfB transporters. In addition, under Zn- and/or Mn-limiting conditions zrfC enables A. fumigatus to grow in the presence of calprotectin, which is detected in fungal abscesses of non-leucopenic animals. This study extends our knowledge about the pathobiology of A. fumigatus and suggests that fungal zinc uptake could be a promising target for new antifungals.
Instituto de Biología Funcional y Genómica (IBFG), centro mixto del Consejo Superior de Investigaciones Científicas y Universidad de Salamanca, Edificio IBFG, Lab. P1.10. C/Zacarías González n°2, 37007, Salamanca, Spain.
Jorge
J
Amich
Rocío
R
Vicentefranqueira
Emilia
E
Mellado
Ana
A
Ruiz-Carmuega
Fernando
F
Leal
José Antonio
JA
Calera
D001232:Aspergillus fumigatus / Q000201:enzymology* / Q000254:growth & development / Q000472:pathogenicity*; D002352:Carrier Proteins / Q000378:metabolism*; D039841:Leukocyte L1 Antigen Complex / Q000378:metabolism*; D008345:Manganese / Q000378:metabolism*; D014774:Virulence; D015032:Zinc / Q000378:metabolism*
D002352:Carrier Proteins; D039841:Leukocyte L1 Antigen Complex; C017800:zinc-binding protein; D008345:Manganese; D015032:Zinc