Abstract
Invasive aspergillosis and other fungal infections occur in immunocompromised individuals, including patients who received blood-building stem cell transplants, patients with chronic granulomatous disease (CGD), and others. Production of reactive oxygen species (ROS) by immune cells, which incidentally is defective in CGD patients, is considered to be a fundamental process in inflammation and antifungal immune response. Here we show that the peroxiredoxin Asp f3 of Aspergillus fumigatus inactivates ROS. We report the crystal structure and the catalytic mechanism of Asp f3, a two-cysteine type peroxiredoxin. The latter exhibits a thioredoxin fold and a homodimeric structure with two intermolecular disulfide bonds in its oxidized state. Replacement of the Asp f3 cysteines with serine residues retained its dimeric structure, but diminished Asp f3’s peroxidase activity, and extended the alpha-helix with the former peroxidatic cysteine residue C61 by six residues. The asp f3 deletion mutant was sensitive to ROS, and this phenotype was rescued by ectopic expression of Asp f3. Furthermore, we showed that deletion of asp f3 rendered A. fumigatus avirulent in a mouse model of pulmonary aspergillosis. The conserved expression of Asp f3 homologs in medically relevant molds and yeasts prompts future evaluation of Asp f3 as a potential therapeutic target.
Highlights
Of the fundamental defense mechanism against infection with A. fumigatus, but whether these toxic molecules target the fungus directly is not known
Aspf[3] wild type (WT) and its C31S/C61S variant crystallized as a homodimer and showed a typical thioredoxin-like fold[11,12,13]
Disruption of the intermolecular disulfide bond in C31S/C61S variant extends the α-helix by 6 residues resulting in a significant movement of S61 by ~7–9 Å from the position occupied by C61 in the WT structure (Fig. 2, Table 1), analogous to the movement of C62 in the reduced form of Ahp[115]
Summary
Of the fundamental defense mechanism against infection with A. fumigatus, but whether these toxic molecules target the fungus directly is not known. We have studied the A. fumigatus protein Asp f3 and its role for the protection of the fungus against ROS. Asp f3 co-localizes with peroxisomes and shows peroxide dependent up-regulation at the transcriptional and translational level[8,10]. It contains 168 amino acid residues and BLAST searches reveal considerable sequence homology to the thioredoxin superfamily, the peroxiredoxin (Prx) family, and the PRX5-like subfamily. We provide evidence for the critical role of Asp f3 in fungal virulence, wherein it protects A. fumigatus against oxidative stress in vitro, and in vivo, in a murine model of invasive pulmonary aspergillosis
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