Aspergillus fumigatusMedA governs adherence, host cell interactions and virulence

Abstract

SummaryIn medically important fungi, regulatory elements that control development and asexual reproduction often govern the expression of virulence traits. We therefore cloned the Aspergillus fumigatus developmental modifier MedA and characterized its role in conidiation, host cell interactions and virulence. As in the model organism Aspergillus nidulans, disruption of medA in A. fumigatus dramatically reduced conidiation. However, the conidiophore morphology was markedly different between the two species. Further, gene expression analysis suggested that MedA governs conidiation through different pathways in A. fumigatus compared with A. nidulans. The A. fumigatus DmedA strain was impaired in biofilm production and adherence to plastic, as well as adherence to pulmonary epithelial cells, endothelial cells and fibronectin in vitro. The DmedA strain also had reduced capacity to damage pulmonary epithelial cells, and stimulate pro-inflammatory cytokine mRNA and protein expression. Consistent with these results, the A. fumigatus DmedA strain also exhibited reduced virulence in both an invertebrate and a mammalian model of invasive aspergillosis. Collectively, these results suggest that the downstream targets of A. fumigatus MedA mediate virulence, and may provide novel therapeutic targets for invasive aspergillosis.

Overlapping and Distinct Roles of Aspergillus fumigatus UDP-glucose 4-Epimerases in Galactose Metabolism and the Synthesis of Galactose-containing Cell Wall Polysaccharides

“…The ⌬uge3 mutant was described previously (22). Unless otherwise noted, strains were grown and harvested on YPD agar (Fisher) at 37°C as described previously (24). For growth in liquid medium, Brian medium (23), Aspergillus Minimum Medium (25), and RPMI 1640 medium (Wissent) were used as indicated.…”

Microbial glycoside hydrolases as antibiofilm agents with cross-kingdom activity

“…Biofilms are complex communities of microorganisms that grow embedded in an extracellular matrix composed of DNA, protein, and exopolysaccharide (7). Biofilm formation provides a significant advantage to these organisms because the matrix mediates adherence to host cells (8,9) and aids in the resistance to both antimicrobial agents (10,11) and host-immune defenses (12,13). A. fumigatus biofilm formation depends on the cationic polysaccharide galactosaminogalactan (GAG), a heteroglycan composed of α1,4-linked galactose and N-acetyl-D-galactosamine (GalNAc) that is partially deacetylated (14,15).…”

Biofilm Exopolysaccharides of Pathogenic Fungi: Lessons from Bacteria

“…External stimuli that induce or suppress biofilm formation have yet to be identified. Production of GAG is dependent on the developmental regulatory proteins MedA (8,41,42), StuA (8), and SomA (43). Activation of the cell wall integrity pathway through deletion of the phosphatases SitA (44) or PtcB (45) has been linked to suppression of biofilm formation and extracellular matrix production.…”