Aspergillus fumigatus MedA governs adherence, host cell interactions and virulence.
In 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. fumigatusDeltamedA 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 DeltamedA 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. fumigatusDeltamedA 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.
Gravelat
Fabrice N
FN
Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.
Ejzykowicz
Daniele E
DE
Chiang
Lisa Y
LY
Chabot
Josée C
JC
Urb
Mirjam
M
Macdonald
K Denyese
KD
al-Bader
Nadia
N
Filler
Scott G
SG
Sheppard
Donald C
DC
D000818:Animals; D001228:Aspergillosis / Q000382:microbiology / Q000401:mortality; D001232:Aspergillus fumigatus / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity*; D018441:Biofilms / Q000254:growth & development; D002448:Cell Adhesion; D002460:Cell Line; D042783:Endothelial Cells / Q000382:microbiology; D004847:Epithelial Cells / Q000382:microbiology; D005353:Fibronectins / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D054884:Host-Pathogen Interactions; D007915:Lepidoptera; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D013172:Spores, Fungal / Q000254:growth & development; D016019:Survival Analysis; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology*
D005353:Fibronectins; D005656:Fungal Proteins; D037521:Virulence Factors