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Aspergillus fumigatus  is one of the major causes of invasive pulmonary aspergillosis in immunocompromised patients. Novel antifungal therapy is in urgent need due to emerging resistance and adverse toxicity of current antifungal drugs. Gene products that are essential for  Aspergillus  viability during infection are attractive drug targets. To characterize these genes  in vivo  we developed a Tet-Off gene expression system in  A. fumigatus , whereby the administration of doxycycline resulted in down regulation of the gene whose expression is under the control of the Tet-Off promoter. We tested the system on two potential drug targets, inosine 5′-monophosphate dehydrogenase ( IMPDH ) and L-ornithine N 5 -oxygenase ( sidA ) in a murine invasive pulmonary aspergillosis model. We show that depletion of  IMPDH  attenuated but did not completely abolish virulence  in vivo  whereas turning off the expression of  sidA , which is required for iron acquisition, resulted in avirulence. We also investigated whether  sidA  expression could be controlled in a time-dependent manner in mice. Our results demonstrated that timing of doxycycline administration dramatically affects survival rate, suggesting that this genetic system can be used for testing whether an antifungal drug target is critical for fungal growth post-infection.

A Tet-Off gene expression system for validation of antifungal drug targets in a murine invasive pulmonary aspergillosis model