The opportunistic pathogen Aspergillus fumigatus (Af) causes the majority of cases of invasive aspergillosis. Because Af enters the body through inhalation of air-borne conidia, the interaction of conidia with the innate immune system (alveolar macrophages) plays a key role in the aetiology of invasive aspergillosis. The mechanisms underlying the anticonidial activity of macrophages and the relative resistance of conidia against the respective effector processes are a matter of debate. Modulation of host cell apoptosis has been reported to be one of the mechanisms pathogens employ to overcome host cell defences. Hence, we focused our attention on the influence of Af conidia on staurosporine (STS)-induced apoptosis of murine alveolar macrophages (MH-S). MH-S cells exposed to Af conidia and treated with STS showed a decreased number of apoptotic cells compared to STS-induced control cells examined by flow cytometry analysis, DNA fragmentation and immunoblotting. The observed anti-apoptotic effect of Af conidia on MH-S cells was found to be associated with a significant reduction of active caspase-3, -6, -7, -8 and -9, which are critical mediators of receptor as well as mitochondria-mediated events of apoptosis. Furthermore, inhibition of apoptosis in MH-S cells exposed to Af conidia correlated with phosphorylation of the proapoptotic Bcl-2 family member Bad and a diminished cytochrome c release from mitochondria. An Af mutant strain lacking a specific enzyme in the dihydroxynapthol (DHN)-melanin biosynthesis pathway, which is required for the biosynthesis of the gray-green pigment, showed no inhibitory effect on STS-induced apoptosis in MH-S cells. Thus, it seems likely that an intermediate or derivative of DHN melanin functions as a virulence factor by enhancing the resistance of fungal cells against attack by host effector mechanisms and also has the ability to modulate host cell apoptosis.
Full conference title:
9th EUROPEAN CONFERENCE ON FUNGAL GENETICS
- ECFG 9th (2008)