Aspergillus fumigatus is an environmental filamentous fungus that can cause life-threatening disease in immunocompromised individuals. The interactions between A. fumigatus and the host environment are dynamic and complex. The host immune system needs to recognize the distinct morphological forms of A. fumigatus to control fungal growth and prevent tissue invasion, whereas the fungus requires nutrients and needs to adapt to the hostile environment by escaping immune recognition and counteracting host responses. Understanding these highly dynamic interactions is necessary to fully understand the pathogenesis of aspergillosis and to facilitate the design of new therapeutics to overcome the morbidity and mortality caused by A. fumigatus. In this Review, we describe how A. fumigatus adapts to environmental change, the mechanisms of host defence, and our current knowledge of the interplay between the host immune response and the fungus.

The Hog1 MAP kinase pathway regulates stress adaptation in several fungi. To assess its role in stress adaptation in Aspergillus fumigatus, we constructed mutants in genes encoding the sensor histidine kinase (HK) tcsB as well as sakA, which are homologues of the Saccharomyces cerevisiae sln1 and Hog1, respectively. Compared to the wild type strain (Wt), growth of sakA (sakAtriangle up) mutant was reduced, and growth inhibition was increased when H(2)O(2), menadione, or SDS was added to the media. On the other hand, the tcsB mutant (tcsBtriangle up) was similar to the Wt strain in regard to growth and morphology, although a partial sensitivity to SDS was observed. Western blot analysis of Wt and the tcsBtriangle up strains indicated that when stressed with H(2)O(2), phosphorylation of Hog1p still occurs in the mutant. Since in Candida albicans, Hog1 regulates transcription of at least one histidine kinase, we performed RT-PCR of 6 histidine kinase genes as well as the ssk1 and skn7 response regulator genes of A. fumigatus. No significant differences in transcription were observed with the sakAtriangle up when compared to the Wt, indicating that the sakA does not regulate transcription of these genes. Our studies indicate that the A. fumigatus sakA is required for optimal growth of the organism with or without oxidant stress, while tcsB gene is dispensable.

In Aspergillus fumigatus, like in other pathogenic fungi, the cell wall is essential for fungal growth as well as for resisting environmental stresses such as phagocytic killing. Most of the chemical analyses undertaken on the cell wall of A. fumigatus are focused on the mycelial cell wall because it is the vegetative stage of the fungus. However, the cell walls of the mycelium and conidium (which is the infective propagule) are different especially at the level of the surface layer, which plays a significant role in the interaction between A. fumigatus conidia and phagocytic cells of the immune system. In spite of the essential function of the cell wall in fungal life, progresses have been extremely slow in the understanding of biosynthesis as well in the identification of the key host responses against the cell wall components. A major difficulty is the fact that the composition and structural organization of the cell wall is not immutably set and is constantly reshuffled depending on the environmental conditions.

Differences were detectable among strains of the opportunist fungal pathogen Aspergillus fumgatus when watersoluble (WS) preparations were analysed by combined SDS-PAGE and Western blotting procedures. A wide range of molecules of apparent molecular masses from approximately 20 to > lo0 kDa showed specific binding to antibodies raised in rabbits to A. fumgatus wall and cytoplasmic components. The ability to bind antibody was markedly reduced by treatment of these antigens with sodium periodate or with specific proteases or glucanases. Pretreatment of blotted antigens with either concanavalin A (ConA) or wheat germ agglutinin (WGA) did not, however, inhibit subsequent antibody binding. The antigens of subfractions prepared from a single strain of A. fumigatus WS material were also susceptible to periodate oxidation and enzymic hydrolysis. Slight crossreactivity was apparent when crude preparations of cellular or culture filtrate antigens, used in this laboratory to detect antibodies to C d i h albkarts, Coccidioides immitis and Cryptococcus neoformans, were probed with hyperimmune rabbit antisera to A. fumigatus. Efforts were made to characterize the WS preparations of A. fumgatus, used as diagnostic antigens in many laboratories. The electrophoretically separated antigenic moieties were shown to be predominantly glycoproteins. Binding of cytoplasmic antigens to antibodies raised to wall material showed the presence of many common components in both wall and cytosol. Antiserum to wall components revealed most differentiation among A. fumigatus strains.

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