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Disparate proteome responses of pathogenic and nonpathogenic aspergilli to human serum measured by activity-based
Susan D Wiedner1, Charles Ansong, Bobbie-Jo Webb-Robertson
1Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, USA.
Abstract:
Aspergillus fumigatus is the primary pathogen causing the devastating pulmonary disease Invasive Aspergillosis in immunocompromised individuals. There is high genomic synteny between A. fumigatus and closely related rarely pathogenic Neosartorya fischeri and Aspergillus clavatus genomes. We applied activity-based protein profiling to compare unique or overexpressed activity-based probe-reactive proteins of all three fungi over time in minimal media growth and in response to human serum. We found 360 probe-reactive proteins exclusive to A. fumigatus, including known virulence associated proteins, and 13 proteins associated with stress response exclusive to A. fumigatus culture in serum. Though the fungi are highly orthologous, A. fumigatus has a significantly greater number of ABP-reactive proteins across varied biological process. Only 50% of expected orthologs of measured A. fumigatus reactive proteins were observed in N. fischeri and A. clavatus. Activity-based protein profiling identified a number of processes that were induced by human serum in A. fumigatus relative to N. fischeri and A. clavatus. These included actin organization and assembly, transport, and fatty acid, cell membrane, and cell wall synthesis. Additionally, signaling proteins regulating vegetative growth, conidiation, and cell wall integrity, required for appropriate cellular response to external stimuli, had higher activity-based probe-protein reaction over time in A. fumigatus and N. fisheri, but not in A. clavatus. Together, we show that measured proteins and physiological processes identified solely or significantly over-represented in A. fumigatus reveal a unique adaptive response to human protein not found in closely related, but rarely pathogenic aspergilli. These unique activity-based probe-protein responses to culture condition may reveal how A. fumigatus initiates pulmonary invasion leading to Invasive Aspergillosis.
Insights
Aspergillus fumigatus exhibits unique protein activity compared to related fungi, revealing adaptive responses to human serum that may drive invasive pulmonary aspergillosis. This study highlights distinct fungal proteomes and physiological processes contributing to pathogenicity.
Area of Science:
- Mycology
- Molecular Biology
- Pathogenomics
Background:
- Aspergillus fumigatus is a primary cause of invasive pulmonary aspergillosis in immunocompromised individuals.
- High genomic similarity exists between A. fumigatus and rarely pathogenic species like Neosartorya fischeri and Aspergillus clavatus.
- Understanding proteomic differences is crucial for identifying virulence factors.
Purpose of the Study:
- To compare the unique and overexpressed activity-based probe-reactive proteins of A. fumigatus, N. fischeri, and A. clavatus.
- To investigate fungal responses to minimal media growth and human serum exposure.
- To identify proteomic distinctions contributing to A. fumigatus pathogenicity.
Main Methods:
- Activity-based protein profiling (ABPP) was employed to analyze protein reactivity across three fungal species.
- Fungi were cultured in minimal media and in the presence of human serum.
- Probe-reactive proteins were quantified and compared over time.
Main Results:
- 360 probe-reactive proteins were exclusive to A. fumigatus, including known virulence factors.
- 13 stress-response proteins were unique to A. fumigatus in serum.
- Human serum induced distinct processes in A. fumigatus, including actin organization, membrane synthesis, and cell wall synthesis.
- Signaling proteins involved in growth and cellular response showed higher reactivity in A. fumigatus and N. fischeri compared to A. clavatus.
Conclusions:
- A. fumigatus possesses a unique set of reactive proteins and physiological processes, particularly in response to human serum, not observed in closely related species.
- These distinct adaptive responses suggest mechanisms by which A. fumigatus initiates pulmonary invasion and causes invasive aspergillosis.
- ABPP is a valuable tool for uncovering species-specific virulence mechanisms in pathogenic fungi.
