Dr Paul Bowyer is the Principle Scientist at the National Aspergillosis Centre. This talk was given to a group of professionals allied to medicine who are attending an education & awareness day at the Centre. Dr Bowyer summarises our current understanding of the pathogenic processes that lead to an aspergillus infection.

1. Aspergillus Research
– What's Coming Next?
Paul Bowyer
University of Manchester

2. The genus Aspergillus
Discovered by Micheli in June 1729
The species A. fumigatus
Diverged ~720,000
years ago

3. - the story so far....
IMMUNE
RESPONSE!
IRON
CELL WALL
With apologies to Hanabusa Itcho

4. - what we know about the disease

5. What the blind monks should really have been asking....
How big is it?
Is it dangerous???

6. Thre real level of disease...
Predominant At Risk Prevalence Annual burden
risk groups population
ABPA 1,5,6 Asthma 34,700,000 2.1% 729,000 (243 –
1,215)
Cystic fibrosis 29,000 15% 4.300
Frequency of aspergillosis
Frequency of aspergillosis
SAFS 1,5 Severe asthma 3,470,000 33% 1,145,000
CPA 4 COPD, >13,600,000 1-10% 204,000
sarcoidosis, TB,
ABPA,
Invasive
Aspergillosis
>25000 /year
Immune dysfunction Immune hyperactivity

7. - what we know about the fungus

8. The fundamental interconnectedness of all things...
Multiple processes in fungal and human cells interact in complicated ways to cause disease
In order to understand how disease occurs it is necessary to look at the whole elephant
New techniques such as systems biology and high throughput sequencing are now used
to do this.
We are moving away from study of single genes or proteins towards studying all
Simultaneously.
- fungi produce about 10,000 proteins and human cells about 25,000

9. Organisms are complex....

10. Candida protein networks involved in biofilm formation:
Nobile et al. A Recently Evolved Transcriptional Network Controls Biofilm Development in Candida albicansCell 148:126-138

11. High throughput approaches used to determine global transcription, genetic polymorphisms
and gene function. Systems biology is used to find patterns and networks...
Condition
Transcription factors
Genes of interest

12. The drugs dont work:
How is Aspergillosis treated now??
- does it work??
– will this change??

13. Global increase in drug resistance

14. Processes involved in drug resistance:

15. - what we know about the patient

16. 'New genetics'
Previously:
- look in families or do crosses and
look at the progeny...
Now:
- follow DNA polymorphisms in populations,
• sequence genomes

17. How does the immune system stop fungal disease?
The innate immune response is a complex multicellular process.
Meet the cells....
IMMUNE CELL: ROLE:
DETECTS PATHOGENS,
SNEAKS OFF AND
PROGRAMS THE
IMMUNE RESPONSE
DENDRITIC CELL

18. IMMUNE CELL: ROLE:
STOPS AND APPREHENDS
KNOWN PATHOGENS
MACROPHAGE
IMMUNE CELL: ROLE:
BRUTALLY ATTACKS THINGS
NEUTROPHIL

19. How the immune system stops fungal disease:
MACROPHAGE
EPITHELIUM
DENDRITIC CELL

20. How the immune system stops fungal disease:
WHATS ALL THIS
'ERE THEN?
MACROPHAGE
EPITHELIUM
I SAY CHAPS! DENDRITIC CELL

21. How the immune system stops fungal disease:
OI! NOW THEN
OI!!
MACROPHAGE
OI!!!
EPITHELIUM
DENDRITIC CELL
NEUTROPHILS

22. Adaptive Immunity – changes may lead to allergy

23. Individuals with fungal disease have:
Changes in genes that affect macrophage or dendritic cell ability to
percieve the pathogen
Changes in genes that affect the ability of cells to move to the point
of infection
Changes in genes that mediate chemical attack on the fungus

24. In conclusion:
Our knowledge of the disease in various forms is increasing rapidly. The huge burden of
fungal disease worldwide is becoming clear.
Our ability to find genetic changes associated with disease has increased in recent years
In fact a Manchester project will discover all of the variants associated with ABPA
within one year...
We may be able to pinpoint the important variants...
Our knowledge of fungal systems is increasing. More than 50 genome sequences and
transcriptomes have been determined. We are expecting to be able to pinpoint processes
involved in disease.