Dr Paul Bowyer - Aspergillosis Study Day May 1st 2012

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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.

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Dr Paul Bowyer - Aspergillosis Study Day May 1st 2012

  1. 1. Aspergillus Research– Whats Coming Next? Paul Bowyer University of Manchester
  2. 2. The genus Aspergillus Discovered by Micheli in June 1729The species A. fumigatusDiverged ~720,000years ago
  3. 3. - the story so far.... IMMUNE RESPONSE! IRON CELL WALL With apologies to Hanabusa Itcho
  4. 4. - what we know about the disease
  5. 5. What the blind monks should really have been asking.... How big is it? Is it dangerous???
  6. 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. 7. - what we know about the fungus
  8. 8. The fundamental interconnectedness of all things...Multiple processes in fungal and human cells interact in complicated ways to cause diseaseIn order to understand how disease occurs it is necessary to look at the whole elephantNew techniques such as systems biology and high throughput sequencing are now usedto do this.We are moving away from study of single genes or proteins towards studying allSimultaneously. - fungi produce about 10,000 proteins and human cells about 25,000
  9. 9. Organisms are complex....
  10. 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. 11. High throughput approaches used to determine global transcription, genetic polymorphismsand gene function. Systems biology is used to find patterns and networks... Condition Transcription factors Genes of interest
  12. 12. The drugs dont work:How is Aspergillosis treated now??- does it work??– will this change??
  13. 13. Global increase in drug resistance
  14. 14. Processes involved in drug resistance:
  15. 15. - what we know about the patient
  16. 16. New geneticsPreviously: - look in families or do crosses and look at the progeny...Now: - follow DNA polymorphisms in populations, • sequence genomes
  17. 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. 18. IMMUNE CELL: ROLE: STOPS AND APPREHENDS KNOWN PATHOGENS MACROPHAGE IMMUNE CELL: ROLE: BRUTALLY ATTACKS THINGS NEUTROPHIL
  19. 19. How the immune system stops fungal disease: MACROPHAGE EPITHELIUM DENDRITIC CELL
  20. 20. How the immune system stops fungal disease: WHATS ALL THIS ERE THEN? MACROPHAGE EPITHELIUM I SAY CHAPS! DENDRITIC CELL
  21. 21. How the immune system stops fungal disease: OI! NOW THENOI!! MACROPHAGE OI!!! EPITHELIUM DENDRITIC CELL NEUTROPHILS
  22. 22. Adaptive Immunity – changes may lead to allergy
  23. 23. Individuals with fungal disease have:Changes in genes that affect macrophage or dendritic cell ability topercieve the pathogenChanges in genes that affect the ability of cells to move to the pointof infectionChanges in genes that mediate chemical attack on the fungus
  24. 24. In conclusion:Our knowledge of the disease in various forms is increasing rapidly. The huge burden offungal disease worldwide is becoming clear.Our ability to find genetic changes associated with disease has increased in recent yearsIn fact a Manchester project will discover all of the variants associated with ABPAwithin one year...We may be able to pinpoint the important variants...Our knowledge of fungal systems is increasing. More than 50 genome sequences andtranscriptomes have been determined. We are expecting to be able to pinpoint processesinvolved in disease.

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