Fungal Infections

Question 1

Fungal infections: explain the cellular mechanisms of antifungal defence, and explain how immune status determines risk of fungal infection

Answer 1

• Complex mechanism govern fungal immunity
• A wide range of pattern recognition receptors are implicated in fungal immunity
• Mutations in Dectin-1 TLR 4 and plasminogen confer increased susceptibility to fungal disease
• Better understanding of fungal immunogenetics will enable the development of personalised medicine

Cellular Immunity to Fungal Infection

• Fungi are opsonised by pentraxin-3 and mannose-binding lectin (MBL).
• Cells involved:
  
  • Phagocytes – are the first line of defence.
  • NK cells – provide early INF-gamma.
  • Dendritic cells – influence T-cell differentiation.
  • Th1 and Th17 cells.
• Virulence of fungal spores:
  
  • Candida – dimorphism allows tissue invasion.
  • Cryptococcus – capsule evades phagocytosis.
  • Aspergillus – inhaled as conidia, invade as hyphae.
• Flies – Toll is an innate PRR (Pattern Recognition Receptor) required for fungal immunity.

Human Deficiencies Leading to Fungal Infections

• Dectin 1 (a fungal PRR) deficiency leads to mucocutaneous fungal infections – e.g. vulvovaginitis & onychomycosis.
  
  • This leads to impaired macrophage IL-6 production and binding in response to fungal infections.
  • Also leads to increased susceptibility to invasive aspergillosis in stem cell transplants.
• CARD-9 deficiency leads to chronic mucocutaneous candidiasis.
  
  • CARD-9 is required for:
    
    • TNFa production in response to b-glucan stimulation.
    • T-cell Th17 differentiation.
• TLR4 polymorphisms lead to an increased risk of Invasive Aspergillosis (IA) in transplantation (i.e. haematopoietic stem cell transplants).
• There are many major SNPs (single nucleotide polymorphisms) associated with increased susceptibility to invasive fungal infections and disease – i.e. CXCL10, IL1-R, IL-23R, TLR-2/4/6/9.

CONCLUSION 1

• Mutations on Dectin-1, TLR4 and plasminogen confer increased susceptibility to fungal disease.

Question 2

Defenses against fungal infections

Answer 2

Cellular and Innate Defences

• Cellular defences:
  
  • Neutrophil are very important in fungal defence:
    
    • Neutrophil NETS – neutrophils throw out chromatin “nets” to capture pathogens.
      
      • These chromatin molecules outside the nucleus act as “danger signals” and recruit’s effector cells to the area as well.
  • Fungal morphogenesis – fungi can transition between yeast, candida and hyphae forms (multicellular) and this can drive a modulation of Dendritic cell response and can be bad for the immune response (as it gets confused).
• Innate defences:
  
  • Mucosal immunity governs fungal tolerance and resistance.

Conclusion

• Macrophages and neutrophils contribute to fungal immunity.
  
  • For Aspergillus, neutrophils are of a primary importance.
• Dendritic cells modulate adaptive immune responses.
• Adaptive T-cell INF-gamma responses augment host immunity to fungi.

Question 3

Outline the treatment of fungal infections

Answer 3

Treatment:

• Adoptive immunotherapy – generate lots of antifungal T-cells in a sample and then give these to the patients that need to fight a fungal infection.
  
  • It can be used in stem cell transplant - give back antifungal T-cells post-chemotherapy
• Gene therapy – e.g. restore gp91 function (make reactive oxidative species to fight fungal spores) to treat chronic granulomatous disorder. E.g. restore neutrophil NET formation.

Conclusion

• New treatments:
  
  • INF-gamma or adoptive T-cell therapy could be new treatments.
  • Gene therapy for primary immunodeficiencies could be a new treatment.

Question 4

Discuss fungal allergies

Answer 4

• Many fungal spores are inhaled daily.
• Host response may be normal, ineffective or exaggerated (allergy).
  
  • This leads to either an allergic or invasive fungal disease.
• Aspergillus is a primary driver – other fungi may contribute.
  
  • Aspergilli – Aspergillus niger, Aspergillus fumigatus (pretty one).
  • Other supporting fungi – Alternaria, Cladosporium, Penicillum.
• Important fungal reactions include type 1, 3, 4 hypersensitivity reactions.
  
  • T1 – IgE-driven, involves histamine and leukotrienes, in minutes.
  • T2 – IgG-, IgM-driven, involves complement, in 1-24 hours.
  • T3 – IgG-, IgM-driven, involves complement, in 1-24 hours.
  • T4 – T-cell-driven, involves lymphokines, in 2-3 days.

Question 5

ABPA – Allergic Bronchopulmonary Aspergillosis:

Answer 5

Aberrant TH1 responses of the lung

Abnormal IgE responses

ABPA – Allergic Bronchopulmonary Aspergillosis:

• Criteria for diagnosis:
  
  • Predisposing condition – asthma or cystic fibrosis.
  • Obligatory criteria – high baseline serum IgE, +ve T1 hypersensitivity (immediate response) skin test OR Aspergillus-specific IgE.
  • Supportive criteria (more than 2) – eosinophilia, IgG AB to Aspergillus fumigatus, consistent radiologic abnormalities.
    
    • Radiologic abnormalities – also have hyper-dense mucus:
      
      1. Dilated bronchi, thick walls.
      2. Upper/central predilection.
      3. Lobar collapse.
      4. Ring or linear opacities.
      5. Proximal bronchiectasis.
      6. Fibrotic scarring.

Conclusion

• Variety of pulmonary allergies to fungi exist.
  
  • ABPA is the best recognised.
• Severe asthma with fungal sensitisation is controversial.
• There is evidence for fungal sensitisation in hypersensitivity pneumonitis.

Diagnosis of these is driven by – skin tests, IgE and IgM in clinically relevant populations

Question 6

Outline the management of ABPA

Answer 6

– Allergic Bronchopulmonary Aspergillosis:

• Management:
  
  • Corticosteroids.
  • Itraconazole (steroid-sparing agent) – benefit past 16 weeks is unclear however.
    
    • Indicated if not responding to steroids or if steroid-dependency.
  • Omalizumab – recombinant IgE monoclonal ABs may be useful.