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Defective Aspergillus killing by neutrophil leucocytes in a case of systemic aspergillosis
Abstract:
A persistent defect of Aspergillus killing was observed in the neutrophils of a 6-year-old patient with a systemic A. fumigatus infection which was highly refractory to anti-mycotic therapy. Aspergillus phagocytosis in vitro was normal, but nearly 80% of the ingested organisms (versus 30% in the controls) survived intracellularly during the 2-hr assay period. The patient's neutrophils showed a subnormal frequency of nitroblue tetrazolium reduction and a subnormal hexose monophosphate shunt activation in response to phagocytosis. The metabolic responsiveness, however, was clearly superior to that of chronic granulomatous disease neutrophils tested for comparison. The immune status of the patient and the following properties of his neutrophils were found to be normal: random and chemotactic motility, killing of S. aureus and C. albicans, and the contents of several granula enzymes. Our findings suggest the existence of neutrophil factors or functions which are required for killing Aspergillus, but not S. aureus and C. albicans.
Insights
Neutrophils from a child with persistent Aspergillus fumigatus infection showed impaired killing of the fungus. This defect is specific to Aspergillus and suggests unique neutrophil functions are involved in antifungal immunity.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Neutrophils are critical for host defense against fungal infections.
- Defects in neutrophil function can lead to severe, recurrent infections.
Observation:
- A 6-year-old patient with systemic Aspergillus fumigatus infection exhibited refractory disease despite antifungal therapy.
- Neutrophils from this patient demonstrated normal phagocytosis of Aspergillus but significantly impaired intracellular killing.
- Patient neutrophils showed reduced nitroblue tetrazolium (NBT) reduction and hexose monophosphate shunt (HMP shunt) activation upon phagocytosis.
Findings:
- Intracellular survival of Aspergillus was high (80%) in patient neutrophils compared to controls (30%).
- Metabolic responses were impaired but superior to those seen in chronic granulomatous disease (CGD).
- Neutrophil motility, killing of bacteria (Staphylococcus aureus) and other fungi (Candida albicans), and granule enzyme content were normal.
Implications:
- Suggests specific neutrophil factors or functions are essential for Aspergillus killing, distinct from those required for S. aureus or C. albicans.
- Highlights a potential novel mechanism of neutrophil dysfunction in invasive fungal infections.
- May inform the development of targeted therapies for refractory Aspergillus infections.