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[Contribution of neutrophils to Aspergillus infection]
1Dept. of Bioactive Molecules NIID-NIH, Tokyo, Japan.
Abstract:
Neutrophil disfunction, caused by a decreased production of effective radical oxygen species by myeloperoxidase (MPO) and NADPH oxidase within the neutrophil, may result in susceptibility to opportunistic fungal infections. In vitro, MPO produces OCl, which kills bacteria and viruses. In the case of MPO deficiency, susceptibility to Candida albicans infection was observed. Furthermore, it was demonstrated that MPO knockout mice were primarily susceptible to C. albicans infection. With regards to NADPH oxidase deficiency, such a patient was found to have severe chronic granulomatous disease (CGD) due to Aspergillus infection. This deficiency may have resulted from a gene mutation and/or abnormality of the NADH oxidase components, particularly cytochrome b558 (gp91phox and p22phox) in membrane and cytosol factors p47phox, p67phox, p40phox and others in neutrophil. Thus,irregular regulation of transcription factors for gene expression of phox molecules and MPO permits susceptibility to Aspergillus and Candida infections.
Insights
Neutrophil dysfunction, marked by reduced reactive oxygen species from myeloperoxidase (MPO) and NADPH oxidase, increases susceptibility to fungal infections like Candida and Aspergillus. This highlights the critical role of these enzymes in host defense.
Area of Science:
- Immunology
- Microbiology
- Biochemistry
Background:
- Neutrophils are crucial for innate immunity, producing reactive oxygen species (ROS) to combat pathogens.
- Myeloperoxidase (MPO) and NADPH oxidase are key enzymes in neutrophils responsible for ROS generation.
- Deficiencies in MPO or NADPH oxidase can impair immune responses, leading to opportunistic infections.
Purpose of the Study:
- To investigate the role of neutrophil dysfunction in susceptibility to fungal infections.
- To explore the specific contributions of MPO and NADPH oxidase deficiencies to candidiasis and aspergillosis.
Main Methods:
- Review of clinical cases and experimental models of MPO and NADPH oxidase deficiencies.
- Analysis of the molecular mechanisms underlying ROS production by MPO and NADPH oxidase.
- Examination of gene expression regulation for phox molecules and MPO.
Main Results:
- MPO deficiency is associated with increased susceptibility to Candida albicans infections.
- NADPH oxidase deficiency leads to chronic granulomatous disease (CGD), particularly with Aspergillus infections.
- Defects in NADPH oxidase components (e.g., cytochrome b558, cytosolic factors) and irregular transcription factor regulation impair ROS production.
Conclusions:
- Impaired neutrophil function due to MPO or NADPH oxidase deficiencies significantly increases the risk of opportunistic fungal infections.
- Understanding the molecular basis of these deficiencies is vital for developing targeted therapies.
- Dysregulation of gene expression for key immune components compromises host defense against Aspergillus and Candida.