This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Aspergillus fumigatus is a fungus that causes fatal infection in humans. Recent decades have seen increasing numbers fatal A. fumigatus infections in patients with immune suppressive disorders, and A. fumigatus is now recognized as the leading airborne fungal pathogen in compromised individuals. Humans with normal immunity rarely develop aspergillosis even when exposed to high concentrations of A. fumigatus conidia, and several deficiencies of polymorphonuclear neutrophils (PMN) are recognized to be a significant risk factor in this disease. In order to study the defensive role of PMN in the lungs, with particular reference to their antimicrobial oxidant activity, responses of PMN to A. fumigatus conidia in normal mice were compared to those in gp91phox-deficient and CXCR2-deficient mice, which are susceptible to aspergillosis. In gp91phox-deficient mice NADPH oxidase is inactive while in CXCR2-deficient mice there is delayed PMN recruitment in response to certain inflammatory stimuli. In normal balb/c mice, recruited PMN inhibited germination by enclosure of conidia within PMN aggregates where oxidase activity was detected with formazan staining. Conidial germination occurred in gp91phox-deficient mice, where PMN aggregates formed but lacked oxidase activity and in CXCR2-deficient mice, where there was a delay in formation of oxidase-active PMN aggregates. Our studies provide in vivo evidence to indicate that while some conidia reaching the lungs of immune competent mice are engaged by alveolar macarophages (AM), recruitment, activation and formation of oxidase-active PMN aggregates around conidia inhibited additional germination. Experiments using CXCR2-deficient and gp91phox-deficient mice indicate that it is essential for these events to occur within 6 h following conidial exposure to prevent hyphal emergence. This information may help explain a lack of disease in immunocompetent humans, even when exposed to large numbers of conidia. Future studies will better describe the molecular mechanisms of conidial killing in both PMN and AM.
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