Oxidative burst and neutrophil elastase contribute to clearance of Aspergillus fumigatus pneumonia in mice.
Polymorphonuclear neutrophils (PMN) are important for the control of invasive aspergillosis (IA), a major threat to immunocompromised individuals. For clearance of Aspergillus fumigatus infections, PMN employ their potent oxidative and non-oxidative mechanisms. To clarify the relative contribution of these mechanisms, we analyzed p47(phox-/-), gp91(phox-/-) and elastase (ELA) deficient mice (ELANE) after intratracheal infection with A. fumigatus. Infected p47(phox-/-) and gp91(phox-/-) mice died within 4 days and had a significant higher fungal burden in the lungs compared to wild-type controls. Interestingly, the survival of ELANE mice after infection was unimpaired suggesting that ELA is not essential here. Nevertheless, A. fumigatus clearance was delayed in ELANE mice indicating a partial contribution of ELA to fungal immunity. Comparing p47(phox-/-), gp91(phox-/-) or ELANE mice for PMN activation and recruitment to the lungs, we were unable to detect significant differences in vitro or in vivo among mutant or wild-type strains suggesting intact PMN functionality of basic effector mechanisms. Fungal killing in vitro by ELA deficient PMN was comparably reduced as in p47(phox-/-) and gp91(phox-/-) deficient PMN corroborating the importance of oxidative and non-oxidative PMN mechanisms for the control of fungal outgrowth. Taken together, this suggests that intact oxidative as well as non-oxidative PMN effector functions are highly relevant for the control of A. fumigatus infections in vitro and in vivo. While ELA contributes to clearance of A. fumigatus, the oxidative functions are essential for survival.
Institute for Immunology, Johannes Gutenberg-University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
Steve
S
Prüfer
Institute for Immunology, Johannes Gutenberg-University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
Michael
M
Weber
Institute for Immunology, Johannes Gutenberg-University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
Pamela
P
Stein
IIIrd Dept. of Medicine, Johannes Gutenberg-University Medical Center, Johannes Gutenberg-University, Mainz, Germany; Center for Thrombosis and Hemostasis, Johannes Gutenberg-University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
Markus
M
Bosmann
Institute for Immunology, Johannes Gutenberg-University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
Michael
M
Stassen
Institute of Pathology, Johannes Gutenberg-University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
Andreas
A
Kreft
Institute for Immunology, Johannes Gutenberg-University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
Hansjörg
H
Schild
IIIrd Dept. of Medicine, Johannes Gutenberg-University Medical Center, Johannes Gutenberg-University, Mainz, Germany. Electronic address: radsak@uni-mainz.de.
Markus P
MP
Radsak
D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology; D001232:Aspergillus fumigatus / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D055744:Invasive Pulmonary Aspergillosis / Q000276:immunology*; D019272:Leukocyte Elastase / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000382:microbiology / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D018384:Oxidative Stress / Q000235:genetics
D000946:Antigens, Fungal; D008562:Membrane Glycoproteins; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D019272:Leukocyte Elastase
Aspergillus fumigatus pneumonia; BAL; CFU; CGD; ELA; Effector functions; IA; NADPH; NET; Neutrophil elastase; Oxidative burst; PMN; Polymorphonuclear neutrophils; bronchoalveolar lavage; chronic granulomatous disease; colony forming units; invasive aspergillosis; neutrophil elastase; neutrophil extracellular trap; nicotinamide dinucleotide phosphate; polymorphonuclear neutrophils