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Fungus, one of multicellular eukaryotes with cell wall, induces life threatening disease, such as candidiasis, aspergillosis and mucormycosis. Rhizopus oryzae and Mucor circinelloides are representative mucorales known to cause mucormycosis, the third most popular fungal disease. They induce the disease in immunocompromised host with attenuated neutrophil function which is critical for respond to fungal infection. Neutrophil extracellular traps (NETs) are networks of decondensed DNA which bind pathogen, and they are known to be caused by large molecules such as fungal hyphae of candida and aspergillus, but the NETs induced by mucorales is largely unknown. Pulmonary infection of mouse was obtained by intranasal instillation of spores of R. oryzae (JJ3-9), M. circinelloides (YF-a). The levels of pulmonary pathology were determined by measuring amount of protein and proinflammatory cytokines within bronchoalveolar lavage (BAL) fluids. In addition, Cell death of bone marrow-derived neutrophils was examined to identify pathogenicity of mucorales to neutrophils. We identified NETs formation in lung section to use immunohistochemistry, In this study, we compared lung injury, lung inflammation, NETs formation, cell death between WT mouse and NOX2 knockout (KO) mouse in lung infection with R. oryzae and M. circinelloides, because NOX2 is a protein which generates reactive oxygen species (ROS) in neutrophil, and the ROS is essential to eliminate pathogen and to induce NETs formation. As a result, the number of infiltrated neutrophils in WT mouse was increased as similar as NOX2 KO mouse, and there was no difference in neutrophil cell death between WT mouse and NOX2 KO mouse, indicating that lung of NOX2 is not involved in neutrophil cell death and lung inflammation by infection with R. oryzae and M. circinelloides. However, interestingly, we observed that NOX2 KO mouse had less lung damage compared to WT mouse by quantifying amount of BAL protein. We also identified NETs formation in WT mouse, but not NOX2 KO mouse. Here, we demonstrate that, during early stage of pulmonary mucormycosis, lung tissue is damaged by the NOX2-mediated NET formation, not by cell death of neutrophils.
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