title: Contribution of the myeloperoxidase-dependent oxidative system to host defence against Cryptococcus neoformans.
abstract: The in vivo contribution of reactive oxygen species produced by neutrophils against Cryptococcus infection is not widely recognized. Myeloperoxidase (MPO) is a neutrophil-specific enzyme that catalyses the production of hypohalous acids such as HOCl from H2O2. This study investigated the role of MPO in immunological defence against Cryptococcus neoformans in an MPO-deficient (MPO-/-) mouse model. The survival of MPO-/- mice infected either intranasally or intravenously with C. neoformans was lower than that of identically challenged wild-type mice. The MPO-/- mice that received intranasal injection of C. neoformans had significantly larger lung fungal burdens than wild-type mice. On day 7, MPO-/- mice had a significantly higher lung concentration of interleukin (IL)-4 and lower concentrations of IL-2, IL-12p70 and interferon (IFN)-gamma than wild-type mice, suggesting a weak Th1 response in the MPO-/- mice to C. neoformans. Pathologically, the MPO-/- mice with intranasal infection showed more severe pneumonia than wild-type mice, which was associated with an increase in the levels of IL-1alpha/beta in the lungs. In addition, in MPO-/- mice, the pulmonary infection disseminated to the brain with occasional meningitis. The keratinocyte-derived cytokine (KC) level in the brain of infected MPO-/- mice was higher than that of control mice. Both intranasal and intravenous infections resulted in a higher number of fungi in the spleen of MPO-/- mice compared to wild-type, suggesting decreased resistance to C. neoformans not only in the lungs but also in the spleen in the absence of MPO. Taken together, these data suggest a major role of MPO in the response to cryptococcal infection.
authors.affiliation: Kihara Institute for Biological Research, Yokohama City University, Maioka-cho 641-12, Totsuka, Yokohama 244-0813, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Aratani
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Kura
authors.forename: Haruo
authors.initials: H
authors.lastname: Watanabe
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Akagawa
authors.forename: Yukie
authors.initials: Y
authors.lastname: Takano
authors.forename: Akiko
authors.initials: A
authors.lastname: Ishida-Okawara
authors.forename: Kazuo
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Pathology and Laboratory Medicine, the University of North Carolina, Chapel Hill, North Carolina 27599-7525, USA.
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.affiliation: Kihara Institute for Biological Research, Yokohama City University, Maioka-cho 641-12, Totsuka, Yokohama 244-0813, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Koyama
mesh_terms: D000818:Animals; D001769:Blood / Q000382:microbiology; D001921:Brain / Q000382:microbiology; D015169:Colony Count, Microbial; D003453:Cryptococcosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D003455:Cryptococcus neoformans / Q000276:immunology*; D016207:Cytokines / Q000032:analysis; D005260:Female; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016919:Meningitis, Cryptococcal / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism*; D011014:Pneumonia / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000382:microbiology; D016019:Survival Analysis
chemical_list: D016207:Cytokines; D017382:Reactive Oxygen Species; D009195:Peroxidase