title: 5-Lipoxygenase activity increases susceptibility to experimental Paracoccidioides brasiliensis infection.
abstract: Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the thermodimorphic fungus Paracoccidioides brasiliensis. Leukotrienes and lipoxins are lipid mediators produced after 5-lipoxygenase (5-LO) activation that exhibit pro- and anti-inflammatory roles, respectively. Here, we have investigated the contribution of 5-LO enzymatic activity in PCM using an experimental model of P. brasiliensis infection. B6.129 wild-type (B6.129) and 5-LO-deficient (5-LO(-/-)) mice were intravenously inoculated with a virulent strain of P. brasiliensis (Pb18), and the survival rate of the infected mice was investigated on different days after yeast infection. 5-LO(-/-) mice exhibited an increased survival rate associated with a decreased number of CFU. The resistance of 5-LO(-/-) during PCM was associated with augmented nitric oxide (NO) production and the formation of compact granulomas. In addition, the absence of 5-LO was associated with a diminished number of CD4(+) CD25(+) regulatory T cells, higher levels of gamma interferon and interleukin-12, and increased T-bet (a T-box transcription factor that directs Th1 lineage commitment) mRNA levels in the lungs. Taken together, our results show for the first time that 5-LO enzymatic activity increases susceptibility to P. brasiliensis, suggesting that this pathway may be a potential target for therapeutic intervention during PCM.
authors: Departamento de Bioquímica e Imunologia, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors: Fabrine Sales Massafera
authors: FS
authors: Tristão
authors: Fernanda Agostini
authors: FA
authors: Rocha
authors: Ana Paula
authors: AP
authors: Moreira
authors: Fernando Queiroz
authors: FQ
authors: Cunha
authors: Marcos Antonio
authors: MA
authors: Rossi
authors: João Santana
authors: JS
authors: Silva
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000378:metabolism*; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006099:Granuloma / Q000382:microbiology / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D010228:Paracoccidioides / Q000472:pathogenicity*; D010229:Paracoccidioidomycosis / Q000382:microbiology* / Q000401:mortality* / Q000473:pathology; D016019:Survival Analysis; D020825:T-Box Domain Proteins / Q000096:biosynthesis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013997:Time Factors; D000098815:T-bet Transcription Factor
chemical_list: D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma; D001094:Arachidonate 5-Lipoxygenase
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