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Histoplasma capsulatum Cell Wall β-Glucan Induces Lipid Body Formation through CD18, TLR2, and Dectin-1 Receptors: Correlation with Leukotriene B₄ Generation and Role in HIV-1 Infection¹

Carlos Artério Sorgi^*, Adriana Secatto^*, Caroline Fontanari^*, Walter Miguel Turato^*, Caroline Belangér, Alexandra Ivo de Medeiros^*, Simone Kashima, Sylvie Marleau, Dimas Tadeu Covas, Patrícia Torres Bozza^¶ and Lúcia Helena Faccioli^2,*

^* Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil; Faculté de Pharmacie, Université de Montréal, Montréal, Canada; Fundação Hemocentro de Ribeirão Preto and Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil; and ^¶ Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil

Histoplasma capsulatum (Hc) is a facultative, intracellular parasite of worldwide significance. Infection with Hc produces a broad spectrum of diseases and may progress to a life-threatening systemic disease, particularly in individuals with HIV infection. Resolution of histoplasmosis is associated with the activation of cell-mediated immunity, and leukotriene B₄ plays an important role in this event. Lipid bodies (LBs) are increasingly being recognized as multifunctional organelles with roles in inflammation and infection. In this study, we investigated LB formation in histoplasmosis and its putative function in innate immunity. LB formation in leukocytes harvested from Hc-infected C57BL/6 mice peaks on day 2 postinfection and correlates with enhanced generation of lipid mediators, including leukotriene B₄ and PGE₂. Pretreatment of leukocytes with platelet-activating factor and BLT1 receptor antagonists showed that both lipid mediators are involved in cell signaling for LB formation. Alveolar leukocytes cultured with live or dead Hc also presented an increase in LB numbers. The yeast alkali-insoluble fraction 1, which contains mainly β-glucan isolated from the Hc cell wall, induced a dose- and time-dependent increase in LB numbers, indicating that β-glucan plays a signaling role in LB formation. In agreement with this hypothesis, β-glucan-elicited LB formation was inhibited in leukocytes from 5-LO^–/–, CD18^low and TLR2^–/– mice, as well as in leukocytes pretreated with anti-Dectin-1 Ab. Interestingly, human monocytes from HIV-1-infected patients failed to produce LBs after β-glucan stimulation. These results demonstrate that Hc induces LB formation, an event correlated with eicosanoid production, and suggest a role for these lipid-enriched organelles in host defense during fungal infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo (Grant 02/12856-2), Conselho Nacional de Desenvolvimento Científico e Tecnológico, and Fundação de Apoio Ensino, Pesquisa e Assistência, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo.

² Address correspondence and reprint requests to Dr. Lúcia Helena Faccioli, Universidade de São Paulo, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Av. do Café s/n, Monte Alegre, Ribeirão Preto, São Paulo, Brazil. E-mail address: faccioli{at}fcfrp.usp.br

³ Abbreviations used in this paper: Hc, Histoplasma capsulatum; ADRP, adipose differentiation-related protein; AM, alveolar macrophage; BALF, bronchoalveolar lavage fluid; DAPI, 4',6'-diamidino-2-phenylindole; F1, yeast alkali-insoluble fraction; F2, yeast alkali-soluble fraction; F3, yeast galactomannan fraction; F1β-gluc, β-glucan from chitinase-treated F1; i.t., intratracheal(ly); LB, lipid body; 5-LO, 5-lipoxigenase; LT, leukotriene; PAF, platelet-activating factor; PC, peritoneal cavity; PM, peritoneal macrophage; PRR, pattern-recognizing receptor; WT, wild type.

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