title: Absence of interleukin-4 determines less severe pulmonary paracoccidioidomycosis associated with impaired Th2 response.
abstract: Host resistance to paracoccidiodomycosis, the main deep mycosis in Latin America, is mainly due to cellular immunity and gamma interferon (IFN-gamma) production. To assess the role of interleukin-4 (IL-4), a Th2-inducing cytokine, pulmonary paracoccidioidomycosis was studied in IL-4-deficient (IL-4(-/-)) and wild-type (WT) C57BL/6 mice at the innate and acquired phases of immune response. Forty-eight hours after infection, equivalent numbers of viable Paracoccidioides brasiliensis yeast cells were recovered from the lungs of IL-4(-/-) and WT mice intratracheally infected with one million fungal cells. Alveolar macrophages from infected IL-4(-/-) mice controlled in vitro fungal growth more efficiently than macrophages from WT mice and secreted higher levels of nitric oxide. Compared with WT mice, IL-4(-/-) animals presented increased levels of pulmonary IFN-gamma and augmented polymorphonuclear leukocyte influx to the lungs. Decreased pulmonary fungal loads were characterized in deficient mice at week 2 postinfection, concomitant with diminished presence of IL-10. At week 8, lower numbers of yeasts were recovered from lungs and liver of IL-4(-/-) mice associated with increased production of IFN-gamma but impaired synthesis of IL-5 and IL-10. However, a clear shift to a Th1 pattern was not characterized, since IL-4(-/-) mice did not alter delayed-type hypersensitivity anergy or IL-2 levels. In addition, IL-4 deficiency resulted in significantly reduced levels of pulmonary IL-12, granulocyte-macrophage colony-stimulating factor, IL-3, monocyte chemotactic protein 1, and specific antibody isotypes. In IL-4(-/-) mice, well-organized granulomas restraining fungal cells replaced the more extensive lesions containing high numbers of fungi and inflammatory leukocytes developed by IL-4-sufficient mice. These results clearly showed that genetically determined deficiency of IL-4 can exert a protective role in pulmonary paracoccidioidomycosis.
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Adriana
authors.initials: A
authors.lastname: Pina
authors.forename: Rita C
authors.initials: RC
authors.lastname: Valente-Ferreira
authors.forename: Eugênia E W
authors.initials: EE
authors.lastname: Molinari-Madlum
authors.forename: Celidéia A C
authors.initials: CA
authors.lastname: Vaz
authors.forename: Alexandre C
authors.initials: AC
authors.lastname: Keller
authors.forename: Vera L G
authors.initials: VL
authors.lastname: Calich
mesh_terms: D000818:Animals; D000908:Antibodies, Fungal / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D006968:Hypersensitivity, Delayed; D015847:Interleukin-4 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008168:Lung / Q000276:immunology; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000382:microbiology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010228:Paracoccidioides / Q000472:pathogenicity*; D010229:Paracoccidioidomycosis / Q000276:immunology* / Q000382:microbiology; D012720:Severity of Illness Index; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology*
chemical_list: D000908:Antibodies, Fungal; D016207:Cytokines; D015847:Interleukin-4