Absence of Interleukin-4 determines less severe pulmonary Paracoccidioidomycosis associated with impaired Th2 response

Author(s)

Pina, Adriana ; Valente-Ferreira, Rita C. ; Molinari-Madlum, Eugênia E. W. ; Vaz, Celidéia A. C. ; Keller, Alexandre C. ; Calich, Vera L. G. ^[6]

• Document type: Journal article
• Source: Infection and Immunity; v. 72, n. 4, p. 2369-2378, Apr. 2004.
• Field of knowledge: Biological Sciences - Immunology

Abstract

Host resistance to paracoccidiodomycosis, the main deep mycosis in Latin America, is mainly due to cellular immunity and gamma interferon (IFN-) 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- 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- 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. (AU)

• FAPESP's process: 98/13766-0 - Pulmonary Paracoccidioidomycosis in isogenic mice: characterization of mediators of natural and acquired immunity which determine resistance to the fungus
• Grantee: Vera Lucia Garcia Calich
• Support Opportunities: Research Projects - Thematic Grants