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Infection and Immunity, April 2004, p. 2369-2378, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.2369-2378.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Absence of Interleukin-4 Determines Less Severe Pulmonary Paracoccidioidomycosis Associated with Impaired Th2 Response

Adriana Pina, Rita C. Valente-Ferreira, Eugênia E. W. Molinari-Madlum, Celidéia A. C. Vaz, Alexandre C. Keller, and Vera L. G. Calich*

Departamento de Imunologia, Instituto de Ciências Biomédicas da Universidade de São Paulo, São Paulo, Brazil

Received 14 July 2003/ Returned for modification 18 September 2003/ Accepted 15 January 2004

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.

* Corresponding author. Mailing address: Departamento de Imunologia, Instituto de Ciências Biomédicas da Universidade de São Paulo, Av. Prof. Lineu Prestes 1730, CEP 05508-900, São Paulo, SP, Brazil. Phone: 55-11-30917397. Fax: 55-11-30917224. E-mail: vlcalich{at}icb.usp.br.

Editor: S. H. E. Kaufmann

Infection and Immunity, April 2004, p. 2369-2378, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.2369-2378.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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