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IFN-/β Signaling Is Required for Polarization of Cytokine Responses toward a Protective Type 1 Pattern during Experimental Cryptococcosis

Carmelo Biondo^*, Angelina Midiri^*, Maria Gambuzza^*, Elisabetta Gerace^*, Maria Falduto^*, Roberta Galbo^*, Antonella Bellantoni^*, Concetta Beninati^*, Giuseppe Teti^*, Tomas Leanderson and Giuseppe Mancuso^1,*

^* Dipartimento di Patologia e Microbiologia Sperimentale, Università degli Studi di Messina, Messina, Italy; and Immunology Group, University of Lund, Lund, Sweden

The antiviral activities of type I IFNs have long been established. However, comparatively little is known of their role in defenses against nonviral pathogens. We examined here the effects of type I IFNs on host resistance against the model pathogenic yeast Cryptococcus neoformans. After intratracheal or i.v. challenge with this fungus, most mice lacking either the IFN-/β receptor (IFN-/βR) or IFN-β died from unrestrained pneumonia and encephalitis, while all wild-type controls survived. The pulmonary immune response of IFN-/βR^–/– mice was characterized by increased expression of IL-4, IL-13, and IL-10, decreased expression of TNF-, IFN-, inducible NO synthetase, and CXCL10, and similar levels of IL-12 mRNA, compared with wild-type controls. Histopathological analysis showed eosinophilic infiltrates in the lungs of IFN-/βR^–/– mice, although this change was less extensive than that observed in similarly infected IFN-R-deficient animals. Type I IFN responses could not be detected in the lung after intratracheal challenge. However, small, but statistically significant, elevations in IFN-β levels were measured in the supernatants of bone marrow-derived macrophages or dendritic cells infected with C. neoformans. Our data demonstrate that type I IFN signaling is required for polarization of cytokine responses toward a protective type I pattern during cryptococcal 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 Address correspondence and reprint requests to Dr. Giuseppe Mancuso, Dipartimento di Patologia e Microbiologia Sperimentale, Università degli Studi di Messina, Torre Biologica IIp, Policlinico, Via C. Valeria 1, I-98125 Messina, Italy. E-mail address: mancusog{at}unime.it

² Abbreviations used in this paper: WT, wild type; EU, endotoxin unit; IP-10, inducible protein 10; iNOS, inducible NO synthetase; i.t., intratracheal; cDC, conventional dendritic cell; pDC, plasmacytoid dendritic cell.