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

Abstract

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-α/β receptor (IFN-α/βR) or IFN-β died from unrestrained pneumonia and encephalitis, while all wild-type controls survived. The pulmonary immune response of IFN-α/βR−/− mice was characterized by increased expression of IL-4, IL-13, and IL-10, decreased expression of TNF-α, IFN-γ, 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-α/βR−/− mice, although this change was less extensive than that observed in similarly infected IFN-γR-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.

Recognition of yeast nucleic acids triggers a host‐protective type I interferon response

“…Little is known of the ability of fungi to induce type I IFNs and of the in vivo role of these cytokines during fungal infections. We have recently found that, in the absence of type I IFN signaling, there is a polarization toward a type 2, detrimental, cytokine response during infection with the pathogenic yeast C. neoformans [15]. However, IFN responses induced by this pathogen were barely detectable in vitro and occurred in a very restricted range of MOIs.…”

“…www.eji-journal.eu pathophysiologic manifestations and risk of death [15,32]. Thus, it is possible that the contribution of TLR9 to host defenses against C. albicans can be evidenced only under experimental conditions associated with mild, sublethal infection.…”

“…It is presently unclear why some heat-killed (HK) Candida species demonstrated a linear, whereas others demonstrated a bell-shaped, dose-response curve. However, bell-shaped curves are not uncommon in in vitro responses to yeast [15] and may reflect an immunosuppressive effect of high fungal doses. Moreover, HK Candida spp.…”

“…While some bacterial components, such as lipopolysaccharide (LPS) and DNA, are well-known IFN-b inducers [13], little is known about the ability of fungi to stimulate the production of this cytokine. We previously proposed that constitutive and/or induced production of IFN-a/b plays a key role in host defenses against cryptococcal infection by driving the polarization of cytokine responses toward a protective type I pattern [15]. In the present study, we examined whether and by what mechanism IFN-a/b is produced in response to stimulation with different species of yeast.…”

“…The cells were collected by centrifugation and resuspended in hypotonic Tris-ammonium chloride buffer at 371C for 5 min to lyse red blood cells. After centrifugation, the cells were resuspended to a concentration of 2.5 Â 10 6 cells/mL and cultured for 10 days in medium consisting of RPMI 1640 supplemented with 10% FCS, sodium pyruvate, hepes, penicillin, streptomycin, and 2-mercaptoethanol (all purchased from Euroclone) as described previously [15]. Medium was supplemented with 100 ng/mL of M-CSF or GM-CSF (both from Peprotech) to obtain, respectively, macrophages and cDCs.…”