Date Published: May 9, 2013
Publisher: Public Library of Science
Author(s): Selinda J. Orr, Ashley R. Burg, Tim Chan, Laura Quigley, Gareth W. Jones, Jill W. Ford, Deborah Hodge, Catherine Razzook, Joseph Sarhan, Yava L. Jones, Gillian C. Whittaker, Kimberly C. Boelte, Lyudmila Lyakh, Marco Cardone, Geraldine M. O’Connor, Cuiyan Tan, Hongchuan Li, Stephen K. Anderson, Simon A. Jones, Weiguo Zhang, Philip R. Taylor, Giorgio Trinchieri, Daniel W. McVicar, Stuart M. Levitz.
Fungal infections are a major healthcare problem and the incidence of fungal infections has increased significantly in recent years. Mortality rates are high even with treatment, highlighting the need for a better understanding of anti-fungal immunity in order to develop improved therapies. Adaptive T-helper 1 and T-helper 17 (Th1 and Th17) responses are important mediators of anti-fungal immunity. Dendritic cells express Dectin-1, Dectin-2 and Toll-like receptors, which interact with fungal pathogens to induce these adaptive immune responses. Here we identify LAB as an important facilitator of IFN-γ production by regulating β-catenin activation. Susceptibility to fungal infections is increased in the absence of LAB, in association with reduced IFN-γ production. β-catenin activation in dendritic cells inhibits the IL-12 production required for IFN-γ production. Thus targeting β-catenin therapeutically could help to promote efficient IFN-γ production in patients suffering from fungal infections. These findings are important for fungal infections and potentially for other diseases where IFN-γ production is important for disease outcome.
Fungal infections with pathogens such as Candida albicans are a significant health risk for immunocompromised individuals . There is a high degree of mortality in these cases even with treatment, highlighting the need for a better understanding of the immune response involved in controlling fungal infections in order to develop improved treatments , . Responses to fungal infections involve both innate and adaptive immunity . The host response relies on the recognition, ingestion and elimination of C. albicans by phagocytic cells. During fungal infections, various pro-inflammatory cytokines such as TNF, IL-12p70, IL-23 and IL-6, produced by the activated leukocytes, result in the promotion of a sustained Th1 and Th17 response , , . The requirement for these cytokines and pathways has been demonstrated by increased susceptibility of several knockout mice to C. albicans infections. For example, mice deficient in genes associated with Th1 responses such as Il12a, Ifng or Ifngr1 are more susceptible to systemic C. albicans infection , . In addition, Il18−/− mice display enhanced susceptibility to disseminated C. albicans due to their inability to produce sufficient IFN-γ . More recently, fungal responses have been shown to involve the Th17 pathway; Il23a−/−, Il17ra−/− and Il17a−/− mice are more susceptible to oral and/or systemic candidiasis , , . Therefore, the level of inflammatory cytokine production in response to C. albicans infection is important in determining whether the host will eliminate or succumb to the infection.
Here we identify for the first time an important role for LAB in anti-fungal immunity. Lat2−/− mice displayed increased susceptibility to C. albicans infection and the fungal burden was significantly increased in these mice, similar to Clec4n−/− mice and Clec7a−/− mice , . Lat2−/− mice displayed reduced NK and T cell-mediated IFN-γ production which reflects the attenuated production of IL-12 by Lat2−/− DCs, while Lat2−/− neutrophil cytokine responses were not impaired. Moreover, we defined a novel role for LAB in the repression of β-catenin nuclear translocation in DCs, resulting in regulated cytokine production from a range of PAMPs, which is important in mounting an effective immune response in an infectious disease model. These data also suggest that LAB will be important in other diseases where IL-12 is involved in disease outcome.