Pathogenic fungi regulate immunity by inducing neutrophilic myeloid-derived suppressor cells.

Nikolaus Rieber,Markus Mezger,Dominik Hartl,Maik Engeholm,Maria Bouzani,Iris Schäfer,Zhiyong Ye,Anurag Singh,Andreas Beilhack,Rebecca Schüle,Rupert Handgretinger,Jürgen Ruland,Jorge Amich,Sven Krappmann,Marlene Ballbach,Melanie Carevic,Bodo Grimbacher,Carsten Speckmann,Juergen Loeffler,Johannes G Liese ,Gordon D Brown ,László Maródi ,Hasan Halit Öz ,Sascha N Klimosch ,Michael C Ost ,Helmut R Salih ,Alexander N.r Weber

doi:10.1016/j.chom.2015.02.007

Abstract

SummaryDespite continuous contact with fungi, immunocompetent individuals rarely develop pro-inflammatory antifungal immune responses. The underlying tolerogenic mechanisms are incompletely understood. Using both mouse models and human patients, we show that infection with the human pathogenic fungi Aspergillus fumigatus and Candida albicans induces a distinct subset of neutrophilic myeloid-derived suppressor cells (MDSCs), which functionally suppress T and NK cell responses. Mechanistically, pathogenic fungi induce neutrophilic MDSCs through the pattern recognition receptor Dectin-1 and its downstream adaptor protein CARD9. Fungal MDSC induction is further dependent on pathways downstream of Dectin-1 signaling, notably reactive oxygen species (ROS) generation as well as caspase-8 activity and interleukin-1 (IL-1) production. Additionally, exogenous IL-1β induces MDSCs to comparable levels observed during C. albicans infection. Adoptive transfer and survival experiments show that MDSCs are protective during invasive C. albicans infection, but not A. fumigatus infection. These studies define an innate immune mechanism by which pathogenic fungi regulate host defense.

Highlights

Fungi are recognized through pattern recognition receptors, mainly C-type lectin receptors (Steele et al, 2005), toll-like receptors (TLRs), and pentraxin 3 (PTX3) (Garlanda et al, 2002; Werner et al, 2009)
The underlying tolerogenic mechanisms are incompletely understood. Using both mouse models and human patients, we show that infection with the human pathogenic fungi Aspergillus fumigatus and Candida albicans induces a distinct subset of neutrophilic myeloid-derived suppressor cells (MDSCs), which functionally suppress T and natural killer (NK) cell responses
Fungal MDSC induction is further dependent on pathways downstream of Dectin-1 signaling, notably reactive oxygen species (ROS) generation as well as caspase-8 activity and interleukin-1 (IL-1) production

Summary

Introduction

Fungi are recognized through pattern recognition receptors, mainly C-type lectin receptors (with Dectin-1 as the prototypic one) (Steele et al, 2005), toll-like receptors (TLRs), and pentraxin 3 (PTX3) (Garlanda et al, 2002; Werner et al, 2009). A certain level of inflammation is essential to control fungal infections (Brown, 2010), but hyperinflammatory responses seem to cause more harm than good to the host. Th17driven hyperinflammatory responses have been shown to promote fungal growth (Zelante et al, 2012), to impair fungal clearance, and to drive tissue damage (Romani et al, 2008; Zelante et al, 2007). Generation of reactive oxygen species (ROS), indoleamine 2,3-dioxygenase (IDO) activity, and activation of the TIR domain-containing adaptor-inducing interferon-b (TRIF) pathway were found to limit hyperinflammatory responses toward Aspergillus fumigatus (Romani, 2011; Romani et al, 2009).

Results

Discussion

Conclusion