Controlling pathogenic inflammation to fungi

Abstract

The balance between pro- and anti-inflammatory signaling is a prerequisite for successful host–fungal interactions. Although inflammation is an essential component of the protective response to fungi, its dysregulation may significantly worsen fungal diseases and limit protective, antifungal immune responses. The newly described Th17 developmental pathway may play an inflammatory role previously attributed to uncontrolled Th1 cell responses. The capacity of regulatory T cells to inhibit aspects of innate and adaptive antifungal immunity, including functional Th17 antagonism, is required for protective tolerance to fungi. Indoleamine 2,3-dioxygenase and tryptophan catabolites contribute to such a homeostatic condition by providing the host with immune defense mechanisms adequate for protection, without necessarily eliminating fungal pathogens – which would impair immune memory – or causing an unacceptable level of tissue damage. These new findings provide a molecular connection between the failure to resolve inflammation and lack of antifungal immune resistance, and point to strategies for immune therapy of fungal infections that attempt to limit inflammation in order to stimulate an effective immune response.

Keywords::

• fungi
• indoleamine 2,3-dioxygenase
• inflammation
• regulatory T cells
• T helper cells
• Toll-like receptors

Financial & competing interests disclosure

This study was supported by the Specific Targeted Research Project, EURAPS (LSHM-CT-2005), contract number 005223 (FP6) and MANASP (LSHE-CT-2006), contract number 037899 (FP6). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript. We thank Dr Cristina Massi Benedetti for editorial assistance.

Notes

IDO: Indoleamine 2,3-dioxygenase; RORγt: Retinoid-related orphan receptor-γ-t.