DAMP signaling in fungal infections and diseases

Abstract

Fungal infections and diseases predominantly affect patients with deregulated immunity. Compelling experimental and clinical evidence indicate that severe fungal diseases belong to the spectrum of fungus-related inflammatory diseases. Some degree of inflammation is required for protection during the transitional response occurring temporally between the rapid innate and slower adaptive response. However, progressive inflammation worsens disease and ultimately prevents pathogen eradication. The challenge now is to elucidate cellular and molecular pathways distinguishing protective vs. pathogenic inflammation to fungi. In addition to fungal ligands of pattern recognition receptors (pathogen-associated molecular patterns, PAMPs), several host-encoded proteins, the damage-associated molecular patterns (DAMPs), are released during tissue injury and activate innate recognition receptors. DAMPs have been shown to regulate inflammation in fungal diseases. The DAMP/receptor for advanced glycation end-products axis integrated with the PAMP/Toll-like receptors axis in the generation of the inflammatory response in experimental and clinical fungal pneumonia. These emerging themes better accommodate fungal pathogenesis in the face of high-level inflammation seen in several clinical settings and point to DAMP targeting as a novel immunomodulatory strategy in fungal diseases.

Keywords: DAMPs; PAMPs; fungal diseases; immunoregulation; inflammation.

FIGURE 1

Signaling pathways in fungal pathogen-associated molecular patterns (PAMPs) recognition. PAMPs are recognized by pattern recognition receptors (PRRs). The major PRRs are Toll-like receptors (TLRs); C-type lectin receptors [CLRs; such as dectin 1, dectin 2, DC-specific ICAM3 grabbing non-integrin (DC-SIGN), mincle, and the mannose receptor], galectin family proteins (such as galectin 3), and the class B scavenger receptor CD36. TLRs and CLRs activate multiple intracellular pathways upon binding to specific fungal PAMPs, including β glucans [especially β (1,3)-glucans with varying numbers of β (1,6) branches], chitin, a polymer of N-acetylglucosamine, mannans linked to proteins through N or O linkages, β (1,2) linked oligomannosides, and fungal nucleic acids. These signals activate canonical or non-canonical nuclear factor-κB (NF-κB) and the NOD, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, and this culminates in the production of defensins, chemokines, cytokines, and reactive oxygen species (ROS). CR3, complement receptor 3; ASC, apoptosis-associated speck-like protein containing a CARD; BCL 10, B cell lymphoma 10; CARD9, caspase recruitment domain-containing protein 9; ERK, extracellular signal-regulated kinase; FcRγ, Fc receptor γ chain; IL, interleukin; IRF3, IFN-regulatory factor 3; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; MYD88, myeloid differentiation primary response protein 88; SYK, spleen tyrosine kinase.

FIGURE 2

Damage-associated molecular patterns (DAMP) signaling in response to fungi. After TLR activation, protease-activated receptors (PARs) sense proteolytic virulence factors and tissue injury and contribute to fungal recognition through a dual sensor system. In addition, the DAMP, S100B, through the spatio-temporal integration of signals from TLRs and RAGE, allows the immune system to discriminate between pathogen-derived and endogenous danger signals (see text for details). TRIF, TIR domain-containing adaptor protein inducing IFN-β; MYD88, myeloid differentiation primary response protein 88; RAGE, receptor for advanced glycation end-products.