Skin infections are eliminated by cooperation of the fibrinolytic and innate immune systems

Abstract

Nuclear factor of activated T cells (NFAT) is activated in innate immune cells downstream of pattern recognition receptors, but little is known about NFAT’s functions in innate immunity compared with adaptive immunity. We show that early activation of NFAT balances the two major phases of the innate response to Candida albicans skin infections: the protective containment (abscess) and the elimination (expulsion) phases. During the early containment phase, transforming growth factor–β (TGF-β) induces the deposit of collagen around newly recruited polymorphonuclear cells to prevent microbial spreading. During the elimination phase, interferon-γ (IFN-γ) blocks differentiation of fibroblasts into myofibroblasts by antagonizing TGF-β signaling. IFN-γ also induces the formation of plasmin that, in turn, promotes abscess capsule digestion and skin ulceration for microbial discharge. NFAT controls innate IFN-γ production and microbial expulsion. This cross-talk between the innate immune and the fibrinolytic systems also occurs during infection with Staphylococcus aureus and is a protective response to minimize tissue damage and optimize pathogen elimination.

The physical form of microbial ligands bypasses the need for dendritic cell migration to stimulate adaptive immunity

“…Pathway analysis of the cluster of differentially expressed genes (DEGs) upregulated by b-glucans revealed enrichment for pro-inflammatory and type II interferon (IFN) pathways, which is consistent with the innate immune response elicited by C. albicans skin infection ( Fig. S3) (22). In contrast to the model of peripheral inflammation-elicited LIR, mannans induced dLN expansion and lymphocyte accrual as early as 6 hours post-injection (h.p.i.)…”

Robust interferon signature and suppressed tissue repair gene expression in synovial tissue from patients with postinfectious,Borrelia burgdorferi‐induced Lyme arthritis

“…In addition to its antibacterial activity, IFNγ likely plays an important role in suppressing TGF‐β expression and promoting fibrinolytic responses during B. burgdorferi infection. A recent report by Santus et al () showed that Candida albicans and Staphylococcus aureus skin infections are initially contained through NFAT/TGF‐β‐dependent collagen deposition and are subsequently eliminated through IFNγ‐dependent suppression of TGF‐β and promotion of fibrinolysis. Analogous processes are likely occurring initially in B. burgdorferi infection and are necessary for trapping and eliminating the pathogen from connective tissue (Duray & Steere, ; Johnston et al, ).…”

Dermatophyte Immune Memory Is Only Skin-Deep

“…A recent study indicated that resolution of dermal candidiasis occurs in two steps: i) a containment phase wherein fungi are "walled-in" within an organized abscess to prevent spread, and ii) an elimination phase in which proteinases digest the abscess and destroy fungi that are trapped within these microstructures. IFN-gamma was crucial for the latter stage by activating the fibrinolytic system (Santus et al, 2017). Hence, it is plausible that IFN-gamma might play an analogous role in controlling dermatophyte clearance.…”