Restoration of Pattern Recognition Receptor Costimulation to Treat Chromoblastomycosis, a Chronic Fungal Infection of the Skin

Abstract

SummaryChromoblastomycosis is a chronic skin infection caused by the fungus Fonsecaea pedrosoi. Exploring the reasons underlying the chronic nature of F. pedrosoi infection in a murine model of chromoblastomycosis, we find that chronicity develops due to a lack of pattern recognition receptor (PRR) costimulation. F. pedrosoi was recognized primarily by C-type lectin receptors (CLRs), but not by Toll-like receptors (TLRs), which resulted in the defective induction of proinflammatory cytokines. Inflammatory responses to F. pedrosoi could be reinstated by TLR costimulation, but also required the CLR Mincle and signaling via the Syk/CARD9 pathway. Importantly, exogenously administering TLR ligands helped clear F. pedrosoi infection in vivo. These results demonstrate how a failure in innate recognition can result in chronic infection, highlight the importance of coordinated PRR signaling, and provide proof of the principle that exogenously applied PRR agonists can be used therapeutically.

Black Yeasts and Their Filamentous Relatives: Principles of Pathogenesis and Host Defense

“…While C-type lectin receptors (CLRs) were able to recognize fungi, there was a lack of sufficient costimulation of the TLRs, which resulted in defective inflammatory responses. However, the cytokine responses were costimulated by exogenous administration of TLR agonists (91). Collectively, the above-described data suggest that CD4 ϩ T-helper cells secreting IFN-␥ may be a useful option for inducing protective immunity against black yeast infections (97,116), and these can be provided by adjunct cytokine immunotherapy (175,176).…”

“…The chronic nature of infections seems to be due to inadequate innate recognition and subsequent failure to mount protective inflammatory responses (91). In an experimental chromoblastomycosis model, the restoration of pattern recognition receptors was demonstrated to be a costimulatory factor in treating the chronic form of infections (91).…”

“…Interleukin-1 (IL-1) was induced only by F. pedrosoi and R. aquaspersa, and IL-6 production by macrophages was induced when the cells were in contact with C. carrionii, indicating that the production of IL-6 or IL-1 by macrophages was dependent on the fungal species. In another study, the cytokine response to F. pedrosoi was defective due to a lack of fungus recognition by Tolllike receptors (TLRs), while addition of TLR ligands restored cytokine production in vitro and resulted in protection against the fungus in an in vivo experimental model (91).…”

“…This is in line with the cytokine responses to classical fungal molecules such as beta-glucans (107), indicating that such immune mechanisms may be involved in the innate response to black yeasts. However, another study reported that the cytokine response to F. pedrosoi was defective due to a lack of recognition of the fungus by TLRs (91). Cytokine stimulation can be considered for the control of severity of corresponding infection (108), as beta-glucans are also ligands involved in the activation of the fungicidal activity of neutrophils through binding to Dectin-1 (109).…”

“…However, several studies have demonstrated that both innate and adaptive immune responses are required for effective containment of infections (27,91). A schematic representation of known mechanisms of host defenses against black yeasts is shown in Fig.…”