Restoration of pattern recognition receptor costimulation to treat chromoblastomycosis, a chronic fungal infection of the skin

Maria da Glória Sousa, Delyth M. Reid, Edina Schweighoffer, Victor Tybulewicz, Jürgen Ruland, Jean Langhorne, Sho Yamasaki, Philip R. Taylor, Sandro R. Almeida, Gordon D. Brown

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Abstract

Chromoblastomycosis 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.
Original languageEnglish
Pages (from-to)436-443
Number of pages8
JournalCell Host & Microbe
Volume9
Issue number5
Early online date18 May 2011
DOIs
Publication statusPublished - 19 May 2011

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Chromoblastomycosis
Pattern Recognition Receptors
Mycoses
Toll-Like Receptors
C-Type Lectins
Skin
Infection
Cytokines
Ligands

Cite this

Sousa, M. D. G., Reid, D. M., Schweighoffer, E., Tybulewicz, V., Ruland, J., Langhorne, J., ... Brown, G. D. (2011). Restoration of pattern recognition receptor costimulation to treat chromoblastomycosis, a chronic fungal infection of the skin. Cell Host & Microbe, 9(5), 436-443. https://doi.org/10.1016/j.chom.2011.04.005

Restoration of pattern recognition receptor costimulation to treat chromoblastomycosis, a chronic fungal infection of the skin. / Sousa, Maria da Glória; Reid, Delyth M.; Schweighoffer, Edina; Tybulewicz, Victor; Ruland, Jürgen; Langhorne, Jean; Yamasaki, Sho; Taylor, Philip R.; Almeida, Sandro R.; Brown, Gordon D.

In: Cell Host & Microbe, Vol. 9, No. 5, 19.05.2011, p. 436-443.

Research output: Contribution to journalArticle

Sousa, MDG, Reid, DM, Schweighoffer, E, Tybulewicz, V, Ruland, J, Langhorne, J, Yamasaki, S, Taylor, PR, Almeida, SR & Brown, GD 2011, 'Restoration of pattern recognition receptor costimulation to treat chromoblastomycosis, a chronic fungal infection of the skin', Cell Host & Microbe, vol. 9, no. 5, pp. 436-443. https://doi.org/10.1016/j.chom.2011.04.005
Sousa, Maria da Glória ; Reid, Delyth M. ; Schweighoffer, Edina ; Tybulewicz, Victor ; Ruland, Jürgen ; Langhorne, Jean ; Yamasaki, Sho ; Taylor, Philip R. ; Almeida, Sandro R. ; Brown, Gordon D. / Restoration of pattern recognition receptor costimulation to treat chromoblastomycosis, a chronic fungal infection of the skin. In: Cell Host & Microbe. 2011 ; Vol. 9, No. 5. pp. 436-443.
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AB - Chromoblastomycosis 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.

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