Caspofungin increases fungal chitin and eosinophil and gd T Cell-dependent pathology in invasive aspergillosis nansalmaa amarsaikhan

Ethan M. Sands, Anand Shah, Ali Abdolrasouli, Anna Reed, James E. Slaven, Darius Armstrong-James, Steven Templeton

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The polysaccharide-rich fungal cell wall provides pathogen-specific targets for antifungal therapy and distinct molecular patterns that stimulate protective or detrimental host immunity. The echinocandin antifungal caspofungin inhibits synthesis of cell wall b-1,3-glucan and is used for prophylactic therapy in immune-suppressed individuals. However, breakthrough infections with fungal pathogen Aspergillus fumigatus are associated with caspofungin prophylaxis. In this study, we report in vitro and in vivo increases in fungal surface chitin in A. fumigatus induced by caspofungin that was associated with airway eosinophil recruitment in neutropenic mice with invasive pulmonary aspergillosis (IA). More importantly, caspofungin treatment of mice with IA resulted in a pattern of increased fungal burden and severity of disease that was reversed in eosinophil-deficient mice. Additionally, the eosinophil granule proteins major basic protein and eosinophil peroxidase were more frequently detected in the bronchoalveolar lavage fluid of lung transplant patients diagnosed with IA that received caspofungin therapy when compared with azole-treated patients. Eosinophil recruitment and inhibition of fungal clearance in caspofungin-treated mice with IA required RAG1 expression and gd T cells. These results identify an eosinophil-mediated mechanism for paradoxical caspofungin activity and support the future investigation of the potential of eosinophil or fungal chitin-targeted inhibition in the treatment of IA.

Original languageEnglish (US)
Pages (from-to)624-632
Number of pages9
JournalJournal of Immunology
Volume199
Issue number2
DOIs
StatePublished - Jul 15 2017
Externally publishedYes

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caspofungin
Chitin
Aspergillosis
Invasive Pulmonary Aspergillosis
Eosinophils
Pathology
T-Lymphocytes
Aspergillus fumigatus
Cell Wall
Fungal Polysaccharides
Eosinophil Granule Proteins
Eosinophil Peroxidase
Echinocandins
Therapeutics
Azoles
Glucans
Mycoses
Bronchoalveolar Lavage Fluid
Immunity

ASJC Scopus subject areas

  • Immunology

Cite this

Caspofungin increases fungal chitin and eosinophil and gd T Cell-dependent pathology in invasive aspergillosis nansalmaa amarsaikhan. / Sands, Ethan M.; Shah, Anand; Abdolrasouli, Ali; Reed, Anna; Slaven, James E.; Armstrong-James, Darius; Templeton, Steven.

In: Journal of Immunology, Vol. 199, No. 2, 15.07.2017, p. 624-632.

Research output: Contribution to journalArticle

Sands, Ethan M. ; Shah, Anand ; Abdolrasouli, Ali ; Reed, Anna ; Slaven, James E. ; Armstrong-James, Darius ; Templeton, Steven. / Caspofungin increases fungal chitin and eosinophil and gd T Cell-dependent pathology in invasive aspergillosis nansalmaa amarsaikhan. In: Journal of Immunology. 2017 ; Vol. 199, No. 2. pp. 624-632.
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