Journal
INFECTION AND IMMUNITY
Volume 85, Issue 3, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.00903-16
Keywords
Dectin-1; Exserohilum; fungi; macrophages; molds
Categories
Funding
- MGH Infectious Diseases Division
- KL2/Catalyst Medical Research Investigator Training
- Harvard Catalyst | The Harvard Clinical and Translational Science Center
- National Center for Research Resources
- National Center for Advancing Translational Sciences
- National Institutes of Health[NIH] [KL2 TR001100, T32 AI007061, 5R01 AI092084, 5R21 AI109303]
- NIH/NIAID [1K08 AI110655]
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Dematiaceous molds are found ubiquitously in the environment and cause a wide spectrum of human disease, including infections associated with high rates of mortality. Despite this, the mechanism of the innate immune response has been less well studied, although it is key in the clearance of fungal pathogens. Here, we focus on Exserohilum rostratum, a dematiaceous mold that caused 753 infections during a multistate outbreak due to injection of contaminated methylprednisolone. We show that macrophages are incapable of phagocytosing Exserohilum. Despite a lack of phagocytosis, macrophage production of tumor necrosis factor alpha is triggered by hyphae but not spores and depends upon Dectin-1, a C-type lectin receptor. Dectin-1 is specifically recruited to the macrophage-hyphal interface but not the macrophage-spore interface due to differences in carbohydrate antigen expression between these two fungal forms. Corticosteroid and antifungal therapy perturb this response, resulting in decreased cytokine production. In vivo soft tissue infection in wild-type mice demonstrated that Exserohilum provokes robust neutrophilic and granulomatous inflammation capable of thwarting fungal growth. However, coadministration of methylprednisolone acetate results in robust hyphal tissue invasion and a significant reduction in immune cell recruitment. Our results suggest that Dectin-1 is crucial for macrophage recognition and the macrophage response to Exserohilum and that corticosteroids potently attenuate the immune response to this pathogen.
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