2189. Macrophage recognition and response to Exserohilum rostratum
Session: Poster Abstract Session: Host-Pathogen Interactions
Saturday, October 29, 2016
Room: Poster Hall
Background:

Dematiacious molds cause disease under conditions of host immunosuppression, allergic disease, or iatrogenic introduction and have high mortality rates. In 2012, a dematiacious mold, Exserohilum rostratum (ER), caused 751 infections during a multistate outbreak due to contaminated methylprednisolone. Our aim was to evaluate the pathways involved in macrophage recognition and response to ER and develop a murine soft-tissue model of disease.

Methods:

Time-lapsed confocal microscopy was used to evaluate interactions between macrophage and ER. Cell surface antigens were visualized using fluorescently labeled antibodies or carbohydrate-binding lectins. A GFP-Dectin1 fusion protein-expressing macrophage cell line was used to track Dectin-1 recruitment to ER. Cytokine responses to ER in wild-type or immune deficient macrophage were measured using ELISA. For in vivo infections spores of ER were injected subcutaneously into the flank of wild-type or Dectin-1 deficient mice with or without concomitant steroids. All mice also received vehicle control injections.

Results:

We show that macrophages are incapable of phagocytosing large spores and hyphae. However, macrophages are preferentially recruited to hyphae rather than spores of ER due to differences in cell surface antigen display. Additionally, production of TNFalpha is induced more robustly by hyphae and depends upon the C-type lectin receptor Dectin-1, but not Toll-Like receptor signaling. GFP tagged-Dectin-1 is preferentially recruited to hyphae, but not spores of ER. In vivo,histology from wild-type and Dectin-1 deficient mice demonstrate a neutrophilic infiltrate and formation of caseating granulomas with minimal spore germination (similar to histology from human patient samples). Co-administration with steroids resulted in dramatic increase in hyphal growth and absence of granuloma formation.

Conclusion:

Our results suggest that despite lack of phagocytosis, macrophages are capable of recognizing ER hyphae and producing a pro-inflammatory response in a partially Dectin-1 dependent manner. Our in vivo model produced similar inflammatory responses to those seen in human patient samples suggesting that this may be a valuable system for further probing the role of drugs or immune deficiencies in infection.

Jennifer Reedy, M.D., Ph.D.1, Paige Negoro, B.A.2, Marianela Feliu, M.S.2, Nida Khan, B.A.2, Jenny Tam, Ph.D.1, Michael Mansour, MD, PhD2, Daniel Lukason, B.S.2 and Jatin Vyas, MD, PhD, FIDSA3, (1)Massachsetts General Hospital, Division of Infectious Diseases, Boston, MA, (2)Massachusetts General Hospital, Division of Infectious Diseases, Boston, MA, (3)Medicine; Infectious Disease, Massachusetts General Hospital, Boston, MA

Disclosures:

J. Reedy, None

P. Negoro, None

M. Feliu, None

N. Khan, None

J. Tam, None

M. Mansour, None

D. Lukason, None

J. Vyas, None

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