Susceptibility to Coccidioides species in C57BL/6 mice is associated with expression of a truncated splice variant of Dectin-1 (Clec7a)

M del Pilar Jiménez-A, S Viriyakosol, L Walls, S K Datta, T Kirkland, S E M Heinsbroek, Gordon Douglas Brown, J Fierer

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Coccidioides posadasii spherules stimulate macrophages to make cytokines via TLR-2 and Dectin-1. We used formalin-killed spherules and 1,3-beta-glucan purified from spherules to stimulate elicited peritoneal macrophages and myeloid dendritic cells (mDCs) from susceptible (C57BL/6) and resistant (DBA/2) mouse strains. DBA/2 macrophages produced more TNF-alpha and IL-6 than macrophages from C57BL/6 mice, and the amount of TNF-alpha made was dependent on both TLR2 and Dectin-1. DCs from C57BL/6 mice made more IL-10 and less IL-23p19 and IL-12p70 than did DBA/2 DC. These responses were inhibited by a monoclonal antibody to Dectin-1. DBA/2 mice expressed full-length Dectin-1, whereas C57BL/6 mice spliced out exon 3, which encodes most of the stalk. RAW cells transduced to express the full-length Dectin-1 responded better to FKS than cells expressing truncated Dectin-1. We compared the isoform of Dectin-1 expressed by 34 C57BL/6 X DBA/2 recombinant inbred (BXD RI) lines with their susceptibility to Coccidioides immitis. In 25 of 34 RI lines susceptibility or resistance corresponded to short or full-length isoforms, respectively. These results suggest that alternative splicing of the Dectin-1 gene contributes to susceptibility of C57BL/6 mice to coccidioidomycosis, and affects the cytokine responses of macrophages and mDCs to spherules.
Original languageEnglish
Pages (from-to)338-348
Number of pages11
JournalGenes and Immunity
Volume9
Issue number4
Early online date17 Apr 2008
DOIs
Publication statusPublished - Jun 2008

Keywords

  • alternative splicing
  • animals
  • cell line
  • coccidioides
  • coccidioidomycosis
  • dendritic cells
  • gene expression
  • genetic predisposition to disease
  • immunity, innate
  • interleukin-10
  • macrophages, peritoneal
  • membrane proteins
  • mice
  • mice, inbred C57BL
  • mice, inbred DBA
  • nerve tissue proteins
  • protein isoforms
  • species specificity
  • tumor necrosis factor-alpha

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