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

Genes & Immunity volume 9, pages 338–348 (2008)Cite this article

Abstract

Coccidioides posadasii spherules stimulate macrophages to make cytokines via TLR-2 and Dectin-1. We used formalin-killed spherules and 1,3-β-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-α and IL-6 than macrophages from C57BL/6 mice, and the amount of TNF-α 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.

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Acknowledgements

This work was supported in part by Merit Review Grants from the Veterans Administration (JF and TK). Dr Jiménez-A was supported by Convenio Especial de Cooperación No. 067-2002 Suscrito entre Colciencias-Icetex, Colombia. This work was performed as part to fulfill her requirements as a PhD student of the Medical Sciences PhD program of UPB-CIB-CES, Medellin, Colombia. We thank Dr John Galgiani (University of Arizona) for the generous gift of 96 h (young) spherules.

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Author notes

  1. M del Pilar Jiménez-A

    Present address: 6Current address: Corporación para Investigaciones Biológicas Carrera 72 A #78 B 141, Medellín, Colombia.,

Authors and Affiliations

  1. Research Service, VA San Diego Healthcare, San Diego, CA, USA

    M del Pilar Jiménez-A, S Viriyakosol, L Walls & J Fierer

  2. Department of Medicine, Division of Infectious Diseases, UC San Diego School of Medicine, San Diego, CA, USA

    S K Datta, T Kirkland & J Fierer

  3. Department of Pathology, UC San Diego School of Medicine, San Diego, CA, USA

    T Kirkland

  4. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK

    S E M Heinsbroek

  5. Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa

    G Brown

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Correspondence to J Fierer.

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del Pilar Jiménez-A, M., Viriyakosol, S., Walls, L. et al. Susceptibility to Coccidioides species in C57BL/6 mice is associated with expression of a truncated splice variant of Dectin-1 (Clec7a). Genes Immun 9, 338–348 (2008). https://doi.org/10.1038/gene.2008.23

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