1. ¹Research Service, VA San Diego Healthcare, San Diego, CA, USA
2. ²Department of Medicine, Division of Infectious Diseases, UC San Diego School of Medicine, San Diego, CA, USA
3. ³Department of Pathology, UC San Diego School of Medicine, San Diego, CA, USA
4. ⁴Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
5. ⁵Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa

Correspondence: Dr J Fierer, VA San Diego Healthcare, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. E-mail: jfierer@ucsd.edu

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

Received 7 November 2007; Revised 5 March 2008; Accepted 5 March 2008; Published online 17 April 2008.

Abstract

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