Neither Dectin-2 nor the Mannose Receptor Is Required for Resistance to Coccidioides immitis in Mice

Suganya Viriyakosol,Sinobu Saijo,Maria Del Pilar Jimenez,Joshua Fierer

doi:10.1128/iai.01355-13

Suganya Viriyakosol, Sinobu Saijo + Show 2 more

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https://doi.org/10.1128/iai.01355-13

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Abstract

We investigated the roles of the mannose receptor (MR) and Dectin-2 in resistance to pulmonary coccidioidomycosis in C57BL/6 (B6) mice and in the interaction of myeloid cells with spherules, using B6 mice with targeted mutations in Mrc1 and Clec4n. Spherules are the tissue form of Coccidioides, and we determined that the MR on bone marrow-derived dendritic cells (BMDC) was important for recognition of spherules (formalin-killed spherules [FKS]) and for secretion of interleukin 10 (IL-10) and proinflammatory cytokines in response to FKS by both elicited macrophages and BMDC. Infected MR knockout (KO) mice produced more IL-10 in their lungs than did B6 mice, and MR KO mice also made more protective Th-17 cytokines. In contrast to the MR, Dectin-2 was not required for recognition of FKS by BMDC or for the production of cytokines by BMDC in response to FKS. However, Dectin-2 KO was required for stimulation of elicited peritoneal macrophages. Despite that, lung cytokine levels were not significantly different in Dectin-2 KO mice and B6 mice 14 days after infection, except for IL-1β, which was higher in Dectin-2 KO lungs. Although both Dectin-2(-/-) and MR(-/-) myeloid cells had reduced proinflammatory cytokine responses to FKS in vitro, neither MR nor Dectin-2 deficiency reduced the resistance of B6 mice to pulmonary coccidioidomycosis.

Highlights

We investigated the roles of the mannose receptor (MR) and Dectin-2 in resistance to pulmonary coccidioidomycosis in C57BL/6 (B6) mice and in the interaction of myeloid cells with spherules, using B6 mice with targeted mutations in Mrc1 and Clec4n
We previously showed that live spherules and formalin-killed spherules (FKS) are equivalent in their abilities to stimulate inflammatory macrophages to secrete proinflammatory cytokines and chemokines [49]
Since we had not established that live and formalin-killed spherules were equivalent for activation of bone marrow-derived dendritic cells (BMDC), we compared the abilities of FKS and freshly made live spherules to stimulate cytokine production by B6 BMDC; there were no differences between their stimulatory activities as measured by cytokine secretion (Fig. 1)

Summary

Introduction

We investigated the roles of the mannose receptor (MR) and Dectin-2 in resistance to pulmonary coccidioidomycosis in C57BL/6 (B6) mice and in the interaction of myeloid cells with spherules, using B6 mice with targeted mutations in Mrc and Clec4n. Lung cytokine levels were not significantly different in Dectin-2 KO mice and B6 mice 14 days after infection, except for IL-1␤, which was higher in Dectin-2 KO lungs Both Dectin-2؊/؊ and MR؊/؊ myeloid cells had reduced proinflammatory cytokine responses to FKS in vitro, neither MR nor Dectin-2 deficiency reduced the resistance of B6 mice to pulmonary coccidioidomycosis. The genes responsible for resistance in mice have not been identified, but one locus mapped to chromosome 6, not far from the cluster of Clec genes that includes Clec7A (which encodes Dectin-1) and Clec4N ( known as Clec6A; encodes Dectin-2) Both of those C-type lectin receptors (CLR) are transmembrane proteins expressed on myeloid cells [19]. Expression of Dectin-1 on macrophages is regulated by a number of cytokines, and we found that genetically resistant DBA/2 mice

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