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

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-1␤, 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.

Dectin-2 Deficiency Promotes Th2 Response and Mucin Production in the Lungs after Pulmonary Infection with Cryptococcus neoformans

“…A compensatory mechanism may operate to activate the critical Th1-mediated immune response in place of the Dectin-2-mediated pathway. Recently, Viriyakosol and coworkers reported a similar discrepancy between in vitro and in vivo experiments in a fungal infection, in which in vitro production of proinflammatory cytokines by macrophages stimulated with Coccidioides immitis was reduced in Dectin-2KO mice, whereas the clearance of this fungal pathogen in the lungs and spleen was comparable to that in WT mice (45).…”

Pathogenesis of Coccidioidomycosis

“…Mice deficient in Dectin-1, a C-type lectin (CLR) that binds to β-1,3-glucans, were found to be more susceptible to experimental pulmonary coccidioidal infection than wild-type mice [21]. In a follow-up study [22], the mannose receptor (MR), which binds terminal mannoses, was associated with binding of coccidioidal spherules by immune cells, an observation noted in humans [23]. On the other hand, Dectin-2, whose ligands are high mannose residues, was not.…”

Immune Interactions with Pathogenic and Commensal Fungi: A Two-Way Street

“…Dectin-2 on macrophages also recognizes Aspergillus fumigatus hyphae and contributes to fungal clearance in vivo (Carrion et al, 2013). In contrast, the absence of Dectin-2 had no effect on clearance of Coccidiomycoses infection, even though Dectin-2 is expressed in the lungs of infected mice (Viriyakosol et al, 2014). …”