Dectin-1 Is Required for Resistance to Coccidioidomycosis in Mice

Abstract

We assessed the role of Dectin-1 in the immune response to the pathogenic fungus Coccidioides, both in vitro and in vivo, using mice with a targeted mutation in Clec7a. Elicited peritoneal macrophages responded to formalin-killed spherules (FKS) and alkali-treated FKS by secreting proinflammatory cytokines in a Dectin-1- and β-glucan-dependent manner. The responses of bone marrow-derived dendritic cells (BMDC) to the same stimulants were more complex; interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α) secretion was independent of Dectin-1, while IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were largely but not entirely dependent on Dectin-1. After intranasal infection, Dectin-1−/− mice had lower concentrations of IL-12p70, gamma interferon (IFN-γ), IL-1β, and the Th17 cytokines IL-22, IL-23, and 17A in the lung lavage fluid, which may explain why they were significantly more susceptible to pulmonary coccidioidomycosis two weeks after infection. The Dectin-1 mutation was even more deleterious in (B6 × DBA/2)F2 mice, which are more resistant to coccidioidomycosis than B6 mice by virtue of protective genes from DBA/2, a genetically resistant strain. We also found that two susceptible strains of mice (B6 and BALB/c) expressed much less Dectin-1 in their lungs than did resistant DBA/2 mice. We conclude that Dectin-1 is necessary for resistance to Coccidioides immitis, that Dectin-1 promotes both Th1 and Th17 protective immune responses to this infection, and that there is a correlation between expression of Dectin-1 by the inflammatory infiltrate and resistance to coccidioidomycosis.

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

“…In a set of BXD recombinant inbred mice, we found an association between the expression of full-length Dectin-1 and resistance to coccidioidomycosis (20). Expression of Dectin-1 on macrophages is regulated by a number of cytokines, and we found that genetically resistant DBA/2 mice express much more Dectin-1 in their infected lungs than do two genetically susceptible mouse strains (23). However, even this reduced level of Dectin-1 expression is somewhat protective, because Dectin-1 knockout (KO) mice are even more susceptible than B6 mice.…”

“…There is experimental evidence in mice that CLR are important for resistance to opportunistic fungal pathogens, such as Candida albicans and Pneumocystis carinii (30,31). We recently showed that Dectin-1 is required for resistance to Coccidioides immitis in mice, and so far this is the only example of Dectin-1 playing a role in resistance to a primary pathogenic fungus (23). A mutation in human Clec7A that deletes the carbohydrate recognition domain on Dectin-1 predisposes to a mild form of vulvovaginal candidiasis and to onychomycosis, demonstrating that the gene plays a nonredundant role in resistance to mucocutaneous fungal infections in humans (32).…”

Card9- and MyD88-Mediated Gamma Interferon and Nitric Oxide Production Is Essential for Resistance to Subcutaneous Coccidioides posadasii Infection

“…The mannose receptor and Mincle are dispensable for resistance to pulmonary coccidioidomycosis (18,47). All three Dectin receptors contribute to recognition of spherules (18,47,48; unpublished data). However, these receptors may function either alone or in synergy in resistance to pulmonary and subcutaneous infections and their regulatory mechanisms await clarification (18,43).…”

Coccidioides immitis and posadasii; A review of their biology, genomics, pathogenesis, and host immunity

“…In mice, increased IL-10 production results in increased susceptibility, and conversely, IL-10 KO mice are more resistant than the susceptible parental strain, closely resembling DBA/2, the most resistant inbred strain [60]. The only known driver of those differences in mice is Dectin-1, the β glucan receptor, which is expressed on dendritic and other myeloid cells [61]. There is a difference in the structure and function of Dectin-1 in susceptible B6 mice and resistant DBA/2 mice that is based on alternative splicing of the encoding gene, Clec7a [59].…”