The recognition of carbohydrate moieties by cells of the innate immune system is emerging as an essential element in antifungal immunity, but despite the number and diversity of lectins expressed by innate immune cells, few carbohydrate receptors have been characterized. Mincle, a C-type lectin, is expressed predominantly on macrophages, and is here shown to play a role in macrophage responses to the yeast Candida albicans. After exposure to the yeast in vitro, Mincle localized to the phagocytic cup, but it was not essential for phagocytosis. In the absence of Mincle, production of TNF-α by macrophages was reduced, both in vivo and in vitro. In addition, mice lacking Mincle showed a significantly increased susceptibility to systemic candidiasis. Thus, Mincle plays a novel and nonredundant role in the induction of inflammatory signaling in response to C. albicans infection.
The consortium for functional glycomics (CFG) was a large research initiative providing networking and resources for investigators studying the role of glycans and glycan-binding proteins in health and disease. Starting in 2001, six scientific cores were established to generate data, materials and new technologies. By the end of funding in 2011, the mouse phenotype core (MPC) submitted data to a website from the phenotype screen of 36 mutant mouse strains deficient in a gene for either a glycan-binding protein (GBP) or glycosyltransferase (GT). Each mutant strain was allotted three months for analysis and screened by standard phenotype assays used in the fields of immunology, histology, hematology, coagulation, serum chemistry, metabolism and behavior. Twenty of the deficient mouse strains had been studied in other laboratories, and additional tests were performed on these strains to confirm previous observations and discover new data. The CFG constructed 16 new homozygous mutant mouse strains and completed the initial phenotype screen of the majority of these new mutant strains. In total, >300 phenotype changes were observed, but considering the over 100 assays performed on each strain, most of the phenotypes were unchanged. Phenotype differences include abnormal testis morphology in GlcNAcT9- and Siglec-H-deficient mice and lethality in Pomgnt1-deficient mice. The numerous altered phenotypes discovered, along with the consideration of the significant findings of normality, will provide a platform for future characterization to understand the important roles of glycans and GBPs in the mechanisms of health and disease.
CD14 is a membrane protein (mCD14) found on monocytes and neutrophils that is required for the innate immune response to lipopolysaccharide (LPS) and lipoarabinomannan (LAM). CD14 can also be found in serum as soluble CD14 (sCD14) that when bound to bacterial products, enables many non-CD14 bearing cells to be activated. Lipopolysaccharide binding protein (LBP) is a plasma protein that disaggregates and catalytically transfers LPS to CD14. To examine the role of CD14 and LBP in LAM-dependent activation, we used the U373 astrocyte cell line to stably express membrane-bound CD14 (U373-CD14). In serum-free conditions, U373-CD14 cells could respond to LAM stimulation as measured by expression of intracellular adhesion molecule-1 (ICAM-1). Vector control cells (U373-RSV) could not respond to LAM or LPS; but, upon the addition of serum as a source of soluble CD14, control U373-RSV cells could respond to LPS, but not LAM. Therefore, LAM can activate U373 cells only through membrane CD14 and not soluble CD14. We also demonstrate that this membrane CD14-dependent LAM response is greatly facilitated by the addition of LBP.
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