Carbohydrates are thought to function as tags that mark circulatory glycoproteins for rapid clearance. To examine the role of the mannose receptor (MR) in glycoprotein clearance, we generated mice genetically deficient in MR. MR-/- mice were defective in clearing proteins bearing accessible mannose and N-acetylglucosamine residues and had elevated levels of eight different lysosomal hydrolases. Proteomic analysis of MR-/- and control mouse sera showed that an additional 4 out of 52 proteins identified were elevated in MR-/- serum. Each of these is up-regulated during inflammation and wound healing. Thus, MR appears to operate as an essential regulator of serum glycoprotein homeostasis.

Pathogen pattern recognition receptors (PRRs) recognize common structural and molecular motifs present on microbial surfaces and contribute to induction of innate immune responses. The mannose receptor (MR), a carbohydrate-binding receptor expressed on subsets of macrophages, is considered one such PRR. In vitro experiments have implicated the MR in phagocytosis of mannose-bearing microbes, including Candida albicans, and enhancement of antifungal response by macrophages. However, the significance of the MR's contribution to immune response during systemic C. albicans infection has never been directly demonstrated. Using MRdeficient mice in an in vivo infection experiment, we examined the role of the MR in immune response during disseminated candidiasis. MR ؊/؊ and wild-type control mice were challenged intraperitoneally with C. albicans, and the survival rates, tissue fungal burden, inflammatory cell recruitment, and specific antibody production after infection were evaluated. We found no significant difference in survival between the two mouse strains. MR ؊/؊ mice had higher average fungal burdens in some of the organs on days 7 and 21 but exhibited competence in inflammatory cell recruitment and antibody production. We also observed in vitro that MR ؊/؊ peritoneal cavity macrophages were equally capable of C. albicans uptake and that phagocytosis could be blocked with ␤-glucan. We conclude that the MR is not required for the normal host defense during disseminated candidiasis or for the phagocytosis of C. albicans and that a ␤-glucan receptor may be required for C. albicans phagocytosis.

Host defense against the opportunistic pathogen Pneumocystis carinii requires functional interactions of many cell types. Alveolar macrophages are presumed to be a vital host cell in the clearance of P. carinii, and the mechanisms of this interaction have come under scrutiny. The macrophage mannose receptor is believed to play an important role as a receptor involved in the binding and phagocytosis of P. carinii. Although there is in vitro evidence for this interaction, the in vivo role of this receptor in P. carinii clearance in unclear. Using a mouse model in which the mannose receptor has been deleted, we found that the absence of this receptor is not sufficient to allow infection by P. carinii in otherwise immunocompetent mice. Furthermore, when mice were rendered susceptible to P. carinii by CD4؉ depletion, mannose receptor knockout mice (MR-KO) had pathogen loads equal to those of wild-type mice. However, the MR-KO mice exhibited a greater influx of phagocytes into the alveoli during infection. This was accompanied by increased pulmonary pathology in the MR-KO mice, as well as greater accumulation of glycoproteins in the alveoli (glycoproteins, including harmful hydrolytic enzymes, are normally cleared by the mannose receptor). We also found that the surface expression of the mannose receptor is not downregulated during P. carinii infection in wild-type mice. Our findings suggest that while the macrophage mannose receptor may be important in the recognition of P. carinii, in vivo, this mechanism may be redundant, and the absence of this receptor may be compensated for.Pulmonary host defense typically involves cooperation among many cell types, including resident epithelium and macrophages as well as circulating inflammatory cells. However, the importance of each type of cell may differ, depending on the nature of the pathogen presented. Infection with the opportunistic fungus Pneumocystis carinii, which causes often-fatal pneumonia in immunocompromised patients, is an example of a disease process in which many cell types have important but distinct roles. The appearance of antibodies against P. carinii by age 2 in most children, coupled with the low occurrence of the disease in healthy people, led early investigators to conclude that humoral immunity and B cells were of primary importance in host defense against P. carinii (reviewed in reference 68). However, the high incidence of P. carinii infections in AIDS patients (42, 43) and later experimental mouse models highlights the crucial importance of CD4 ϩ lymphocytes in the control of P. carinii infections (5,20).In spite of their importance, CD4 ϩ lymphocytes are probably not involved with the major effector mechanisms against P. carinii (21, 52); instead, this role probably falls to CD8 ϩ lymphocytes, antibodies, and macrophages. Although the importance of CD8 ϩ cells in defense against P. carinii (3, 27) as well as their role in host tissue damage (74) is evident, the mechanisms by which these cells cause these responses are not clear. And although ther...