Normal Host Defense during Systemic Candidiasis in Mannose Receptor-Deficient Mice

Candida albicans, an opportunistic fungal pathogen, is a major cause of morbidity and mortality among immunocompromised individuals. The mortality rate among these patients with disseminated candida infection is about 30%, in spite of antifungal drug treatment (34). Predisposing factors such as neutropenia and low CD4-T-cell counts in human immunodeficiency virus patients suggest that both innate and adaptive cell-mediated immune mechanisms are critical in preventing this normal commensal organism from establishing an invasive infection (20). The coordination of the innate and adaptive arms of antifungal defense may also be important; it is believed that Th1, not Th2, response confers protection against candidiasis and that induction of Th1 CD4+ cells depends on activation of phagocytic cells (17). Phagocytosis of serum-opsonized C. albicans is carried out by neutrophils, macrophages, and eosinophils (7, 13), presumably via complement and Fc receptors. In contrast, uptake of unopsonized C. albicans has been attributed to lectin-like receptors that function as pattern recognition receptors (PRRs). PRRs distinguish self from nonself by recognizing common structural and molecular motifs that are present on microbes but absent from mammalian proteins. It is believed that upon the recognition of foreign motifs PRRs induce innate immune responses (8). The mannose receptor (MR) has been implicated as one such PRR, which can directly bind specific glycans found on C. albicans (28). The MR is a 180-kDa Ca2+-dependent lectin that functions as an endocytic receptor. It was first isolated from macrophages, but it has been found on a variety of other cells types, including dendritic cells (24), hepatic endothelial cells (29), retinal pigment epithelial cells (27, 30), and kidney mesangial cells (14). The receptor consists of 10 extracellular domains followed by a transmembrane region and short cytoplasmic tail. The extracellular domains are the amino-terminal cysteine-rich domain, a fibronectin type II repeat domain, and eight tandem carbohydrate recognition domains. The carbohydrate recognition domains bind accessible mannose, fucose, and N-acetylglucosamine residues but have a higher affinity for complex ligands with multiple binding sites, such as mannan on yeast surface (31, 32). Involvement of the MR in phagocytosis of C. albicans and antifungal response has been demonstrated in vitro. Transfection with an MR expression vector enabled COS-1 cells to ingest C. albicans (3), and uptake of unopsonized C. albicans by human monocyte-derived macrophages was inhibited by MR ligands, e.g., mannan and mannosylated bovine serum albumin (BSA) (15). Furthermore, the MR has been implicated in enhancement of C. albicans killing and cytokine production. CSF-1 has been shown to augment fungicidal activity by increasing MR-mediated uptake of C. albicans (11). Likewise, gamma interferon (IFN-γ)-mediated increase in C. albicans phagocytosis and subsequent killing was abolished by addition of MR ligands (16). An alternate receptor-blocking approach, antisense MR oligonucleotide treatment, abolished increases in mRNA levels of interleukin-1β (IL-1β), IL-6, and granulocyte-macrophage colony-stimulating factor in C. albicans-stimulated macrophages (35). Despite extensive in vitro evidence suggesting a role for the MR in immune responses, the function of the MR in host defense has never been determined in vivo. To examine the physiological importance of the MR in host defense against C. albicans, we studied the course of experimental fungal infection in MR-deficient mice (12).