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Candida albicans Is Phagocytosed, Killed, and Processed

Candida albicans Is Phagocytosed, Killed, and Processed

Simon L. Newman* and Angela Holly

"Candida albicans is a component of the normal flora of the alimentary tract and also is found on the mucocutaneous membranes of the healthy host. However, when immune defenses are compromised or the normal microflora balance is disrupted, Candida transforms itself into an opportunistic pathogenic killer. Candida is the leading cause of invasive fungal disease in premature infants, diabetics, and  , and of oropharyngeal disease in AIDS patients. As the induction of cell-mediated immunity to Candida is of critical importance in host defense, we sought to determine whether human dendritic cells (DC) could phagocytose and degrade Candida and subsequently present Candida antigens to T cells. Immature DC obtained by culture of human monocytes in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4 phagocytosed unopsonized Candida in a time-dependent manner, and phagocytosis was not enhanced by opsonization of Candida in serum. Like macrophages (M[var phi]), DC recognized Candida by the mannose-fucose receptor. Upon ingestion, DC killed Candida as efficiently as human M[var phi], and fungicidal activity was not enhanced by the presence of fresh serum. Although phagocytosis of Candida by DC stimulated the production of superoxide anion, inhibitors of the respiratory burst (or NO production) did not inhibit killing of Candida, even when phagocytosis was blocked by preincubation of DC with cytochalasin D. Further, although apparently only modest phagolysosomal fusion occurred upon DC phagocytosis of Candida, killing of Candida under anaerobic conditions was almost equivalent to killing under aerobic conditions. Finally, DC stimulated Candida-specific lymphocyte proliferation in a concentration-dependent manner after phagocytosis of both viable and heat-killed Candida cells. These data suggest that, in vivo, such interactions between DC and C. albicans may facilitate the induction of cell-mediated immunity. Despite appropriate therapy, mortality from systemic Candida infections in immunocompromised individuals is nearly 30%. In human immunodeficiency virus-infected individuals who have not yet developed advanced immunodeficiency, the prevalence of oropharyngeal Candida is from 7 to 48% of patients. As the immunodeficiency in AIDS patients progresses, the prevalence of oral candidiasis increases to 43 to 93%. Furthermore, the development of oral candidiasis in the early stages of human immunodeficiency virus infection is highly predictive of worsening immunodeficiency."

Host resistance against infections with C. albicans is mediated predominantly by neutrophils and macrophages (M[var phi]). During the induction of cell-mediated immunity (CMI), Candida antigens are presented to T cells and stimulate their proliferation with subsequent cytokine synthesis, and in both humans and mice these cytokines enhance the candidacidal functions of the phagocytic cells (3, 18, 26, 46). In systemic candidiasis in mice, cytokine production has been found to be a function of CD4+ T helper (Th) cells. The Th1 response, characterized by the production of interleukin-2 (IL-2), IL-12, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α), is associated with M[var phi] activation and enhanced resistance against reinfection. The Th2 response, which produces IL-4, IL-6, and IL-10, is linked with the development of chronic disease (10, 11, 60, 64, 65, 67). However, while it is generally accepted that production of Th1 cytokines is important for M[var phi] activation and clearance of the fungus, recent studies suggest that a critical balance of both Th1 and Th2 cytokines is necessary to develop protective immunity (48, 49, 66). Furthermore, the balance of Th1 and Th2 cytokines produced depends on the model of candidiasis being studied.
Although M[var phi] can serve as antigen-presenting cells (APC), dendritic cells (DC) are more potent antigen presenters than M[var phi] (70). DC precursors originate in the bone marrow, enter the blood, and seed nonlymphoid tissues. These DC are classified as immature and are specialized in antigen uptake and processing (5). The immature DC differentiate into mature DC as they migrate to tissue-draining secondary lymphoid organs, where they efficiently present antigen to T cells (4, 14, 42, 54, 63, 68). The strategic location of DC in tissues, on mucosal surfaces, and in the skin suggests that these cells are in a prime position to initiate protective immune responses against Candida.
For these adaptive immune responses to occur, the DC either would have to take up soluble fungal antigens or phagocytose the fungus themselves. If the latter occurs, it would require not only uptake of the fungus but also killing, degradation, and processing of fungal antigens. Teleologically, it would seem to be more efficient if the DC ingested the Candida rather than their having to wait for antigens to be shed or regurgitated by other immune cells such as M[var phi]. Recently, we demonstrated that immature human DC were able to phagocytose, kill, and degrade the fungal pathogen Histoplasma capsulatum (24). Furthermore, the DC were able to process H. capsulatum antigens and stimulate T-cell proliferation.
Human and mouse M[var phi] bind and internalize Candida cells via the mannose-fucose receptor (MFR) (37, 47). As human DC and Langerhans cells also express the MFR on their surface (6, 13), we hypothesized that immature DC might phagocytose Candida through the MFR and subsequently kill the organism, process Candida-specific antigens, and stimulate lymphocyte proliferation.
Most recently it was reported that mouse DC phagocytose and kill Candida and that recognition was through the MFR (19). The data presented herein confirm these observations for human DC and also demonstrate two important differences in the interaction of human and mouse DC with Candida. The first is that human and mouse DC apparently kill Candida by different mechanisms. The second difference is that Candida-infected human DC stimulate T-cell proliferation without the requirement for the addition of exogenous IL-2.

Full Article

Keywords: Candida albicans Phagocytosed Killed Processed normal flora alimentary tract mucocutaneous membranes invasive fungal disease infants diabetics surgical patients oropharyngeal disease immunocompromised human immunodeficiency virus drjefftop advanced

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