MicrobiologyBytes: Infection & Immunity: Complement Updated: January 7, 2007 Search

THE INTERACTION OF MICROORGANISMS WITH THE COMPLEMENT SYSTEM:

FUNGI

Candida albicans is a widespread saprophyte of the mucous membrane which may cause opportunistic infections in patients with immune disorders (251) . T-cell deficiencies, for example, human immunodeficiency virus infection, are often accompanied by a mucocutanous form of candidiasis. In contrast, the disseminated form is frequently associated with defects of the phagocytic system. Neutropenia caused by immunosuppressive or cytostatic therapies serves as an example. The host defence against fungal infections is accomplished by phagocytes, including monocytes/macrophages, in addition to cell-mediated and humoral immune mechanisms (252). Opsonisation of C.albicans by complement factors and immunoglobulins enhances phagocytosis and intracellular killing of the organism by the phagocytes (253). The influence of C.albicans on monocyte production of the complement factors C3 and factor B has been investigated (254), since the optimal opsonisation of fungi is important for their engulfment by phagocytes, it is known that granulocyte-macrophage colony-stimulating factor (GM-CSF) is released from leukocytes in response to C.albicans (255). In addition to its stimulatory effects, on myelopoiesis, this cytokine affects several functions of mature granulocytes and monocytes/macrophages (256,257). Since GM-CSF has been reported to enhance monocyte function against fungi (258), the possible impact of this cytokine on complement biosynthesis by monocytes treated with C. albicans has been evaluated. Such a study has shown that the production of both C3 and factor B by cultured monocytes is increased when the cells are treated with C.albicans. This cellular response to a pathogenic fungus may be important, since opsonisation by complement components secreted by monocytes/macrophages has been reported (259). This may cause an augmented binding and ingestion of the fungi by phagocytes. Complement activation initiated by micro-organisms results in the cleavage of C3. The resulting activation products, such as C3a and C3b/C3bi, have important proinflammatory effects (260). C3a is an anaphylatoxin and chemotaxin, and stimulates monocyte release of cytokines, while C3b/C3bi are opsonins which bind to fungi and other micro-organisms and facilitate binding to complement receptors on the phagocytes.

It is well known that phagocytosis affects not only complement factor production, but also other secretory functions of the monocytes/ macrophages. Zymosan and opsonised bacteria trigger the release of prostaglandins (261). C.albicans has been shown to induce the release of tumour necrosis factor (TNF) from monocytes (262), and the release of TNF, gamma interferon, and GM-CSF from large granular lymphocytes with natural killer function (263). GM-CSF cytokine is released from monocytes after stimulation with various parasites, bacteria, and LPS, but induction by C.albicans has not been reported.

Several indications have been found (254) that GM-CSF may inhibit monocyte C3 production induced by C.albicans. Interestingly, monocytes become insensitive to the stimulatory effects of the organism on C3 production after pre-treatment with GM-CSF. Furthermore, GM-CSF caused no increase in C3 binding to the surface of C.albicans. Such an inhibitory effect of GM-CSF on C.albicans factor B production is not seen. Thus, the regulatory mechanisms for the biosynthesis of these two complement factors seem to differ. In addition, the killing of C.albicans by monocytes is increased after treatment with GM-CSF, possibly through an augmentation of the respiratory burst (264).

At an infectious site, however, with the rapid growth of C.albicans and increased activation of complement, the extravascular supply of plasma-derived complement factors may be limited. Monocyte production of complement components may then be particularly important in maintaining adequate local complement concentrations. GM-CSF-induced suppression of stimulated complement production in monocytes may consequently reduce the local opsonisation of C.albicans. The suppressive effect of GM-CSF on C3 production may also lead to a reduced local production of complement activation products with potent chemotactic and anaphylactic properties, which then may reduce the recruitment of leukocytes to the site of inflammation. GM-CSF may in this way suppress an inflammatory response caused by the fungus. The consequences of this mechanism for the host resistance against fungi clearly warrant further investigation.

Several mannoproteins of the cell wall of C.albicans have been identified as binding structures for fibronectin (265), fibrinogen (266), laminin (267), type I and IV collagen (268), mucin and salivary proteins (269), and even acrylic (270) and plastic (271). C.albicans pseudohyphal forms, in contrast to yeast forms, express C3bi and C3d binding structures on their surfaces (272,273,274). Several proteins with different molecular weights have been proposed by different groups to be involved in the binding of C3bi to C.albicans. Recently, C3bi-binding proteins of 66, 55, and 42-kDa were purified by affinity chromatography (275). Since the binding of C3bi to the human or murine complement receptor type 3 (CR3) requires Ca2+ and Mg2+, an investigation has been carried out to see whether the binding of C3bi to C.albicans is also dependent on the presence of divalent cations (276). The results of such an investigation concluded that the binding of C3bi to the cell wall of C.albicans is influenced by Ca2+ ions. The ability of C.albicans to bind to C3bi via a specific receptor may play an important role in the adherence of this fungus to the vascular endothelium. Neutrophils, for example, are able to adhere to endothelial cells which are coated with C3 fragments by means of their CR3. C3 fragments thus function as a bridge between neutrophils and endothelium. In the case of C3bi-mediated adherence of C.albicans to endothelium, this binding must be stable in order to avoid the detachment of the fungus, for example, by the flow of blood. It could be demonstrated that the physiological Ca2+ concentration in blood is high enough to stabilise the adherence in vitro. Thus, calcium could be an important factor in the pathogenesis of disseminated candidiasis.

Finally, it is thought that C. albicans has evolved a strategy for acquiring iron from erythrocytes by means of complement (277), which would represent another function of the C3bi binding moieties. C.albicans is dependent on iron for growth. By rosetting complement coated erythrocytes, C.albicans may be capable of obtaining iron from them. Rosetting can be

inhibited by monoclonal antibodies to the human CR3. In vivo, erythrocytes can be opsonised during a candida infection because the activation of the alternative pathway of complement by candida organisms leads to 'bystander' deposition of C3 fragments on the surfaces of autologous erythrocytes (276). Presumably, the C3b1-binding structures of C.albicans pseudohyphae carry out some important functions in the pathogenesis of disseminated candidiasis. Ca2+ ions are required to accomplish this function effectively.

   

© AJC 2007.