RESUMO
Oropharyngeal candidiasis is one of the first and most commonly reported opportunistic infections of untreated AIDS patients. With the introduction of the new antiviral HAART therapy, including HIV protease inhibitors, this mucocutaneous infection is nowadays only rarely observed in treated patients. It was recently shown that HIV protease inhibitors have a direct attenuating effect on Candida albicans secreted aspartic proteinases (Saps), an investigation prompted by the fact that both Sap and HIV protease belong to the superfamily of aspartic proteinases and by the observation that mucocutaneous infections sometimes resolve even in the absence of an immunological improvement of the host. As these Saps are important fungal virulence factors and play a key role in adhesion to human epithelial cells we tried to assess the effect of the HIV protease inhibitors Ritonavir, Indinavir and Saquinavir on fungal adhesion to these cells. The effect on phagocytosis by polymorphonuclear leukocytes was also assessed. Ritonavir was found to be the most potent inhibitor of fungal adhesion. A dose-dependent inhibition of adhesion to epithelial cells was found already at 0.8 microM and was significant at 4 microM or higher, at 500 microM the inhibition was about 55%. Indinavir and Saquinavir inhibited significantly at 4 microM or 20 microM, respectively; at 500 microM the inhibition was 30% or 50%. In contrast, no protease inhibitor was able to modulate phagocytosis of Candida by polymorphonuclear leukocytes. In conclusion, inhibition of Saps by HIV protease inhibitors may directly help to ease the resolution of mucosal candidiasis. In future, derivatives of HIV protease inhibitors, being more specific for the fungal Saps, may form an alternative in the treatment of mucosal candidiasis insensitive to currently available antimycotics.
Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Candida albicans/efeitos dos fármacos , Inibidores da Protease de HIV/farmacologia , Candida albicans/patogenicidade , Candida albicans/fisiologia , Adesão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Indinavir/farmacologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Fagocitose , Ritonavir/farmacologia , Saquinavir/farmacologiaRESUMO
The influence of six antifungal agents on the expression of the fungal iC3b binding protein was studied in germ-tubes and the mycelial form of several Candida albicans strains. All antifungal agents inhibited not only the yeast-mycelial transformation, but also the formation of rosettes consisting of complement-coated sheep erythrocytes (EAiC3b) bound to the mycelial form of C. albicans. Immunofluorescence as well as ELISA, employing the monoclonal antibody OKM-1 which recognizes the alpha chain of human CR3 and which cross-reacts with the fungal iC3b binding protein, revealed that subinhibitory concentrations of 0.1 mg l(-1) (which did not affect the growth of either germ-tubes or the mycelial form of C. albicans) inhibited the expression of the iC3b binding protein, while lower concentrations (0.01 mg l(-1)) allowed a comparable and sometimes even slightly higher expression of this protein, in comparison with the untreated control. However, treatment with antifungal agents apparently did not lead to a major cleavage of the protein. The dependence of the amount of the iC3b binding protein expressed on the concentration of added antifungal drugs and on the morphological forms of individual C. albicans isolates suggests a drug dependent influence on the expression of this protein and a possible association with the changing virulence of C. albicans strains during antifungal therapy.
Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Receptores de Complemento 3b/efeitos dos fármacos , Anfotericina B/farmacologia , Animais , Candida albicans/crescimento & desenvolvimento , Candida albicans/metabolismo , Clotrimazol/farmacologia , Complemento C3b/imunologia , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Eritrócitos/imunologia , Fluconazol/farmacologia , Humanos , Immunoblotting , Testes de Sensibilidade Microbiana , Nistatina/farmacologia , Receptores de Complemento 3b/biossíntese , Receptores de Complemento 3b/imunologia , Formação de Roseta , Ovinos , Especificidade da Espécie , Tiazóis/farmacologia , Tunicamicina/farmacologiaRESUMO
Tat, the human immunodeficiency virus type 1 (HIV-1) transactivating protein, binds through its RGD-motif to human integrin receptors. Candida albicans, the commonest cause of mucosal candidiasis in subjects infected with HIV-1, also possesses RGD-binding capacity. The present study reveals that Tat binds to C. albicans but not to C. tropicalis. Tat binding was markedly reduced by laminin and to a lesser extent by a complement C3 peptide containing the RGD motif, but not by a control peptide. The outgrowth of C. albicans was accelerated following binding of Tat, but phagocytosis of opsonized C. albicans was also increased after Tat binding. Thus, Tat binding promotes fungal virulence by inducing hyphae but may also reduce it by augmenting phagocytosis. The net effect of Tat in vivo is difficult to judge but in view of the many disease-promoting effects of Tat we propose that accelerating the formation of hyphae dominates over the augmentation of phagocytosis.