Pathogenic fungi represent a major threat particularly to immunocompromised hosts, leading to severe, and often lethal, systemic opportunistic infections. Although the impaired immune status of the host is clearly the most important factor leading to disease, virulence factors of the fungus also play a role. Factor H (FH) and its splice product FHL-1 represent the major fluid phase inhibitors of the alternative pathway of complement, whereas C4b-binding protein (C4bp) is the main fluid phase inhibitor of the classical and lectin pathways. Both proteins can bind to the surface of various human pathogens conveying resistance to complement destruction and thus contribute to their pathogenic potential. We have recently shown that Candida albicans evades complement by binding both Factor H and C4bp. Here we show that moulds such as Aspergillus spp. bind Factor H, the splicing variant FHL-1 and also C4bp. Immunofluorescence and flow cytometry studies show that the binding of Factor H and C4bp to Aspergillus spp. appears to be even stronger than to Candida spp. and that different, albeit possibly nearby, binding moieties mediate this surface attachment.

CaHgt1p is a multifunctional evasion molecule, as complement inhibitor, CR3 analogue and HIV receptor.

The putative vesicle transport protein Vac1p of the human pathogenic yeast Candida albicans plays an important role in virulence. To determine the cellular functions of Vac1p, a null mutant was generated by sequential disruption of both alleles. The vac1 null mutant strain showed defective endosomal vesicle transport, demonstrating a role of Vac1p in protein transport to the vacuole. Vac1p also contributes to resistance to metal ions, as the null mutant strain was hypersensitive to Cu 2+ , Zn 2+ and Ni 2+ . In addition, the loss of Vac1p affected several virulence factors of C.albicans. In particular, the vac1 null mutant strain showed defective hyphal growth, even when hyphal formation was induced via different pathways. Furthermore, Vac1p affects chlamydospore formation, adherence to human vaginal epithelial cells, and the secretion of aspartyl proteinases (Saps). Avirulence in a mouse model of systemic infection of the vac1 null mutant strongly suggests that Vac1p of C. albicans is essential for pathogenicity. In summary, the Vac1p protein is required for several cellular pathways, in particular those that control virulence and pathogenicity. Consequently, Vac1p is a novel and interesting target for antifungal drugs.

Four cases are described in which livedo reticularis was associated with repeated cerebrovascular accidents, which eventually resulted in severe disability in two cases. Patients with severe disability had a history of many years, whereas two patients with little or moderate residual disability had a follow-up of 3 years each. CT scan revealed multifocal cerebral infarctions and cortical atrophy in all cases. Repeated cerebral angiograms, done in three cases, showed no signs of a vascular disease. There were no parameters that pointed to active immunological or inflammatory disorder. Neither clinical evidence of heart or large vessel disease was found. Observations suggest that a so-far unknown progressive cerebral vessel disease associated with livedo is the cause of a steady increase in multiple small cerebral infarctions. Because of the progressive character of the disease the search for effective therapy is needed.

The phosphatidylinositol (PI) 3-kinase Vps34p of Candida albicans influences vesicular intracellular transport, filamentous growth and virulence. To get a clearer understanding how these phenomena are connected, we analysed hyphal growth in a matrix under microaerophilic conditions at low temperature, the detoxification of metal ions and antifungal drugs, the secretion of aspartic proteinases (Saps), as well as expression of adhesion-associated proteins of the C. albicans vps34 null mutant strain. The hyphal growth in a matrix, which is repressed in the wild-type strain by Efg1p, was derepressed in the mutant. CZF1, which encodes an activator of hyphal growth in a matrix, was up-regulated in the mutant. In addition, CZF1 expression was pH-dependent in the wild-type. Expression of EFG1 was not changed. Examination of Saps secretion showed a reduction in the vps34 null mutant. Determination of sensitivity against metal ions and antimycotic drugs revealed defects in detoxification. Expression studies indicated that the vps34 mutant reacts to the phenotypical defects with an up-regulation of genes involved in these processes, including the aspartyl proteinases SAP2 and SAP9, adhesion proteins ALS1 and HWP1, and the ABC transporters CDR1 and HST6. We also found an increased expression of the PI 4-kinase LSB6 indicating a complex feed-back mechanism for the compensation of the multiple defects arising from the lack of the PI3-kinase VPS34.