Candida albicans and host interaction : the many faces of the Candida Pra1 protein
C. albicans is an opportunistic human pathogen that causes superficial, as well as lifethreatening infections in immuno-compromised patients. In order to establish an infection, C. albicans has developed multiple mechanisms to avoid host immune recognition and cross host tissue barriers. The aim of the work was to identify proteins from C. albicans that mediate immune evasion and to characterize these proteins on a molecular level. In this project, I identified C. albicans Pra1 as a multifunctional virulence factor which mediates C. albicans for immune evasion and tissue invasion at different locations: (i) as a surface protein, Pra1 binds human complement regulators Factor H, FHL-1, C4BP, as well as plasminogen. The attached human regulators mediate complement evasion and degradation of extra-cellular matrices, and consequently favoring C. albicans invasion; (ii) as a secreted protein, Pra1 complexes C3 in solution, blocks C3 cleavage by C3 convertases, thereby inhibiting further complement amplification and progression, and downstream complement effector functions; and (iii) binding to the surface of host cells. Upon binding, surface Pra1 functions as an invasin to mediate C. albicans for adhesion and invasion into host endothelial cells, secreted Pra1 blocks CR3 mediated recognition of pneumococcus by PMNs by binding to CR3. In addition, I identified Pra1 surface expression and sequence variation in clinical isolates derived from Candida infected patients. Pra1 is expressed at all tested clinical isolates surface. Sequence analyses of PRA1 identify a relevant nucleotide exchange (A73G) which also affects the amino acid (Asn25Asp) in all test isolates with homozygousity. Thus, Pra1 is a multifunctional virulence factor that favors fungal survival at distinct sites. A detailed understanding of these multiple roles of Pra1 may allow defining new strategies to interfere with and fight against C. albicans infection.