Capsule biogenesis in Cryptococcus neoformans

Abstract

Cryptococcus neoformans is a human pathogen that mainly causes disease in immuno-compromised individuals. The yeast cells or basidiospores spread through dissemination from environmental sources, for example pigeon droppings and dust, and causes a systemic infection, cryptococcosis. A severe clinical manifestation of cryptococcosis is meningo-encephalitis, but also infection of other organs like the lungs, and skin have been reported. Since the increased incidence of AIDS due to the spread of the HIV virus, especially in third world countries, C. neoformans has become one of the most emerging opportunistic pathogens in hospitals. In fact, it is one of the leading causes of death in patients suffering from AIDS. The incidence of cryptococcosis is also increasing in the Western world especially due to use of immunosuppressive drugs and increasing numbers of organ transplantations. The surface of the C. neoformans yeast cell can be surrounded by a thick capsule. This capsule is mainly composed of the polysaccharides GXM and GalXM. GalXM consists of the monosaccharides mannose, xylose and glucuronic acid, whereas GXM contains galactose, mannose and xylose. The capsule is critical for pathogenesis and harbors components that have immuno-modulatory properties. This and the physical properties of the capsule makes it a barrier for the immune system to reach receptors on the cell wall. Mutants have been isolated that have an acapsular phenotype. These mutants of the serotype A strain of C. neoformans are called CAP10, CAP59, CAP60 and CAP64. CAP67 is a serotype D mutant strain. The genes that are affected in these strains have been identified, but the exact role of the CAP genes is not clear. In this Thesis biosynthesis of the capsule and its role in pathogenesis was studied. This was done by investigating the content and the structure of the capsule, by looking at the genes involved in capsule biogenesis and by investigating the effect of mutants affected in capsule biogenesis on human dendritic cells. This is not only interesting from a fundamental point of view, it may also identify targets that can be used to improve treatment of cryptococcosis in the future.