Cryptococcus neoformans

Cryptococcosis is the leading cause of life-threatening mycological disease of the central nervous system, with a high worldwide mortality and morbidity in immunocompromised patients.In the Netherlands from 1996 on incidence numbers are declining, in parallel with incidence numbers in the rest of the Western world. This decline is due to the introduction of highly active antiretroviral therapy (HAART). In countries that can not afford costs of HAART, like for example in Sub Saharan Africa and India, cryptococcal related infection are an enormous problem. C. neoformans enters the body by inhalation of poorly encapsulated yeast cells. In the lungs innate immune responses like phagocytosis of C. neoformans by resident macrophages (alveolar macrophages) take place. We developed a new, rapid and objective method to measure interaction between the yeast C. neoformans and adherent phagocytic cells. This method was used to investigate if surfactant proteins like surfactant protein A and D play a role in innate host defense against cryptococci.In contrast to many other micro-organisms like E. coli, M. tuberculosis and influenza A virus, pulmonary surfactant proteins do not support phagocytosis of C. neoformans. Cytokines that are present during the initiation ofresponse will determine whether CMI or B-cell development will take place. The time kinetics of cytokine release in PBMC of healthy donors stimulated with cryptococcal capsular polysaccharides indicate an autocrine-paracrine network regulation of the cytokines. Proinflammatory cytokines like TNF-aDPAF, IL-8 and fMLP. Another capsular component of C. neoformans Mannoprotein 4 (MP4) was found to potent inhibitor of PMN migration. Neutrophil infiltration into the central nervous system is a dual-edged sword in that it protects the tissue from infection and injury but can also be detrimental to the host. In diseases such as bacterial meningitis or cerebrovascular ischemia there is evidence that a high influx of PMN plays an adverse role in the pathogenesis of neurological damage Accordingly, it is now assumed that adjunctive therapeutic strategies with anti- inflammatory agents may favor neurological recovery. Therefore we will investigate the possibilities to use GXM and MP4 therapeutically