Cryptococcus neoformans is a fungal pathogen that can cause life-threatening infections of the central nervous system in immunocompromised patients. Following pulmonary infection, patrolling alveolar macrophages are a first line of defence against cryptococcosis. NO — generated by NO synthase, the product of the iNOS locus — exerts a fungistatic effect against C. neoformans in vitro and it has been known for some time that C. neoformans detoxifies NO activity in macrophages. Enzymes that are active against NO include flavohaemoglobin denitrosylase — found in yeasts and bacteria — which converts NO to nitrate, and GSNO reductase, which is conserved from bacteria to man and reduces GSNO to ammonia and glutathione disulphide. The C. neoformans flavohaemoglobin denitrosylase (FHB1) and GSNO reductase (GNO1) genes were identified by mining the available TIGR and Stanford genomic sequences for C. neoformans with gene sequences from Saccharomyces cerevisiae.
By analysing single and double gene disruption mutants, de Jesús-Berríos et al. showed that C. neoformans converts GSNO to NO (by the action of Gno1), which is subsequently metabolized by flavohaemoglobin denitrosylase (by the action of Fhb1). Using a mouse model for C. neoformans, which mimics human disease progression, they established that flavohaemoglobin denitrosylase activity contributes to virulence. By itself, GSNO reductase does not; however, mutants that lacked both enzymes were more attenuated for virulence than either single mutant, so GSNO reductase can contribute to counteract nitrosative challenge and promote disease progression.
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