Unusual Galactofuranose Modification of a Capsule Polysaccharide in the Pathogenic Yeast Cryptococcus neoformans

Abstract

Background: Galactofuranose, the five-membered ring form of galactose, occurs in the encapsulated pathogenic fungus Cryptococcus neoformans but not in humans. Results: We established the position of galactofuranose within a capsule polysaccharide and characterized cryptococci lacking this modification. Conclusion: Galactofuranose occurs in an unusual linkage but is not required for growth or virulence. Significance: This work fills a gap in knowledge about a pathogen-specific modification.

Cryptococcus neoformans and Cryptococcus gattii, the Etiologic Agents of Cryptococcosis

“…Enzymes required for synthesis of the first four have been biochemically characterized, and genes encoding synthetic machinery for all five have been identified and deleted to assess the impact on cells (Bar-Peled et al 2001Wills et al 2001;Moyrand et al 2002Moyrand et al , 2007Moyrand et al , 2008Griffith et al 2004;Moyrand and Janbon 2004;Beverley et al 2005;Doering 2009). The lack of these proteins reduces capsule production and virulence in animal models, except for the enzyme responsible for UDP-galactofuranose synthesis; this may be because galactofuranose is a minor component of capsule polysaccharides (Heiss et al 2013). Two nucleotide sugar transporters for GDP-mannose and one for UDP-galactose have also been investigated (Cottrell et al 2007;Moyrand et al 2007;Wang et al 2014).…”

Cryptococcus neoformans Dual GDP-Mannose Transporters and Their Role in Biology and Virulence

“…The second capsule polymer, GXMGal, is less well understood but is also associated with cryptococcal virulence (35). GXMGal is based on a linear polymer of galactose, and its side chains contain mannose residues along with galactose, glucuronic acid, and xylose (36)(37)(38).…”

Oral Abstracts

“…By comparing the inositol polyposphate (IP) profiles of the CnIPK deletion mutants, deltaarg1 and deltakcs1, using HPLC (3) , we demonstrated that Arg1 (the major IP 3 kinase in Cn) and Kcs1, another IPK predicted to function downstream of Arg1 as an IP 6 kinase, convert IP 3 to (IP) [4][5] , and IP 6 to the inositol pyrophosphates (PP-IP) 7-8 ,respectively. IP [3][4][5][6] have only a single phosphate at any given position on the inositol ring, while PP-IP 7-8 have one or more diphosphates at a given position. Loss of Arg1 and Kcs1 function in deltaarg1 and deltakcs1, respectively, had a pleotropic effect on the virulence composite, with virulence attenuation in deltaarg1 being more severe than in deltakcs1.…”

“…Although the structures of the two major capsule polysaccharides are known (2)(3)(4)(5), only one glycosyltransferase of the many required for their synthesis has been conclusively identified. Genome sequence alone is of limited utility in this regard, partly due to the unique structures of capsule glycans and the challenge of identifying specific glycoactive enzymes from primary sequence alone.…”

“…1A. Indeed, a review of recent experiences with biomarkers as potential surrogate endpoints is particularly sobering and includes many high-profile failures such as the Cardiac Arrhythmia Suppression Trial (CAST) in which a strong prognostic biomarker for sudden death (ventricular arrhythmias) proved to be a poor surrogate for mortality, but, nevertheless, was used for the development of antiarrhythmic agents with tragic consequences [5]. A study of high vs. lower-dose clarithromycin showed superior mycobacterial clearance with the higher doses, but resulted in a doubling of death rates in a randomized trial [6].…”