Variation in the structure of glucuronoxylomannan in isolates from patients with recurrent cryptococcal meningitis

Abstract

Capsular glucuronoxylomannans (GXM) of Cryptococcus neoformans var. neoformans isolates from patients with recurrent cryptococcal meningitis were analyzed by 1 H nuclear magnetic resonance spectroscopy and for reactivity with factor sera (Iatron, Tokyo, Japan). For each patient the initial and relapse isolates had previously been shown to be indistinguishable by DNA restriction fragment length polymorphism analysis. For patients J11 and J22 the GXM of the initial and relapse isolates were identical. For patients SB4 and SB6 the GXM of the initial and relapse isolates differed in structure and reactivity with factor sera. In patient SB4 the initial isolate had a serotype A/D structure, and the first relapse isolate had a serotype A structure. The second relapse isolate was a mixture of structures composed of serotype D components, glucuronomannan (GM), and a minor serotype A component. Analysis of the initial isolate from patient SB6 showed a structure composed mainly of serotype D, GM, and minor serotype A components and components not assigned to a particular serotype (N). The relapse isolate had the same composition as the initial isolate except for an increase in the serotype A component. This increase in the serotype A component of the relapse isolate resulted in a change in the serological specificity from serotype D to serotype A/D. The initial isolate from patient J9 had serotype D and GM structures. The first two relapse isolates had serotype D, N, and GM structures and a minor serotype A component. The third relapse isolate had mainly a serotype D structure. All the J9 isolates reacted only with serotype D-specific factor serum. These results indicate that some isolates obtained from patients with recurrent C. neoformans infections have undergone a change in GXM structure during the course of infection. The modification of GXM structure observed in some relapse isolates is reflected in changed serological properties. The results may have important implications for the design of vaccines and antibodybased therapeutic strategies against C. neoformans.

Phenotypic switching and its implications for the pathogenesis ofCryptococcus neoformans

“…For C. neoformans strain 24067, analysis of different isolates maintained in different laboratories has revealed striking differences in phenotypic characteristics and virulence Chen & Casadevall, 1999). Several observations support the concept that microevolution of C. neoformans also occurs during the course of human infection and contributes to persistence of infection: (1) serial C. neoformans isolates from chronically infected HIV-positive patients demonstrated differences in murine infection models as well as changes in the polysaccharide capsule (Cherniak et al, 1995;Jain, 2005); (2) investigations in chronic murine infection models have documented the emergence of both giant cells and poorly encapsulated forms (Feldmesser et al, 2001); (3) the emergence of variants that exhibit changes of the sterol content in the cell membrane has been demonstrated (Currie et al, 1995); and (4) changes in colony morphology and karyotype pattern occur during chronic infection (Fries et al, 1996;Sukroongreung et al, 2001). In addition, careful analysis of primary clinical specimens has shown that phenotypic variation in colony morphology can be observed in isolates from the spinal fluid .…”

VARIATIONS IN THE SUBSTITUTED 3‐LINKED MANNANS CLOSELY ASSOCIATED WITH THE SILICIFIED WALLS OF DIATOMS1

“…The present study demonstrated that the 3-linked mannan backbone is the common scaffold to which the anionic substituents are attached. Polysaccharides with a 3-linked mannan backbone are relatively rare in nature, but substituted a-1,3-linked mannans have been reported in the fruiting bodies of some fungi and as lipopolysaccharides in some mycobacteria (Ogawa and Yamamoto 1985, Cherniak et al 1995, Senchenkova et al 1997, Ichikawa et al 2001, Guérardel et al 2002. Interestingly, the substitution patterns of the mannan backbone in several of these polysaccharides bear some similarities to those of the diatom mannans, with GlcpA and Xylp substitutions attached at O-2 of approximately every second 3-linked Manp residue.…”

Antibody action after phagocytosis promotesCryptococcus neoformansandCryptococcus gattiimacrophage exocytosis with biofilm-like microcolony formation

“…This phenomenon also occurred with IgG and F(ab) 2 fragments, and consequently IgG phagocytosis occurred through both Fc and CR receptors even in the absence of complement (Netski and Kozel, 2002). As the capsular polysaccharide of C. gattii is more highly substituted than that of the other varieties (Cherniak et al, 1995) we sought to establish whether antibody-mediated complement-independent phagocytosis through CR also occurred with this variety, especially when considering comparative studies of macrophage fungal cell interactions involving the different cryptococcal varieties and species. A dose-dependent relationship was observed with IgM mAb 12A1 in phagocytosis assays, whereby increasing concentrations of IgM promoted an increase in phagocytosis by J774.16 cells in the absence of complement ( Fig.…”