In Vivo Clearance of Glucuronoxylomannan, the Major Capsular Polysaccharide of<i>Cryptococcus neoformans:</i>A Critical Role for Tissue Macrophages

Grinsell, Matthew M.; Weinhold, Leanne C.; Cutler, Jim E.; Ye, Han; Kozel, Thomas R.

doi:10.1086/322787

Cited by 54 publications

(63 citation statements)

References 48 publications

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“…This suggests an essential role for macrophages in acquiring and storing GXM in various organs and is consistent with previous observations of GXM accumulation inside tissue macrophages in vivo (43,44). The mechanism responsible for enhanced GXM accumulation inside macrophages as opposed to monocytes is unknown.…”

Section: Discussionsupporting

confidence: 93%

Microbial Immune Suppression Mediated by Direct Engagement of Inhibitory Fc Receptor

Monari

Kozel

Paganelli

et al. 2006

The Journal of Immunology

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A microbial polysaccharide (glucuronoxylomannan (GXM)) exerts potent immunosuppression by direct engagement to immunoinhibitory receptor FcγRIIB. Activation of FcγRIIB by GXM leads to the recruitment and phosphorylation of SHIP that prevents IκBα activation. The FcγRIIB blockade inhibits GXM-induced IL-10 production and induces TNF-α secretion. GXM quenches LPS-induced TNF-α release via FcγRIIB. The addition of mAb to GXM reverses GXM-induced immunosuppression by shifting recognition from FcγRIIB to FcγRIIA. These findings indicate a novel mechanism by which microbial products can impair immune function through direct stimulation of an inhibitory receptor. Furthermore, our observations provide a new mechanism for the ability of specific Ab to reverse the immune inhibitory effects of certain microbial products.

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Section: Discussionsupporting

confidence: 93%

Microbial Immune Suppression Mediated by Direct Engagement of Inhibitory Fc Receptor

Monari

Kozel

Paganelli

et al. 2006

The Journal of Immunology

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“…Several previous studies examined the in vivo distribution of capsular antigens (9,10,16,21). In perhaps the first such study, Kaplan (9) found similar results with glucuronoxylomannan, the major capsular polysaccharide from Cryptococcus neoformans.…”

Section: Discussionmentioning

confidence: 68%

“…All estimates of the amounts of ␥DPGA in tissues were corrected for ␥DPGA found in the plasma volume in each tissue (8). Estimates of serum ␥DPGA were calculated in a manner similar to that of Grinsell et al (10), assuming that the blood volume for a mouse is 5.77 ml/100g, that half of the blood volume is plasma, and that the average weight of each mouse is 20 g. A preliminary experiment was done in which tissues were spiked with purified ␥DPGA. A comparison of immunoassays using purified ␥DPGA alone and ␥DPGA in the presence of tissue homogenates showed no effect of the tissue homogenates on assay performance.…”

Section: Methodsmentioning

confidence: 99%

In Vivo Fate and Distribution of Poly-γ- d -Glutamic Acid, the Capsular Antigen from Bacillus anthracis

Sutherland¹,

Thorkildson²,

Parks

et al. 2008

Infect Immun

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Bacillus anthracis is surrounded by an antiphagocytic capsule composed of poly-␥-D-glutamic acid (␥DPGA).Bacterial and fungal capsular polysaccharides are shed into body fluids in large amounts during infection. The goal of our study was to examine the in vivo fate and distribution of the ␥DPGA capsular polypeptide. Mice were injected via the intravenous route with various amounts of purified ␥DPGA. Blood, urine, and various organs were harvested at different times after treatment. Sites of ␥DPGA accumulation were determined by immunoassay using monoclonal antibodies specific for ␥DPGA. The results showed that the liver and spleen were the primary sites for the accumulation of ␥DPGA. As found in previous studies of capsular polysaccharides, the Kupffer cells of the liver and splenic macrophages were sites for the cellular accumulation of ␥DPGA. Unlike capsular polysaccharides, the hepatic sinusoidal endothelial cells were also sites for ␥DPGA accumulation. ␥DPGA was rapidly cleared from serum and was excreted into the urine. ␥DPGA in the urine showed a reduced molecular size relative to native ␥DPGA. The results indicate that in vivo clearance of the polypeptide capsular antigen of B. anthracis shares several features with the clearance of capsular polysaccharides. Key differences between the in vivo behaviors of ␥DPGA and capsular polysaccharides include the accumulation of ␥DPGA in hepatic sinusoidal endothelial cells and a ␥DPGA clearance rate that was more rapid than the clearance reported for capsular polysaccharides.Most bacterial capsules are composed of polysaccharides. These capsules are essential to the virulence of many pathogenic bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis as well as the opportunistic yeast Cryptococcus neoformans. The capsules are characteristically antiphagocytic, and antibodies to capsular polysaccharides are protective. Capsular polysaccharides display a repeating epitope structure, have a high molecular weight, and resist degradation in vivo. These properties are characteristic of antigens classified as thymus-independent type 2 (22).Unlike the capsular polysaccharides that surround most bacteria, the capsule of Bacillus anthracis is a homopolymer of D-glutamic acid residues that are linked by the gamma carboxyl group (poly-␥-D-glutamic acid [␥DPGA]) (11). The ␥DPGA capsule is essential for virulence (5,14,30). Like capsular polysaccharides, ␥DPGA is poorly immunogenic, and the coupling of ␥DPGA to immunogenic protein carriers greatly enhances immunogenicity (15,24,25,29). Finally, as with capsular polysaccharides, antibodies to ␥DPGA are protective in murine models of pulmonary anthrax (2,15,18).Studies of the in vivo behaviors of capsular polysaccharides of S. pneumoniae, H. influenzae type b, and C. neoformans found that capsular polysaccharides accumulate in cells of the reticuloendothelial system and persist for weeks in tissues and serum. Despite the essential role played by ␥DPGA in the virulence of B. anthracis, little i...

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“…This prolonged action could be related to the fact that GXM remains internalized in macrophages for Ͼ1 mo (60). Hence, the two effects could be related and follow parallel pathways.…”

Section: Discussionmentioning

confidence: 99%

Cryptococcus neoformansCapsular Glucuronoxylomannan Induces Expression of Fas Ligand in Macrophages

Monari

Pericolini

Bistoni

et al. 2005

The Journal of Immunology

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The major component of capsular material of Cryptococcus neoformans is glucuronoxylomannnan (GXM), a polysaccharide that exhibits potent immunosuppressive properties in vitro and in vivo. The results reported here show that 1) soluble purified GXM induces a prompt, long-lasting, and potent up-regulation of Fas ligand (FasL) on macrophages, 2) the up-regulation of FasL is related to induced synthesis and increased mobilization to the cellular surface, 3) this effect is largely mediated by interaction between GXM and TLR4, 4) FasL up-regulation occurs exclusively in GXM-loaded macrophages, 5) macrophages that show up-regulation of FasL induce apoptosis of activated T cells expressing Fas and Jurkat cells that constitutively express Fas, and 6) anti-Fas Abs rescue T cells from apoptosis induced by GXM. Collectively our results reveal novel aspects of the immunoregulatory properties of GXM and suggest that this nontoxic soluble compound could be used to dampen the immune response, to promote or accelerate the death receptor, and to fix FasL expression in a TLR/ligand-dependent manner. In the present study, we delineate potential new therapeutic applications for GXM that exploit death receptors as key molecular targets in regulating cell-mediated cytotoxicity, immune homeostasis, and the immunopathology of diseases.

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In Vivo Clearance of Glucuronoxylomannan, the Major Capsular Polysaccharide ofCryptococcus neoformans:A Critical Role for Tissue Macrophages

Cited by 54 publications

References 48 publications

Microbial Immune Suppression Mediated by Direct Engagement of Inhibitory Fc Receptor

Microbial Immune Suppression Mediated by Direct Engagement of Inhibitory Fc Receptor

In Vivo Fate and Distribution of Poly-γ- d -Glutamic Acid, the Capsular Antigen from Bacillus anthracis

Cryptococcus neoformansCapsular Glucuronoxylomannan Induces Expression of Fas Ligand in Macrophages

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