Direct Inhibition of T-Cell Responses by the Cryptococcus Capsular Polysaccharide Glucuronoxylomannan

The major virulence factor of the pathogenic fungi Cryptococcus neoformans and C. gattii is the capsule. Glucuronoxylomannan (GXM), the major component of the capsule, is a high-molecular-weight polysaccharide that is shed during cryptococcosis and can persist in patients after successful antifungal therapy. Due to the importance of T cells in the anticryptococcal response, we studied the effect of GXM on the ability of dendritic cells (DCs) to initiate a T-cell response. GXM inhibited the activation of cryptococcal mannoprotein-specific hybridoma T cells and the proliferation of OVA-specific OT-II T cells when murine bone marrow-derived DCs were used as antigen-presenting cells. Inhibition of OT-II T-cell proliferation was observed when either OVA protein or OVA323-339 peptide was used as antigen, indicating GXM did not merely prevent antigen uptake or processing. We found that DCs internalize GXM progressively over time; however, the suppressive effect did not require DCs, as GXM directly inhibited T-cell proliferation induced by anti-CD3 antibody, concanavalin A, or phorbol-12-myristate-13-acetate/ionomycin. Analysis of T-cell viability revealed that the reduced proliferation in the presence of GXM was not the result of increased cell death. GXM isolated from each of the four major cryptococcal serotypes inhibited the proliferation of human peripheral blood mononuclear cells stimulated with tetanus toxoid. Thus, we have defined a new mechanism by which GXM can impart virulence: direct inhibition of T-cell proliferation. In patients with cryptococcosis, this could impair optimal cell-mediated immune responses, thereby contributing to the persistence of cryptococcal infections. SynopsisInfections due to the pathogenic yeast Cryptococcus are a significant cause of morbidity and mortality in persons with impaired T-cell functions, particularly those with AIDS. The major virulence factor of Cryptococcus is its capsule, which is composed primarily of the polysaccharide glucuronoxylomannan (GXM). The capsule not only surrounds the organism but also is shed during cryptococcosis. GXM is taken up by macrophages in vitro and in vivo; however, little is known about the interaction between GXM and dendritic cells, which are the most potent cells capable of activating T cells. Because of the importance of T cells in the anticryptococcal response, the authors investigated the effect of GXM on the ability of dendritic cells to initiate a T-cell response. They found the polysaccharide was internalized by dendritic cells and inhibited antigen-specific T-cell responses. Furthermore, GXM had a direct, inhibitory effect on T-cell proliferation, independent of the effect on dendritic cells. These findings may help explain the persistence of cryptococcal infections and suggest that GXM could be therapeutic in situations where suppression of T-cell responses is desired.National Institutes of Health (R01 AI25780, R01 AI066087, R01 AI37532

Cryptococcus neoformans ex vivo capsule size is associated with intracranial pressure and host immune response in HIV-associated cryptococcal meningitis

<p>Background. The Cryptococcus neoformans polysaccharide capsule is a well-characterised virulence factor with immunomodulatory properties. The organism and/or shed capsule is postulated to raise intracranial pressure(ICP) in cryptococcal meningitis(CM) by mechanical obstruction of cerebrospinal fluid(CSF) outflow. Little is known regarding capsule phenotype in human cryptococcosis. We investigated the relationship of ex vivo CSF capsular phenotype with ICP and CSF immune response, as well as in vitro phenotype.</p> <p>Methods. 134 HIV-infected Ugandan adults with CM had serial lumbar punctures with measurement of CSF opening pressures, quantitative cultures, ex vivo capsule size and shedding, viscosity, and CSF cytokines. 108 had complete data. Induced capsular size and shedding were measured in vitro for 48 C. neoformans isolates.</p> <p>Results. Cryptococcal strains producing larger ex vivo capsules in the baseline(pre-treatment) CSF correlated with higher ICP(P=.02), slower rate of fungal clearance(P=.02), and paucity of CSF inflammation, including decreased CSF white blood cell(WBC) count(P<.001), interleukin(IL)-4(P=.02), IL-6(P=.01), IL-7(P=.04), IL-8(P=.03), and interferon-gamma(P=.03). CSF capsule shedding did not correlate with ICP. On multivariable analysis, capsule size remained independently associated with ICP. Ex vivo capsular size and shedding did not correlate with that of the same isolates grown in vitro.</p> <P>Conclusions. Cryptococcal capsule size ex vivo is an important contributor to virulence in human cryptococcal meningitis.</P&gt

An Euler Solver Based on Locally Adaptive Discrete Velocities

A new discrete-velocity model is presented to solve the three-dimensional Euler equations. The velocities in the model are of an adaptive nature---both the origin of the discrete-velocity space and the magnitudes of the discrete-velocities are dependent on the local flow--- and are used in a finite volume context. The numerical implementation of the model follows the near-equilibrium flow method of Nadiga and Pullin [1] and results in a scheme which is second order in space (in the smooth regions and between first and second order at discontinuities) and second order in time. (The three-dimensional code is included.) For one choice of the scaling between the magnitude of the discrete-velocities and the local internal energy of the flow, the method reduces to a flux-splitting scheme based on characteristics. As a preliminary exercise, the result of the Sod shock-tube simulation is compared to the exact solution.Comment: 17 pages including 2 figures and CMFortran code listing. All in one postscript file (adv.ps) compressed and uuencoded (adv.uu). Name mail file `adv.uu'. Edit so that `#!/bin/csh -f' is the first line of adv.uu On a unix machine say `csh adv.uu'. On a non-unix machine: uudecode adv.uu; uncompress adv.tar.Z; tar -xvf adv.ta

Titan cell production in Cryptococcus neoformans reshapes the cell wall and capsule composition during infection

This work was supported by the National Institutes of Health (R01AI080275 and R21AI22352), the NIH Fogarty International Center (R25TW009345), the University of Minnesota Center for Translational Science Institute (UL1TR000114), Wellcome Trust (086827, 075470, 097377, 101873 & 200208) and MRC Centre for Medical Mycology (N006364/1). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.Peer reviewedPublisher PD

Price elasticities, joint products, and international trade

This paper extends the basic results of Houck’s insight for derived demand elasticities for the case of joint products by allowing for the possibility of the joint and raw products being traded. Theoretical relationships between individual demands for a set of jointly-produced commodities that are traded and composite demand for the raw product from which the joint products originate are derived. It is shown that while the derived price elasticity of domestic demand retains the same form as Houck’s original formula, the relevant price elasticities of demand to include in the formula are elasticities of total demand instead of domestic demand elasticities. Using the USA soybean industry as an example, this generalised formula that takes into account trade is implemented to calculate the elasticity of total demand for USA soybeans. The usefulness of this formula for policy-makers to trace out the impacts of changes in market conditions and trade policy in the joint-products, and how it will impact the price elasticity of domestic and total demand for the raw product, is demonstrated.Demand and Price Analysis, International Relations/Trade,