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

Mean first-passage time of surface-mediated diffusion in spherical domains

We present an exact calculation of the mean first-passage time to a target on the surface of a 2D or 3D spherical domain, for a molecule alternating phases of surface diffusion on the domain boundary and phases of bulk diffusion. The presented approach is based on an integral equation which can be solved analytically. Numerically validated approximation schemes, which provide more tractable expressions of the mean first-passage time are also proposed. In the framework of this minimal model of surface-mediated reactions, we show analytically that the mean reaction time can be minimized as a function of the desorption rate from the surface.Comment: to appear in J. Stat. Phy

Chord distribution functions of three-dimensional random media: Approximate first-passage times of Gaussian processes

The main result of this paper is a semi-analytic approximation for the chord distribution functions of three-dimensional models of microstructure derived from Gaussian random fields. In the simplest case the chord functions are equivalent to a standard first-passage time problem, i.e., the probability density governing the time taken by a Gaussian random process to first exceed a threshold. We obtain an approximation based on the assumption that successive chords are independent. The result is a generalization of the independent interval approximation recently used to determine the exponent of persistence time decay in coarsening. The approximation is easily extended to more general models based on the intersection and union sets of models generated from the iso-surfaces of random fields. The chord distribution functions play an important role in the characterization of random composite and porous materials. Our results are compared with experimental data obtained from a three-dimensional image of a porous Fontainebleau sandstone and a two-dimensional image of a tungsten-silver composite alloy.Comment: 12 pages, 11 figures. Submitted to Phys. Rev.

C3d adjuvant effects are mediated through the activation of C3d-specific autoreactive T cells

Complement fragment C3d covalently attached to antigens enhances immune responses, particularly for antigens lacking T cell epitopes. Enhancement has been attributed to receptor cross-linking between complement receptor CR2 (CD21) and polysaccharide antigen to surface IgM on naïve B cells. Paradoxically, C3d has still been shown to increase immune responses in CD21 KO mice, suggesting that an auxiliary activation pathway exists. In prior studies, we demonstrated the CD21-independent C3d adjuvant effect might be due to T cell recognition of C3d T helper epitopes processed and presented by MHC class II on the B cell surface. C3d peptide sequences containing concentrated clusters of putative human C3 T cell epitopes were identified using the epitope-mapping algorithm, EpiMatrix. These peptide sequences were synthesized and shown in vitro to bind multiple HLA-DR alleles with high affinity, and induce IFNγ responses in healthy donor PBMCs. In the present studies, we establish further correlations between HLA binding and HLA-specific lymphocyte reactions with select epitope clusters. Additionally, we show that the T cell phenotype of C3d-specific reactive T cells is CD4+CD45RO+ memory T cells. Finally, mutation of a single T cell epitope residing within the P28 peptide segment of C3d resulted in significantly diminished adjuvant activity in BALB/c mice. Collectively, these studies support the hypothesis that the paradoxical enhancement of immune responses by C3d in the absence of CD21 is due to internalization and processing of C3d into peptides that activate autoreactive CD4+ T helper cells in the context of HLA class II

Further Confirmation of Broadly Conserved, Highly Immunogenic Cross-Clade HIV CTL Epitopes for Inclusion in the GAIA HIV Vaccine

Poster Presentation From AIDS Vaccine 2012 Boston, MA, USA. 9-12 September 201

Kinetics of active surface-mediated diffusion in spherically symmetric domains

We present an exact calculation of the mean first-passage time to a target on the surface of a 2D or 3D spherical domain, for a molecule alternating phases of surface diffusion on the domain boundary and phases of bulk diffusion. We generalize the results of [J. Stat. Phys. {\bf 142}, 657 (2011)] and consider a biased diffusion in a general annulus with an arbitrary number of regularly spaced targets on a partially reflecting surface. The presented approach is based on an integral equation which can be solved analytically. Numerically validated approximation schemes, which provide more tractable expressions of the mean first-passage time are also proposed. In the framework of this minimal model of surface-mediated reactions, we show analytically that the mean reaction time can be minimized as a function of the desorption rate from the surface.Comment: Published online in J. Stat. Phy

Occupation times of random walks in confined geometries: From random trap model to diffusion limited reactions

We consider a random walk in confined geometry, starting from a site and eventually reaching a target site. We calculate analytically the distribution of the occupation time on a third site, before reaching the target site. The obtained distribution is exact, and completely explicit in the case or parallepipedic confining domains. We discuss implications of these results in two different fields: The mean first passage time for the random trap model is computed in dimensions greater than 1, and is shown to display a non-trivial dependence with the source and target positions ; The probability of reaction with a given imperfect center before being trapped by another one is also explicitly calculated, revealing a complex dependence both in geometrical and chemical parameters

Evaluating Short-Term Patient Outcomes after HIV Care Interventions in a Low Resource Setting: Preparing for an HIV Vaccine Trial Site in Bamako, Mali

Poster Presentation From AIDS Vaccine 2012 Boston, MA, USA. 9-12 September 201

Novel strategies to enhance vaccine immunity against coccidioidomycosis

Coccidioidomycosis is a potentially life-threatening respiratory mycosis endemic to the Americas and caused by inhalation of spores produced by the molds Coccidioides immitis and C. posadasii

Mesoscale texture of cement hydrates

Strength and other mechanical properties of cement and concrete rely upon the formation of calcium-silicate-hydrates (C-S-H) during cement hydration. Controlling structure and properties of the C-S-H phase is a challenge, due to the complexity of this hydration product and of the mechanisms that drive its precipitation from the ionic solution upon dissolution of cement grains in water. Departing from traditional models mostly focused on length scales above the micrometer, recent research addressed the molecular structure of C-S-H. However, small-angle neutron scattering, electron- microscopy imaging, and nanoindentation experiments suggest that its mesoscale organization, extending over hundreds of nanometers, may be more important. Here we unveil the C-S-H mesoscale texture, a crucial step to connect the fundamental scales to the macroscale of engineering properties. We use simulations that combine information of the nanoscale building units of C-S-H and their effective interactions, obtained from atomistic simulations and experiments, into a statistical physics framework for aggregating nanoparticles. We compute small-angle scattering intensities, pore size distributions, specific surface area, local densities, indentation modulus, and hardness of the material, providing quantitative understanding of different experimental investigations. Our results provide insight into how the heterogeneities developed during the early stages of hydration persist in the structure of C-S-H and impact the mechanical performance of the hardened cement paste. Unraveling such links in cement hydrates can be groundbreaking and controlling them can be the key to smarter mix designs of cementitious materials