39 research outputs found
Non-uniform growth and surface friction determine bacterial biofilm morphology on soft substrates
During development, organisms acquire three-dimensional shapes with important
physiological consequences. While the basic mechanisms underlying morphogenesis
are known in eukaryotes, it is often difficult to manipulate them in vivo. To
circumvent this issue, here we present a study of developing Vibrio cholerae
biofilms grown on agar substrates in which the spatiotemporal morphological
patterns were altered by varying the agar concentration. Expanding biofilms are
initially flat, but later experience a mechanical instability and become
wrinkled. Whereas the peripheral region develops ordered radial stripes, the
central region acquires a zigzag herringbone-like wrinkle pattern. Depending on
the agar concentration, the wrinkles initially appear either in the peripheral
region and propagate inward (low agar concentration) or in the central region
and propagate outward (high agar concentration). To understand these
experimental observations, we developed a model that considers diffusion of
nutrients and their uptake by bacteria, bacterial growth/biofilm matrix
production, mechanical deformation of both the biofilm and the agar, and the
friction between them. Our model demonstrates that depletion of nutrients
beneath the central region of the biofilm results in radially-dependent growth
profiles, which in turn, produce anisotropic stresses that dictate the
morphology of wrinkles. Furthermore, we predict that increasing surface
friction (agar concentration) reduces stress anisotropy and shifts the location
of the maximum compressive stress, where the wrinkling instability first
occurs, toward the center of the biofilm, in agreement with our experimental
observations. Our results are broadly applicable to bacterial biofilms with
similar morphologies and also provide insight into how other bacterial biofilms
form distinct wrinkle patterns.Comment: 16 pages, 4 figures + supplementary information (36 pages, 14
figures
HLA-B may be more protective against HIV-1 than HLA-A because it resists negative regulatory factor (Nef) mediated down-regulation
Hydrophobic CDR3 residues promote the development of self-reactive T cells
Studies of individual T cell antigen receptors (TCRs) have shed some light on structural features that underlie self-reactivity. However, the general rules that can be used to predict whether TCRs are self-reactive have not been fully elucidated. Here we found that the interfacial hydrophobicity of amino acids at positions 6 and 7 of the complementarity-determining region CDR3ÎČ robustly promoted the development of self-reactive TCRs. This property was found irrespective of the member of the ÎČ-chain variable region (V[subscript ÎČ]) family present in the TCR or the length of the CDR3ÎČ. An index based on these findings distinguished V[subscript ÎČ]2[superscript +], V[subscript ÎČ]6[superscript +] and V[subscript ÎČ]8.2[superscript +] regulatory T cells from conventional T cells and also distinguished CD4[superscript +] T cells selected by the major histocompatibility complex (MHC) class II molecule I-A[superscript g7] (associated with the development of type 1 diabetes in NOD mice) from those selected by a nonâautoimmunity-promoting MHC class II molecule I-Ab. Our results provide a means for distinguishing normal T cell repertoires versus autoimmunity-prone T cell repertoires
Progression to AIDS in South Africa Is Associated with both Reverting and Compensatory Viral Mutations
We lack the understanding of why HIV-infected individuals in South Africa
progress to AIDS. We hypothesised that in end-stage disease there is a shifting
dynamic between T cell imposed immunity and viral immune escape, which, through
both compensatory and reverting viral mutations, results in increased viral
fitness, elevated plasma viral loads and disease progression. We explored how T
cell responses, viral adaptation and viral fitness inter-relate in South African
cohorts recruited from Bloemfontein, the Free State
(nâ=â278) and Durban, KwaZulu-Natal
(nâ=â775). Immune responses were measured by
Îł-interferon ELISPOT assays. HLA-associated viral polymorphisms were
determined using phylogenetically corrected techniques, and viral replication
capacity (VRC) was measured by comparing the growth rate of gag-protease
recombinant viruses against recombinant NL4-3 viruses. We report that in
advanced disease (CD4 counts <100 cells/”l), T cell responses narrow,
with a relative decline in Gag-directed responses (p<0.0001). This is
associated with preserved selection pressure at specific viral amino acids
(e.g., the T242N polymorphism within the HLA-B*57/5801 restricted TW10
epitope), but with reversion at other sites (e.g., the T186S polymorphism within
the HLA-B*8101 restricted TL9 epitope), most notably in Gag and suggestive
of âimmune relaxationâ. The median VRC from patients with CD4 counts
<100 cells/”l was higher than from patients with CD4 counts â„500
cells/”l (91.15% versus 85.19%,
pâ=â0.0004), potentially explaining the rise in viral load
associated with disease progression. Mutations at HIV Gag T186S and T242N
reduced VRC, however, in advanced disease only the T242N mutants demonstrated
increasing VRC, and were associated with compensatory mutations
(pâ=â0.013). These data provide novel insights into the
mechanisms of HIV disease progression in South Africa. Restoration of fitness
correlates with loss of viral control in late disease, with evidence for both
preserved and relaxed selection pressure across the HIV genome. Interventions
that maintain viral fitness costs could potentially slow progression
LILRB2 Interaction with HLA Class I Correlates with Control of HIV-1 Infection.
Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC) class I locus, and the CD8+ T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1) by changing interactions of human leukocyte antigen (HLA) class I molecules with leukocyte immunoglobulin-like receptors (LILR), a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (Nâ=â5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (pâ=â10-2). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (pâ=â10-11-10-9) and African (pâ=â10-5-10-3) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement
Stochastic effects are important in intrahost HIV evolution even when viral loads are high
Blood plasma viral loads and the time to progress to AIDS differ widely among untreated HIV-infected humans. Although people with certain HLA (HLA-I) alleles are more likely to control HIV infections without therapy, the majority of such untreated individuals exhibit high viral loads and progress to AIDS. Stochastic effects are considered unimportant for evolutionary dynamics in HIV-infected people when viral load is high or when selective forces strongly drive mutation. We describe a computational study of hostâpathogen interaction demonstrating that stochastic effects can have a profound influence on disease dynamics, even in cases of high viral load and strong selective pressure. These stochastic effects are pronounced when the virus must traverse a fitness âbarrierâ in sequence space to escape the hostâs cytotoxic T-lymphocyte (CTL) response, as often occurs when a fitness defect imposed by a CTL-driven mutation must be compensated for by other mutations. These âbarrier-crossingâ events are infrequent and stochastic, resulting in divergent disease outcomes in genetically identical individuals infected by the same viral strain. Our results reveal how genetic determinants of the CTL response control the probability with which an individual is able to control HIV infection indefinitely, and thus provide clues for vaccine design.Jane Coffins Childs FoundationMassachusetts Institute of Technology. Ragon Institute of MGH, MIT and HarvardNational Institutes of Health (U.S.) (Directorâs Pioneer Award