Immunopathologie de la leptospirose humaine : exploration de la réponse immunitaire innée.

Leptospirosis is a bacterial zoonosis caused by Leptospira and affecting 1 million people each year worldwide and mainly in tropical areas such as Reunion Island. Usual presentations encompass flu-like syndrome to multiorgan failure with mortality rate between 5 to 10%. To date, pathophysiology in humans is poorly understood, notably the capacity of innateimmunity to mount a robust response to clear pathogen or to induce tissue damages and contributing to disease severity. Our study aimed at assessing the role of innate immune cells and molecules within the first days of leptospiral infection.Using blood samples, we performed quantitative and qualitative assessment of circulating innate immune cells from leptospirosis cases and healthy controls. The first study explored the levels of gamma-delta T-cells (γδT-cells), a subset of unconventional T cells with innate immune functions. Gamma-delta T cells were found deeply decreased and levels wereinversely correlated to bacterial burden and liver damage. The second study focused on membrane bound receptors indicative of activation and tissue migration ability of neutrophil polymorphonuclear cells: CD15, CD11b, and CD182. Although neutrophil rates were high in leptospirosis cases, the levels of studied receptors were either lower (CD15) or identical to healthy controls (CD11b, CD182). In addition, only low levels of interleukin-8, a key chemokine for neutrophils, was detected in patients. Lastly, we ascertained the plasmatic levels of several shed cell adhesion molecules notably expressed by endothelial cells. The levels of soluble E-selectin and ICAM-1 were significantly increased compared to controls, while P-selectin level was lower. We did not find any correlation with disease severity or organ failure. This finding indicates that endothelial cell may be activated but further experiments are warranted to explain the functional impact of our findings. Altogether, our results add to the field of knowledge of leptospirosis pathophysiology, and in particular the implication of key innate immune cells at the stage of plasmatic bacterial dissemination. Our findings will support the view that there is an inappropriate immune response to Leptospira.La leptospirose est une zoonose causée par les bactéries du genre Leptospira. Elle touche près de 1 million d'individus par an dans le monde entier et sévit à l'état endémique dans les pays au climat tropical tel que La Réunion. Les manifestations habituelles sont variables d'un individu à l'autre et englobent une simple fièvre jusqu'aux défaillances poly-viscérales avec mortalité dans 5 à 10% des cas. Sa physiopathologie est encore mal comprise, en particulier la part que joue une réponse immunitaire inappropriée dans la genèse des manifestations graves qui surviennent en quelques heures, et avant la mise en place d'une réponse immunitaire adaptative propre à éliminer le microorganisme. Si l'échappement de la bactérie au système du complément est bien documenté, le rôle des acteurs cellulaires du système immunitaire inné reste à étayer. Notre étude avait donc pour objectif d'explorer l'immunopathologie de la leptospirose humaine dans la phase initiale de l’infection. Notre méthodologie s'est appuyée principalement sur des analyses quantitatives et qualitatives des acteurs cellulaires du système immunitaire inné à partir de prélèvements sanguins en phase précoce de la maladie, et comparaison avec la phase de convalescence et des sujets contrôles. Dans un premier temps nous avons montré qu'une population particulière de lymphocytes T impliquée dans la réponse immune innée, les lymphocytes Tγδ, avaient un taux abaissé et que cette baisse était corrélée à la charge bactérienne ainsi qu'à l’intensité de l'atteinte hépatique classiquement retrouvée lors de la leptospirose. Dans un deuxième temps, nous avons analysé les polynucléaires neutrophiles circulants dont le taux augmente d’autant plus que la maladie est sévère, mais sans pour autant présenter de modification de certains marqueurs d’activation ou de recrutement tissulaire (CD15, CD11b, CD182). Une des principales chimiokines des neutrophiles, l'interleukine 8, était à taux peu élevés. Les derniers travaux concernent les principales formes solubles issues des molécules membranaires impliquées dans le processus de recrutement/diapédèse leucocytaire. Nous retrouvons de manière isolée une forte élévation des formes solubles d'E-sélectine et ICAM-1 qui sont notamment exprimées par les cellules endothéliales. Ces augmentations n'étaient pas corrélées aux marqueurs de gravité de la maladie. La signification biologique de cette élévation n’est pas encore connue lors de la leptospirose. L'ensemble de nos données permet d’apporter des informations nouvelles sur des acteurs du système immunitaire inné présents dans le compartiment vasculaire lors de la leptospirose humaine. Cette réponse immunitaire semble inadaptée pour permettre une clairance du pathogène au stade de dissémination hématogène

Enhanced Thermoelectric Performance of Synthetic Tetrahedrites

Electrical and thermal transport properties of synthetic tetrahedrites Cu₁₀TM₂Sb₄S₁₃ (TM = Mn, Fe, Co, Ni, Zn) and the solid solution Cu_{12–<i>x</i>}Mn_<i>x</i>Sb₄S₁₃ (0 ≤ <i>x</i> ≤ 2) have been studied in the context of thermoelectric performance. Among these materials, the parent compound Cu₁₂Sb₄S₁₃ exhibits the highest power factor, which is primarily derived from a high electrical conductivity. All substituted derivatives display a significant and uniform reduction in thermal conductivity. Within the TM series, the Mn-substituted sample displays the highest ZT (0.8 at 575 K). Changing the Mn concentration to Cu₁₁MnSb₄S₁₃ produces the highest ZT, i.e., 1.13 at 575 K. The relatively high value derives from a favorable balance of low thermal conductivity and a relatively high power factor

Influence of Structural Disorder on Hollandites A_<i>x</i>Ru₄O₈ (A⁺ = K, Rb, Rb_1–<i>x</i>Na_<i>x</i>)

Structural disorder can play an important role in the electrical properties of correlated materials. In this work we examine the average and local disorder in hollandites A_<i>x</i>Ru₄O₈ (A⁺ = K, Rb, Rb_1–<i>x</i>Na_<i>x</i>) through neutron total scattering techniques. Samples with A⁺ = Rb, Rb_1–<i>x</i>Na_<i>x</i> exhibit the largest amount of local disorder as evidenced by higher atomic displacement parameters, and as a result, a weakened temperature dependence of the resistivity is observed upon cooling as compared to K_<i>x</i>Ru₄O₈. All samples exhibit anisotropic resistivity that is dominated by metallic conductivity at lower temperatures, and this is corroborated by Pauli paramagnetic behavior throughout the measured temperature regime

Structural Evolution and Atom Clustering in β‑SiAlON: β‑Si_6–<i>z</i>Al_<i>z</i>O_<i>z</i>N_8–<i>z</i>

SiAlON ceramics, solid solutions based on the Si₃N₄ structure, are important, lightweight structural materials with intrinsically high strength, high hardness, and high thermal and chemical stability. Described by the chemical formula β-Si_6–<i>z</i>Al_<i>z</i>O_<i>z</i>N_8–<i>z</i>, from a compositional viewpoint, these materials can be regarded as solid solutions between Si₃N₄ and Al₃O₃N. A key aspect of the structural evolution with increasing Al and O (<i>z</i> in the formula) is to understand how these elements are distributed on the β-Si₃N₄ framework. The average and local structural evolution of highly phase-pure samples of β-Si_6–<i>z</i>Al_<i>z</i>O_<i>z</i>N_8–<i>z</i> with <i>z</i> = 0.050, 0.075, and 0.125 are studied here, using a combination of X-ray diffraction, NMR studies, and density functional theory calculations. Synchrotron X-ray diffraction establishes sample purity and indicates subtle changes in the average structure with increasing Al content in these compounds. Solid-state magic-angle-spinning ²⁷Al NMR experiments, coupled with detailed ab initio calculations of NMR spectra of Al in different AlO_<i>q</i>N_4–<i>q</i> tetrahedra (0 ≤ <i>q</i> ≤ 4), reveal a tendency of Al and O to cluster in these materials. Independently, the calculations suggest an energetic preference for Al–O bond formation, instead of a random distribution, in the β-SiAlON system

The Role of Structural and Compositional Heterogeneities in the Insulator-to-Metal Transition in Hole-Doped APd₃O₄ (A = Ca, Sr)

The cubic semiconducting compounds APd₃O₄ (A = Ca, Sr) can be hole-doped by Na substitution on the A site and driven toward more conducting states. This process has been followed here by a number of experimental techniques to understand the evolution of electronic properties. While an insulator-to-metal transition is observed in Ca_1–<i>x</i>Na_<i>x</i>Pd₃O₄ for <i>x</i> ≥ 0.15, bulk metallic behavior is not observed for Sr_1–<i>x</i>Na_<i>x</i>Pd₃O₄ up to <i>x</i> = 0.20. Given the very similar crystal and (calculated) electronic structures of the two materials, the distinct behavior is a matter of interest. We present evidence of local disorder in the A = Sr materials through the analysis of the neutron pair distribution function, which is potentially at the heart of the distinct behavior. Solid-state ²³Na nuclear magnetic resonance studies additionally suggest a percolative insulator-to-metal transition mechanism, wherein presumably small regions with a signal resembling metallic NaPd₃O₄ form almost immediately upon Na substitution, and this signal grows monotonically with substitution. Some signatures of increased local disorder and a propensity for Na clustering are seen in the A = Sr compounds

Crystal Structure Evolution and Notable Thermal Expansion in Hybrid Perovskites Formamidinium Tin Iodide and Formamidinium Lead Bromide

The temperature-dependent structure evolution of the hybrid halide perovskite compounds, formamidinium tin iodide (FASnI₃, FA⁺ = CH­[NH₂]₂⁺) and formamidinium lead bromide (FAPbBr₃), has been monitored using high-resolution synchrotron X-ray powder diffraction between 300 and 100 K. The data are consistent with a transition from cubic <i>Pm</i>3<i>m</i> (No. 221) to tetragonal <i>P</i>4/<i>mbm</i> (No. 127) for both materials upon cooling; this occurs for FAPbBr₃ between 275 and 250 K, and for FASnI₃ between 250 and 225 K. Upon further cooling, between 150 and 125 K, both materials undergo a transition to an orthorhombic <i>Pnma</i> (No. 62) structure. The transitions are confirmed by calorimetry and dielectric measurements. In the tetragonal regime, the coefficients of volumetric thermal expansion of FASnI₃ and FAPbBr₃ are among the highest recorded for any extended inorganic crystalline solid, reaching 219 ppm K^–1 for FASnI₃ at 225 K. Atomic displacement parameters of all atoms for both materials suggest dynamic motion is occurring in the inorganic sublattice due to the flexibility of the inorganic network and dynamic lone pair stereochemical activity on the <i>B</i>-site. Unusual pseudocubic behavior is displayed in the tetragonal phase of the FAPbBr₃, similar to that previously observed in FAPbI₃

The Role of Structural and Compositional Heterogeneities in the Insulator-to-Metal Transition in Hole-Doped APd₃O₄ (A = Ca, Sr)

The cubic semiconducting compounds APd₃O₄ (A = Ca, Sr) can be hole-doped by Na substitution on the A site and driven toward more conducting states. This process has been followed here by a number of experimental techniques to understand the evolution of electronic properties. While an insulator-to-metal transition is observed in Ca_1–<i>x</i>Na_<i>x</i>Pd₃O₄ for <i>x</i> ≥ 0.15, bulk metallic behavior is not observed for Sr_1–<i>x</i>Na_<i>x</i>Pd₃O₄ up to <i>x</i> = 0.20. Given the very similar crystal and (calculated) electronic structures of the two materials, the distinct behavior is a matter of interest. We present evidence of local disorder in the A = Sr materials through the analysis of the neutron pair distribution function, which is potentially at the heart of the distinct behavior. Solid-state ²³Na nuclear magnetic resonance studies additionally suggest a percolative insulator-to-metal transition mechanism, wherein presumably small regions with a signal resembling metallic NaPd₃O₄ form almost immediately upon Na substitution, and this signal grows monotonically with substitution. Some signatures of increased local disorder and a propensity for Na clustering are seen in the A = Sr compounds

Vacancy-Driven Disorder and Elevated Dielectric Response in the Pyrochlore Pb_1.5Nb₂O_6.5

Lone pair-driven distortions are a hallmark of many technologically important lead (Pb)-based materials. The role of Pb2+ in polar perovskites is well understood and easily manipulated for applications in piezo- and ferroelectricity, but the control of ordered lone pair behavior in Pb-based pyrochlores is less clear. Crystallographically and geometrically more complex than the perovskite structure, the pyrochlore structure is prone to geometric frustration of local dipoles due to a triangular arrangement of cations on a diamond lattice. The role of vacancies on the O′ site of the pyrochlore network has been implicated as an important driver for the expression and correlation of stereochemically active lone pairs in pyrochlores such as Pb2Ru2O6.5 and Pb2Sn2O6. In this work we report on the structural, dielectric, and heat capacity behavior of the cation- and anion-deficient pyrochlore Pb1.5Nb2O6.5 upon cooling. We find that local distortions are present at all temperatures that can be described by cristobalite-type cation ordering, and this ordering persists to longer length scales upon cooling. From a crystallographic perspective, the material remains disordered and does not undergo an observable phase transition. In combination with density function calculations, we propose that the stereochemical activity of the Pb2+ lone pairs is driven by proximity to O′ vacancies, and the crystallographic site disorder of the O′ vacancies prohibits long range correlation of lone pair-driven distortions. This in turn prevents a low-temperature phase transition and results in an elevated dielectric permittivity across a broad temperature range

Universal Dynamics of Molecular Reorientation in Hybrid Lead Iodide Perovskites

The role of organic molecular cations in the high-performance perovskite photovoltaic absorbers, methylammonium lead iodide (MAPbI₃) and formamidinium lead iodide (FAPbI₃), has been an enigmatic subject of great interest. Beyond aiding in the ease of processing of thin films for photovoltaic devices, there have been suggestions that many of the remarkable properties of the halide perovskites can be attributed to the dipolar nature and the dynamic behavior of these cations. Here, we establish the dynamics of the molecular cations in FAPbI₃ between 4 K and 340 K and the nature of their interaction with the surrounding inorganic cage using a combination of solid state nuclear magnetic resonance and dielectric spectroscopies, neutron scattering, calorimetry, and ab initio calculations. Detailed comparisons with the reported temperature dependence of the dynamics of MAPbI₃ are then carried out which reveal the molecular ions in the two different compounds to exhibit very similar rotation rates (≈8 ps) at room temperature, despite differences in other temperature regimes. For FA, rotation about the N···N axis, which reorients the molecular dipole, is the dominant motion in all phases, with an activation barrier of ≈21 meV in the ambient phase, compared to ≈110 meV for the analogous dipole reorientation of MA. Geometrical frustration of the molecule–cage interaction in FAPbI₃ produces a disordered γ-phase and subsequent glassy freezing at yet lower temperatures. Hydrogen bonds suggested by atom–atom distances from neutron total scattering experiments imply a substantial role for the molecules in directing structure and dictating properties. The temperature dependence of reorientation of the dipolar molecular cations systematically described here can clarify various hypotheses including those of large-polaron charge transport and fugitive electron spin polarization that have been invoked in the context of these unusual materials

Local Structure Evolution and Modes of Charge Storage in Secondary Li–FeS₂ Cells

In the pursuit of high-capacity electrochemical energy storage, a promising domain of research involves conversion reaction schemes, wherein electrode materials are fully transformed during charge and discharge. There are, however, numerous difficulties in realizing theoretical capacity and high rate capability in many conversion schemes. Here we employ <i>operando</i> studies to understand the conversion material FeS₂, focusing on the local structure evolution of this relatively reversible material. X-ray absorption spectroscopy, pair distribution function analysis, and first-principles calculations of intermediate structures shed light on the mechanism of charge storage in the Li–FeS₂ system, with some general principles emerging for charge storage in chalcogenide materials. Focusing on second and later charge/discharge cycles, we find small, disordered domains that locally resemble Fe and Li₂S at the end of the first discharge. Upon charge, this is converted to a Li–Fe–S composition whose local structure reveals tetrahedrally coordinated Fe. With continued charge, this ternary composition displays insertion–extraction behavior at higher potentials and lower Li content. The finding of hybrid modes of charge storage, rather than simple conversion, points to the important role of intermediates that appear to store charge by mechanisms that more closely resemble intercalation