Most isolates of Toxoplasma from Europe and North America fall into one of three genetically distinct clonal lineages, the type I, II and III lineages. However, in South America these strains are rarely isolated and instead a great variety of other strains are found. T. gondii strains differ widely in a number of phenotypes in mice, such as virulence, persistence, oral infectivity, migratory capacity, induction of cytokine expression and modulation of host gene expression. The outcome of toxoplasmosis in patients is also variable and we hypothesize that, besides host and environmental factors, the genotype of the parasite strain plays a major role. The molecular basis for these differences in pathogenesis, especially in strains other than the clonal lineages, remains largely unexplored. Macrophages play an essential role in the early immune response against T. gondii and are also the cell type preferentially infected in vivo. To determine if non-canonical Toxoplasma strains have unique interactions with the host cell, we infected murine macrophages with 29 different Toxoplasma strains, representing global diversity, and used RNA-sequencing to determine host and parasite transcriptomes. We identified large differences between strains in the expression level of known parasite effectors and large chromosomal structural variation in some strains. We also identified novel strain-specifically regulated host pathways, including the regulation of the type I interferon response by some atypical strains. IFNβ production by infected cells was associated with parasite killing, independent of interferon gamma activation, and dependent on endosomal Toll-like receptors in macrophages and the cytoplasmic receptor retinoic acid-inducible gene 1 (RIG-I) in fibroblasts.
bThe gamma interferon (IFN-␥) response, mediated by the STAT1 transcription factor, is crucial for host defense against the intracellular pathogen Toxoplasma gondii, but prior infection with Toxoplasma can inhibit this response. Recently, it was reported that the Toxoplasma type II NTE strain prevents the recruitment of chromatin remodeling complexes containing Brahma-related gene 1 (BRG-1) to promoters of IFN-␥-induced secondary response genes such as Ciita and major histocompatibility complex class II genes in murine macrophages, thereby inhibiting their expression. We report here that a type I strain of Toxoplasma inhibits the expression of primary IFN-␥ response genes such as IRF1 through a distinct mechanism not dependent on the activity of histone deacetylases. Instead, infection with a type I, II, or III strain of Toxoplasma inhibits the dissociation of STAT1 from DNA, preventing its recycling and further rounds of STAT1-mediated transcriptional activation. This leads to increased IFN-␥-induced binding of STAT1 at the IRF1 promoter in host cells and increased global IFN-␥-induced association of STAT1 with chromatin. Toxoplasma type I infection also inhibits IFN--induced interferon-stimulated gene factor 3-mediated gene expression, and this inhibition is also linked to increased association of STAT1 with chromatin. The secretion of proteins into the host cell by a type I strain of Toxoplasma without complete parasite invasion is not sufficient to block STAT1-mediated expression, suggesting that the effector protein responsible for this inhibition is not derived from the rhoptries. G amma interferon (IFN-␥) is a critical cytokine in both innateand adaptive immune responses to infection (1, 2). The cellular response to IFN-␥ leads to the induction of many effector mechanisms that inhibit the growth and survival of intracellular pathogens. These include the p47 immunity-related GTPases (IRGs), p65 guanylate binding proteins (GBPs), iNOS/Nos2, indoleamine 2,3-dioxygenase 1 (IDO1), and major histocompatibility complex (MHC) genes (2-7). Mice deficient in various components of the IFN-␥ pathway are acutely susceptible to many pathogens, including the parasite Toxoplasma gondii (8-12). Toxoplasma is an obligate intracellular protozoan parasite that infects virtually all warm-blooded animals, including mice and humans (13).IFN-␥ stimulation activates the signal transducer and activator of transcription 1 (STAT1) transcription factor and induces a broad transcriptional program (14). When IFN-␥ binds to its receptors, IFNGR1 and IFNGR2, the receptors oligomerize and cause constitutively associated Janus activated kinase 1 (JAK1) and JAK2 to be activated (15, 16). Activated JAKs tyrosine-phosphorylate the IFN-␥ receptor, creating a docking site for STAT1, which is subsequently phosphorylated by the JAKs at tyrosine 701, leading to its homodimerization and nuclear translocation. In the nucleus, STAT1 binds to gamma-activated sequence (GAS) sites in the DNA, leading to its serine phosphorylation at residue 727 (17). T...
Summary In response to infection, naive CD4+ T‐cells proliferate and differentiate into several possible effector subsets, including conventional T helper effector cells (TH1, TH2, TH17), T regulatory cells (Treg) and T follicular helper cells (TFH). Once infection is cleared, a small population of long‐lived memory cells remains that mediate immune defenses against reinfection. Memory T lymphocytes have classically been categorized into central memory cell (TCM) and effector memory cell (TEM) subsets, both of which circulate between blood, secondary lymphoid organs and in some cases non‐lymphoid tissues. A third subset of memory cells, referred to as tissue‐resident memory cells (TRM), resides in tissues without recirculation, serving as ‘first line’ of defense at barrier sites, such as skin, lung and intestinal mucosa, and augmenting innate immunity in the earliest phases of reinfection and recruiting circulating CD4+ and CD8+ T‐cells. The presence of multiple CD4+ T helper subsets has complicated studies of CD4+ memory T‐cell differentiation, and the mediators required to support their function. In this review, we summarize recent investigations into the origins of CD4+ memory T‐cell populations and discuss studies addressing CD4+ TRM differentiation in barrier tissues.
Machine learning has demonstrated great power in materials design, discovery, and property prediction. However, despite the success of machine learning in predicting discrete properties, challenges remain for continuous property prediction. The challenge is aggravated in crystalline solids due to crystallographic symmetry considerations and data scarcity. Here, the direct prediction of phonon density‐of‐states (DOS) is demonstrated using only atomic species and positions as input. Euclidean neural networks are applied, which by construction are equivariant to 3D rotations, translations, and inversion and thereby capture full crystal symmetry, and achieve high‐quality prediction using a small training set of ≈103 examples with over 64 atom types. The predictive model reproduces key features of experimental data and even generalizes to materials with unseen elements, and is naturally suited to efficiently predict alloy systems without additional computational cost. The potential of the network is demonstrated by predicting a broad number of high phononic specific heat capacity materials. The work indicates an efficient approach to explore materials' phonon structure, and can further enable rapid screening for high‐performance thermal storage materials and phonon‐mediated superconductors.
Thermoelectrics are promising by directly generating electricity from waste heat. However, (sub-)room-temperature thermoelectrics have been a long-standing challenge due to vanishing electronic entropy at low temperatures. Topological materials offer a new avenue for energy harvesting applications. Recent theories predicted that topological semimetals at the quantum limit can lead to a large, non-saturating thermopower and a quantized thermoelectric Hall conductivity approaching a universal value. Here, we experimentally demonstrate the non-saturating thermopower and quantized thermoelectric Hall effect in the topological Weyl semimetal (WSM) tantalum phosphide (TaP). An ultrahigh longitudinal thermopower $$S_{xx} \sim 1.1 \times 10^3 \, \mu \, {\mathrm{V}} \, {\mathrm{K}}^{ - 1}$$ S x x ~ 1.1 × 1 0 3 μ V K − 1 and giant power factor $$\sim 525 \, \mu \, {\mathrm{W}} \, {\mathrm{cm}}^{ - 1} \, {\mathrm{K}}^{ - 2}$$ ~ 525 μ W cm − 1 K − 2 are observed at ~40 K, which is largely attributed to the quantized thermoelectric Hall effect. Our work highlights the unique quantized thermoelectric Hall effect realized in a WSM toward low-temperature energy harvesting applications.
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