Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19

The biological determinants of the wide spectrum of COVID-19 clinical manifestations are not fully understood. Here, over 1400 plasma proteins and 2600 single-cell immune features comprising cell phenotype, basal signaling activity, and signaling responses to inflammatory ligands were assessed in peripheral blood from patients with mild, moderate, and severe COVID-19, at the time of diagnosis. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identified and independently validated a multivariate model classifying COVID-19 severity (multi-class AUCtraining = 0.799, p-value = 4.2e-6; multi-class AUCvalidation = 0.773, p-value = 7.7e-6). Features of this high-dimensional model recapitulated recent COVID-19 related observations of immune perturbations, and revealed novel biological signatures of severity, including the mobilization of elements of the renin-angiotensin system and primary hemostasis, as well as dysregulation of JAK/STAT, MAPK/mTOR, and NF-κB immune signaling networks. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for the prevention of COVID-19 progression

Immunization against Leishmania major Infection Using LACK- and IL-12-Expressing Lactococcus lactis Induces Delay in Footpad Swelling

BACKGROUND: Leishmania is a mammalian parasite affecting over 12 million individuals worldwide. Current treatments are expensive, cause severe side effects, and emerging drug resistance has been reported. Vaccination is the most cost-effective means to control infectious disease but currently there is no vaccine available against Leishmaniasis. Lactococcus lactis is a non-pathogenic, non-colonizing Gram-positive lactic acid bacterium commonly used in the dairy industry. Recently, L. lactis was used to express biologically active molecules including vaccine antigens and cytokines. METHODOLOGY/PRINCIPAL FINDINGS: We report the generation of L. lactis strains expressing the protective Leishmania antigen, LACK, in the cytoplasm, secreted or anchored to the bacterial cell wall. L. lactis was also engineered to secrete biologically active single chain mouse IL-12. Subcutaneous immunization with live L. lactis expressing LACK anchored to the cell wall and L. lactis secreting IL-12 significantly delayed footpad swelling in Leishmania major infected BALB/c mice. The delay in footpad swelling correlated with a significant reduction of parasite burden in immunized animals compared to control groups. Immunization with these two L. lactis strains induced antigen-specific multifunctional T(H)1 CD4(+) and CD8(+) T cells and a systemic LACK-specific T(H)1 immune response. Further, protection in immunized animals correlated with a Leishmania-specific T(H)1 immune response post-challenge. L. lactis secreting mouse IL-12 was essential for directing immune responses to LACK towards a protective T(H)1 response. CONCLUSIONS/SIGNIFICANCE: This report demonstrates the use of L. lactis as a live vaccine against L. major infection in BALB/c mice. The strains generated in this study provide the basis for the development of an inexpensive and safe vaccine against the human parasite Leishmania

TOI-836 : a super-Earth and mini-Neptune transiting a nearby K-dwarf

Funding: TGW, ACC, and KH acknowledge support from STFC consolidated grant numbers ST/R000824/1 and ST/V000861/1, and UKSA grant ST/R003203/1.We present the discovery of two exoplanets transiting TOI-836 (TIC 440887364) using data from TESS Sector 11 and Sector 38. TOI-836 is a bright (T = 8.5 mag), high proper motion (∼200 mas yr−1), low metallicity ([Fe/H]≈−0.28) K-dwarf with a mass of 0.68 ± 0.05 M⊙ and a radius of 0.67 ± 0.01 R⊙. We obtain photometric follow-up observations with a variety of facilities, and we use these data-sets to determine that the inner planet, TOI-836 b, is a 1.70 ± 0.07 R⊕ super-Earth in a 3.82 day orbit, placing it directly within the so-called ‘radius valley’. The outer planet, TOI-836 c, is a 2.59 ± 0.09 R⊕ mini-Neptune in an 8.60 day orbit. Radial velocity measurements reveal that TOI-836 b has a mass of 4.5 ± 0.9 M⊕, while TOI-836 c has a mass of 9.6 ± 2.6 M⊕. Photometric observations show Transit Timing Variations (TTVs) on the order of 20 minutes for TOI-836 c, although there are no detectable TTVs for TOI-836 b. The TTVs of planet TOI-836 c may be caused by an undetected exterior planet.Publisher PDFPeer reviewe

TOI-836: A super-Earth and mini-Neptune transiting a nearby K-dwarf

We present the discovery of two exoplanets transiting TOI-836 (TIC 440887364) using data from TESS Sector 11 and Sector 38. TOI-836 is a bright ($T = 8.5$ mag), high proper motion ($\sim\,200$ mas yr$^{-1}$), low metallicity ([Fe/H]$\approx\,-0.28$) K-dwarf with a mass of $0.68\pm0.05$ M$_{\odot}$ and a radius of $0.67\pm0.01$ R$_{\odot}$. We obtain photometric follow-up observations with a variety of facilities, and we use these data-sets to determine that the inner planet, TOI-836 b, is a $1.70\pm0.07$ R$_{\oplus}$ super-Earth in a 3.82 day orbit, placing it directly within the so-called 'radius valley'. The outer planet, TOI-836 c, is a $2.59\pm0.09$ R$_{\oplus}$ mini-Neptune in an 8.60 day orbit. Radial velocity measurements reveal that TOI-836 b has a mass of $4.5\pm0.9$ M$_{\oplus}$ , while TOI-836 c has a mass of $9.6\pm2.6$ M$_{\oplus}$. Photometric observations show Transit Timing Variations (TTVs) on the order of 20 minutes for TOI-836 c, although there are no detectable TTVs for TOI-836 b. The TTVs of planet TOI-836 c may be caused by an undetected exterior planet

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of diseas

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

TOI-836: A super-Earth and mini-Neptune transiting a nearby K-dwarf

peer reviewe

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease

Mitochondrial Cyclophilin D is a critical regulator of T cell mediated immunity to «Mycobacterium tuberculosis»

Despite the world-wide application of BCG vaccination and other anti–Mycobacterium tuberculosis (Mtb) interventions, Mtb remains one of the most pervasive human pathogens. The ability of Mtb to persist in individuals with apparently normal immune systems implies that Mtb has developed strategies to evade and even subvert innate and adaptive immunity. The high success of this pathogen is closely linked to its ability to alter the intracellular environment of the alveolar macrophages (Mφ). Mtb eventually induces necrosis, a type of cell death that favors Mtb survival and progression of disease. Interestingly, virulent Mtb actively inhibit apoptosis, an alternate form of Mφ death, which is beneficial to the host, allowing for elimination of intracellular bacilli and instruction of adaptive immune responses. Cyclophillin D (CypD) is a mitochondrial matrix protein that has recently been implicated in regulating necrotic but not the apoptotic cell death program. Since CypD is essential for the induction of necrosis, which is also an exit mechanism for Mtb, we hypothesize that the loss- of-function in CypD enhances immunity to tuberculosis. To investigate the potential protective effect of CypD deficiency against tuberculosis infection, wild-type C57BL/6 and CypD-deficient mice were aerosolized with H37Rv (~100 CFU). After 14, 35, and 90 days of infection, the lung bacterial burden was similar between CypD-/- and wild-type mice. Surprisingly, CypD-/- mice were highly susceptible to infection with significantly increased mortality. The frequency and total cell numbers of CD4+, CD8+ T cells, as well as antigen specific CD8+ T cell response (H-2Kb –TB10.44-11), were significantly increased in the lungs of Mtb infected CypD-/- mice. This uncontrolled T cell mediated immune response was correlated with enhanced immunopathology. Subsequent analyses of CypD-deficient T cells revealed intrinsically enhanced proliferation and pro-inflammatory cytokine production, which were linked to substantial increased metabolism of T cells. Collectively these data suggest that the potential protective role of CypD in Mφ fate may be offset by a deficit in T cell contraction, leading to increased accumulation of pathological T cells and immunopathology.Malgré l'utilisation mondiale du vaccin BCG et d'autres interventions liées à la tuberculose anti-Mycobacterium (Mtb), la Mtb reste l'un des pathogènes humains les plus envahissants. Sa capacité à persister chez les individus ayant un système immunitaire apparent normal implique qu'elle a développé des stratégies pour échapper et même dérégler le système immunitaire inné et adaptatif. La virulence de ce pathogène est étroitement liée à sa capacité à modifier l'environnement intracellulaire des macrophages alvéolaires (Mφ). Finalement, la Mtb engendre une nécrose, un type de mort cellulaire qui favorise la survie de la bactérie et la progression de la maladie. Il est intéressant de constater que la Mtb inhibe activement l'apoptose, une forme alternative de la mort des Mφ, bénéfique pour l'hôte, permettant l'élimination de bacilles intracellulaires et l'instruction de la réponse immunitaire adaptative. La cyclophilline D (CypD) est une protéine de la matrice mitochondriale qui a récemment été impliquée dans la régulation du programme de la mort cellulaire nécrotique mais pas dans l'apoptose. Étant donné que la CypD est essentielle pour l'induction d'une nécrose, qui est aussi un mécanisme de sortie pour le Mtb, nous supposons que la perte de fonction dans la CypD renforce l'immunité de la tuberculose. Pour étudier l'effet protecteur de la défiance CypD contre l'infection de la tuberculose, des souris du type sauvage C57BL/6 ayant une carence de CypD, ont été aérosolisées avec du H37Rv (~100 CFU). Après 14, 35 et 90 jours d'infection, la charge bactérienne pulmonaire était similaire entre les souris CypD-/- et les souris sauvages. Étonnamment, les souris CypD-/- étaient très susceptible aux infections en plus d'avoir un taux de mortalité qui augmentait de manière significative. La fréquence et le nombre total de cellules CD4+, de cellules T CD8+, ainsi que la réaction de l'antigène spécifique des cellules T CD8+ (H-2Kb –TB10.44-11), ont augmenté de façon significative dans les poumons des souris CypD-/- affectées par le Mtb. Cette réaction imprévisible à la médiation immunitaire de la cellule T a été mise en corrélation avec l'immunopathologie renforcée. Des analyses ultérieures des cellules T déficientes de CypD ont révélé une plus grande prolifération intrinsèque et une production de cytokine pro-inflammatoire qui ont été liées à une augmentation conséquente du métabolisme des cellules T. Collectivement, ces données suggèrent que le rôle protecteur potentiel de la CypD sur le sort du Mφ peut être contrebalancé par un déficit en contraction des cellules T conduisant à une augmentation de l'accumulation de cellules T pathologiques et immunopathologiques