ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF-and IFN?-driven immunopathology

Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modeling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. maVie16 induced profound pathology in BALB/c and C57BL/6 mice, and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia, and specific adaptive immunity. Inhibition of the proinflammatory cyto-kines IFN? and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo. © Gawish et al

KAT2A complexes ATAC and SAGA play unique roles in cell maintenance and identity in hematopoiesis and leukemia

Author notes: *E.F. and S.W. contributed equally to this study. ChIP-seq and A-seq data have been deposited in GEO (accession numbers GSE128902 and GSE128512). Send data sharing requests via e-mail to the corresponding author. The full-text version of this article contains a data supplement.Copyright © 2021 The Authors. Epigenetic histone modifiers are key regulators of cell fate decisions in normal and malignant hematopoiesis. Their enzymatic activities are of particular significance as putative therapeutic targets in leukemia. In contrast, less is known about the contextual role in which those enzymatic activities are exercised, and specifically, how different macromolecular complexes configure the same enzymatic activity with distinct molecular and cellular consequences. We focus on KAT2A, a lysine acetyltransferase responsible for Histone 3 Lysine 9 acetylation, which we recently identified as a dependence in Acute Myeloid Leukemia stem cells, and that participates in 2 distinct macromolecular complexes: Ada Two- A-Containing (ATAC) and Spt-Ada-Gcn5-Acetyltransferase (SAGA). Through analysis of human cord blood hematopoietic stem cells and progenitors, and of myeloid leukemia cells, we identify unique respective contributions of the ATAC complex to regulation of biosynthetic activity in undifferentiated self-renewing cells, and of the SAGA complex to stabilisation or correct progression of cell type-specific programs with putative preservation of cell identity. Cell type and stage-specific dependencies on ATAC and SAGA-regulated programs explain multi-level KAT2A requirements in leukemia and in erythroid lineage specification and development. Importantly, they set a paradigm against which lineage specification and identity can be explored across developmental stem cell systems.Rosetrees Trust PhD Studentship; Kendall Leukaemia Fund Intermediate Fellowship (KKL888); Leuka John Goldman Fellowship for Future Science (2017); Wellcome Trust/University of Cambridge ISSF Grant; Lady Tata Memorial Trust PhD Studentship; Trinity Henry Barlow Trust Studentship; NIH RO1 grant (1R01GM131626-01); Agence Nationale de la Recherche (ANR) Program grants (AAPG2019 PICen, PRCI AAPG2019 EpiCAST, ANR-10-LABX-0030-INRT, frame program Investissements d’Avenir ANR-10IDEX-0002-02); Brunel University

Epithelial damage and tissue γδ T cells promote a unique tumor-protective IgE response

IgE is an ancient and conserved immunoglobulin isotype with potent immunological function. Nevertheless, the regulation of IgE responses remains an enigma, and evidence of a role for IgE in host defense is limited. Here we report that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress surveillance by γδTCR+ intraepithelial lymphocytes that resulted in class switching to IgE in B cells and the accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that γδ T cells shaped the IgE repertoire by supporting specific variable-diversity-joining (VDJ) rearrangements with unique characteristics of the complementarity-determining region CDRH3. This endogenous IgE response, via the IgE receptor FcεRI, provided protection against epithelial carcinogenesis, and expression of the gene encoding FcεRI in human squamous-cell carcinoma correlated with good disease prognosis. These data indicate a joint role for immunosurveillance by T cells and by B cells in epithelial tissues and suggest that IgE is part of the host defense against epithelial damage and tumor development

Nitration of the Egg-Allergen Ovalbumin Enhances Protein Allergenicity but Reduces the Risk for Oral Sensitization in a Murine Model of Food Allergy

Nitration of proteins on tyrosine residues, which can occur due to polluted air under "summer smog" conditions, has been shown to increase the allergic potential of allergens. Since nitration of tyrosine residues is also observed during inflammatory responses, this modification could directly influence protein immunogenicity and might therefore contribute to food allergy induction. In the current study we have analyzed the impact of protein nitration on sensitization via the oral route.BALB/c mice were immunized intragastrically by feeding untreated ovalbumin (OVA), sham-nitrated ovalbumin (snOVA) or nitrated ovalbumin (nOVA) with or without concomitant acid-suppression. To analyze the impact of the sensitization route, the allergens were also injected intraperitoneally. Animals being fed OVA or snOVA under acid-suppressive medication developed significantly elevated levels of IgE, and increased titers of specific IgG1 and IgG2a antibodies. Interestingly, oral immunizations of nOVA under anti-acid treatment did not result in IgG and IgE formation. In contrast, intraperitoneal immunization induced high levels of OVA specific IgE, which were significantly increased in the group that received nOVA by injection. Furthermore, nOVA triggered significantly enhanced mediator release from RBL cells passively sensitized with sera from allergic mice. Gastric digestion experiments demonstrated protein nitration to interfere with protein stability as nOVA was easily degraded, whereas OVA and snOVA remained stable up to 120 min. Additionally, HPLC-chip-MS/MS analysis showed that one tyrosine residue (Y(107)) being very efficiently nitrated is part of an ovalbumin epitope recognized exclusively after oral sensitization.These data indicated that despite the enhanced triggering capacity in existing allergy, nitration of OVA may be associated with a reduced de novo sensitizing capability via the oral route due to enhanced protein digestibility and/or changes in antibody epitopes

An integrated assessment of options for rural wastewater management in Austria

M. Starkl, M. Ornetzeder, E. Binner, P. Holubar, M. Pollak, M. Dorninger, F. Mascher, M. Fuerhacker and R. Haberl;Water Science & Technology, 56 (2007): 5, 105-113This paper reports a recently finished, interdisciplinary project on rural wastewater management in Austria. The objective of the project was to study alternative wastewater management options based on separation of the wastewater into its constituent parts, and to compare them with conventional ones. Thereby, a feasibility study of both conventional and alternative options for wastewater management in six model regions was carried out. Life cycle costs and social acceptance were analysed by using a case study-based assessment approach. However, hygienic and environmental risks were evaluated on a more general level. In order to complement the findings, a survey on urine separation system users in the Solar City of Linz was conducted. Based on these assessments and empirical findings, the paper concludes that options using a full separation of all wastewater fractions should be considered with care. Options based on a separation of only grey water and black water or in the liquid/solid phase can offer ecological and financial advantages over conventional options. Further, options combining wastewater management and regional biogas plants were identified as an interesting solution. However, legal constraints restrict this option currently

Potential of natural treatment technologies for wastewater management in India

High population growth, increasing urbanization and rapid economic development are exerting pressure on the already scarce water resources in India. Treatment and reuse of wastewater can play an important role in addressing some of the urban water challenges. Conventional treatment plants have many challenges, therefore, natural treatment systems (NTSs) are viewed as a cost-effective alternative, which are more suitable in the Indian context. This study builds on a desktop study of NTSs and presents a rapid sustainability assessment of 12 NTSs, highlighting the potential and viability of NTSs in India. The results show that the NTSs have a high potential for wastewater treatment. However, there are still gaps in knowledge related to aspects that hinder the sustainability of the systems. Risks associated with reuse of treated wastewater in agriculture, operational problems and social acceptance were perceived as frequent challenges. Self-sustaining financing methods and the use of by-products were viewed as added benefits

Potential of natural technologies for decentralised wastewater management in India.

High population growth, increasing urbanization and rapid economic development are exerting pressure on the already scarce water resources in India. Treatment and reuse of wastewater can play an important role in addressing some of the urban water challenges. Conventional treatment plants have many challenges, therefore, natural treatment systems (NTSs) are viewed as a cost-effective alternative, which are more suitable in the Indian context. This study builds on a desktop study of NTSs and presents a rapid sustainability assessment of 12 NTSs, highlighting the potential and viability of NTSs in India. The results show that the NTSs have a high potential for wastewater treatment. However, there are still gaps in knowledge related to aspects that hinder the sustainability of the systems. Risks associated with reuse of treated wastewater in agriculture, operational problems and social acceptance were perceived as frequent challenges. Self-sustaining financing methods and the use of by-products were viewed as added benefits

PLA2G3 promotes mast cell maturation and function.

Mast cell-derived group III phospholipase A(2) (PLA2G3) and fibroblast prostaglandin synthase contribute to a PGD(2) and mast-cell-DP-1-dependent mast cell-fibroblast paracrine axis that can enhance mast cell maturation and mediator secretion