Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Evaluation of Pseudopteroxazole and Pseudopterosin Derivatives against <em>Mycobacterium</em> <em>tuberculosis</em> and Other Pathogens

Pseudopterosins and pseudopteroxazole are intriguing marine natural products that possess notable antimicrobial activity with a commensurate lack of cytotoxicity. New semi-synthetic pseudopteroxazoles, pseudopteroquinoxalines and pseudopterosin congeners along with simple synthetic mimics of the terpene skeleton were synthesized. In order to build structure-activity relationships, a set of 29 new and previously reported compounds was assessed for <em>in</em> <em>vitro</em> antimicrobial and cytotoxic activities. A number of congeners exhibited antimicrobial activity against a range of Gram-positive bacteria including <em>Mycobacterium</em> <em>tuberculosis</em> H<sub>37</sub>Rv, with four displaying notable antitubercular activity against both replicating and non-replicating persistent forms of <em>M.</em> <em>tuberculosis</em>. One new semi-synthetic compound, 21-((1<em>H</em>-imidazol-5-yl)methyl)-pseudopteroxazole (<strong>7a</strong>), was more potent than the natural products pseudopterosin and pseudopteroxazole and exhibited equipotent activity against both replicating and non-replicating persistent forms of <em>M.</em> <em>tuberculosis</em> with a near absence of <em>in</em> <em>vitro</em> cytotoxicity. Pseudopteroxazole also exhibited activity against strains of <em>M.</em> <em>tuberculosis</em> H<sub>37</sub>Rv resistant to six clinically used antibiotics

Isolation of steroidal glycosides from the Caribbean SpongePandaros acanthifolium

Four new steroidal glycosides, acanthifoliosides G-J (1-4), were isolated as minor constituents from the Caribbean marine sponge Pandaros acanthifolium. These metabolites are characterized by a highly oxygenated D ring and the presence of a disaccharide rhamnose-glucose residue and a rhamnose at positions C-3 and C-15, respectively. Their structures were established on the basis of extensive interpretation of 1D and 2D NMR data and HRESIMS analyses. The absolute configurations of the glucose and rhamnose sugars were determined by preparing aldose o-tolylthiocarbamate derivatives and comparison to authentic standards by LC/HRESIMS. Acanthifolioside G (1) exhibited antioxidant and cytoprotective activities

Isolation of Steroidal Glycosides from the Caribbean Sponge <i>Pandaros acanthifolium</i>

Four new steroidal glycosides, acanthifoliosides G–J (<b>1</b>–<b>4</b>), were isolated as minor constituents from the Caribbean marine sponge <i>Pandaros acanthifolium</i>. These metabolites are characterized by a highly oxygenated D ring and the presence of a disaccharide rhamnose-glucose residue and a rhamnose at positions C-3 and C-15, respectively. Their structures were established on the basis of extensive interpretation of 1D and 2D NMR data and HRESIMS analyses. The absolute configurations of the glucose and rhamnose sugars were determined by preparing aldose <i>o</i>-tolylthiocarbamate derivatives and comparison to authentic standards by LC/HRESIMS. Acanthifolioside G (<b>1</b>) exhibited antioxidant and cytoprotective activities

The big ecological questions inhibiting effective environmental management in Australia

The need to improve environmental management in Australia is urgent because human health, well-being and social stability all depend ultimately on maintenance of life-supporting ecological processes. Ecological science can inform this effort, but when issues are socially and economically complex the inclination is to wait for science to provide answers before acting. Increasingly, managers and policy-makers will be called on to use the present state of scientific knowledge to supply reasonable inferences for action based on imperfect knowledge. Hence, one challenge is to use existing ecological knowledge more effectively; a second is to tackle the critical unanswered ecological questions. This paper identifies areas of environmental management that are profoundly hindered by an inability of science to answer basic questions, in contrast to those areas where knowledge is not the major barrier to policy development and management. Of the 22 big questions identified herein, more than half are directly related to climate change. Several of the questions concern our limited understanding of the dynamics of marine systems. There is enough information already available to develop effective policy and management to address several significant ecological issues. We urge ecologists to make better use of existing knowledge in dialogue with policy-makers and land managers. Because the challenges are enormous, ecologists will increasingly be engaging a wide range of other disciplines to help identify pathways towards a sustainable future.9 page(s