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

A chemist and biologist talk to each other about caged neurotransmitters

Caged compounds are small organic molecules that can be photoactivated with brief pulses of light. They are widely used to study a great variety of biological processes by physiologists, cell biologists and neuroscientists. Initially made and invented by biologists in the late 1970s, they are now made mostly by chemists, often without any dialogue with the end users, the biologists. The idea for this review is to stimulate interaction between the two communities to further the creative development and application of these powerful optical probes

Astrocyte-Mediated Distributed Plasticity at Hypothalamic Glutamate Synapses

SummaryAfferent activity can induce fast, feed-forward changes in synaptic efficacy that are synapse specific. Using combined electrophysiology, caged molecule photolysis, and Ca2+ imaging, we describe a plasticity in which the recruitment of astrocytes in response to afferent activity causes a fast and feed-forward, yet distributed increase in the amplitude of quantal synaptic currents at multiple glutamate synapses on magnocellular neurosecretory cells in the hypothalamic paraventricular nucleus. The plasticity is largely multiplicative, consistent with a proportional increase or “scaling” in the strength of all synapses on the neuron. This effect requires a metabotropic glutamate receptor-mediated rise in Ca2+ in the astrocyte processes surrounding the neuron and the release of the gliotransmitter ATP, which acts on postsynaptic purinergic receptors. These data provide evidence for a form of distributed synaptic plasticity that is feed-forward, expressed quickly, and mediated by the synaptic activation of neighboring astrocytes

Kinetics of Cardiac Thin-Filament Activation Probed by Fluorescence Polarization of Rhodamine-Labeled Troponin C in Skinned Guinea Pig Trabeculae

A genetically engineered cardiac TnC mutant labeled at Cys-84 with tetramethylrhodamine-5-iodoacetamide dihydroiodide was passively exchanged for the endogenous form in skinned guinea pig trabeculae. The extent of exchange averaged nearly 70%, quantified by protein microarray of individual trabeculae. The uniformity of its distribution was verified by confocal microscopy. Fluorescence polarization, giving probe angle and its dispersion relative to the fiber long axis, was monitored simultaneously with isometric tension. Probe angle reflects underlying cTnC orientation. In steady-state experiments, rigor cross-bridges and Ca(2+) with vanadate to inhibit cross-bridge formation produce a similar change in probe orientation as that observed with cycling cross-bridges (no Vi). Changes in probe angle were found at [Ca(2+)] well below those required to generate tension. Cross-bridges increased the Ca(2+) dependence of angle change (cooperativity). Strong cross-bridge formation enhanced Ca(2+) sensitivity and was required for full change in probe position. At submaximal [Ca(2+)], the thin filament regulatory system may act in a coordinated fashion, with the probe orientation of Ca(2+)-bound cTnC significantly affected by Ca(2+) binding at neighboring regulatory units. The time course of the probe angle change and tension after photolytic release [Ca(2+)] by laser photolysis of NP-EGTA was Ca(2+) sensitive and biphasic: a rapid component ∼10 times faster than that of tension and a slower rate similar to that of tension. The fast component likely represents steps closely associated with Ca(2+) binding to site II of cTnC, whereas the slow component may arise from cross-bridge feedback. These results suggest that the thin filament activation rate does not limit the tension time course in cardiac muscle