Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes

It is unclear how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to the strong but ineffective inflammatory response that characterizes severe Coronavirus disease 2019 (COVID-19), with amplified immune activation in diverse cell types, including cells without angiotensin-converting enzyme 2 receptors necessary for infection. Proteolytic degradation of SARS-CoV-2 virions is a milestone in host viral clearance, but the impact of remnant viral peptide fragments from high viral loads is not known. Here, we examine the inflammatory capacity of fragmented viral components from the perspective of supramolecular self-organization in the infected host environment. Interestingly, a machine learning analysis to SARS-CoV-2 proteome reveals sequence motifs that mimic host antimicrobial peptides (xenoAMPs), especially highly cationic human cathelicidin LL-37 capable of augmenting inflammation. Such xenoAMPs are strongly enriched in SARS-CoV-2 relative to low-pathogenicity coronaviruses. Moreover, xenoAMPs from SARS-CoV-2 but not low-pathogenicity homologs assemble double-stranded RNA (dsRNA) into nanocrystalline complexes with lattice constants commensurate with the steric size of Toll-like receptor (TLR)-3 and therefore capable of multivalent binding. Such complexes amplify cytokine secretion in diverse uninfected cell types in culture (epithelial cells, endothelial cells, keratinocytes, monocytes, and macrophages), similar to cathelicidin’s role in rheumatoid arthritis and lupus. The induced transcriptome matches well with the global gene expression pattern in COVID-19, despite using <0.3% of the viral proteome. Delivery of these complexes to uninfected mice boosts plasma interleukin-6 and CXCL1 levels as observed in COVID-19 patients

Overview of JET results

Since the last IAEA conference, the scientific programme of JET has focused on the qualification of the integrated operating scenarios for ITER and on physics issues essential for the consolidation of design choices and the efficient exploitation of ITER. Particular attention has been given to the characterization of the edge plasma, pedestal energy and edge localized modes (ELMs), and their impact on plasma facing components (PFCs). Various ELM mitigation techniques have been assessed for all ITER operating scenarios using active methods such as resonant magnetic field perturbation, rapid variation of the radial field and pellet pacing. In particular, the amplitude and frequency of type I ELMs have been actively controlled over a wide parameter range (q95 = 3-4.8, βN ≥ 3.0) by adjusting the amplitude of the n = 1 external perturbation field induced by error field correction coils. The study of disruption induced heat loads on PFCs has taken advantage of a new wide-angle viewing infrared system and a fast bolometer to provide a detailed account of time, localization and form of the energy deposition. Specific ITER-relevant studies have used the unique JET capability of varying the toroidal field (TF) ripple from its normal low value δBT = 0.08% up to δBT = 1% to study the effect of TF ripple on high confinement-mode plasmas. The results suggest that δBT < 0.5% is required on ITER to maintain adequate confinement to allow QDT = 10 at full field. Physics issues of direct relevance to ITER include heat and toroidal momentum transport, with experiments using power modulation to decouple power input and torque to achieve first experimental evidence of inward momentum pinch in JET and determine the threshold for ion temperature gradient driven modes. Within the longer term JET programme in support of ITER, activities aiming at the modification of the JET first wall and divertor and the upgrade of the neutral beam and plasma control systems are being conducted. The procurement of all components will be completed by 2009 with the shutdown for the installation of the beryllium wall and tungsten divertor extending from summer 2009 to summer 2010

Overview of JET results

Since the last IAEA Conference JET has been in operation for one year with a programmatic focus on the qualification of ITER operating scenarios, the consolidation of ITER design choices and preparation for plasma operation with the ITER-like wall presently being installed in JET. Good progress has been achieved, including stationary ELMy H-mode operation at 4.5 MA. The high confinement hybrid scenario has been extended to high triangularity, lower \u3c1 17 and to pulse lengths comparable to the resistive time. The steady-state scenario has also been extended to lower \u3c1 17 and \u3bd 17 and optimized to simultaneously achieve, under stationary conditions, ITER-like values of all other relevant normalized parameters. A dedicated helium campaign has allowed key aspects of plasma control and H-mode operation for the ITER non-activated phase to be evaluated. Effective sawtooth control by fast ions has been demonstrated with 3He minority ICRH, a scenario with negligible minority current drive. Edge localized mode (ELM) control studies using external n = 1 and n = 2 perturbation fields have found a resonance effect in ELM frequency for specific q95 values. Complete ELM suppression has, however, not been observed, even with an edge Chirikov parameter larger than 1. Pellet ELM pacing has been demonstrated and the minimum pellet size needed to trigger an ELM has been estimated. For both natural and mitigated ELMs a broadening of the divertor ELM-wetted area with increasing ELM size has been found. In disruption studies with massive gas injection up to 50% of the thermal energy could be radiated before, and 20% during, the thermal quench. Halo currents could be reduced by 60% and, using argon/deuterium and neon/deuterium gas mixtures, runaway electron generation could be avoided. Most objectives of the ITER-like ICRH antenna have been demonstrated; matching with closely packed straps, ELM resilience, scattering matrix arc detection and operation at high power density (6.2MWm 122) and antenna strap voltages (42 kV). Coupling measurements are in very good agreement with TOPICA modelling

Inadequacy of technology and innovation systems at the periphery

Scientific and technical activities on JET focus on the issues likely to affect the ITER design and operation. Our understanding of the ITER reference mode of operation, the ELMy H-mode, has progressed significantly. The extrapolation of ELM size to ITER has been re-evaluated. Neoclassical tearing modes have been shown to be meta-stable in JET, and their beta limits can be raised by destabilization (modification) of sawteeth by ion cyclotron radio frequency heating (ICRH). Alpha simulation experiments with ICRH accelerated injected 4 (He) beam ions provide a new tool for fast particle and magnetohydrodynamic studies, with up to 80-90% of plasma heating by fast 4 He ions. With or without impurity seeding, a quasi-steady-state high confinement (H(98) = 1), high density(n(e)/n(GW) = 0.9-1) and high beta (betaN = 2) ELMy H-mode has been achieved by operating near the ITER triangularity ( similar to 0.40-0.5) and safety factor (q(95) similar to 3), at Z(eff) similar to 1.5-2. In advanced tokamak (AT) scenarios, internal transport barriers (ITBs) are now characterized in real time with a new criterion, rhoT(*). Tailoring of the current profile with T lower hybrid current drive provides reliable access to a variety of q profiles, lowering access power for barrier formation. Rational q surfaces appear to be associated with ITB formation. Alfven cascades were observed in reversed shear plasmas, providing identification of q profile evolution. Plasmas with 'current holes' were observed and modelled. Transient high confinement AT regimes with H(89) = 3.3, beta(N) = 2.4 and ITER-relevant q < 5 were achieved with reversed magnetic shear. Quasi-stationary ITBs are developed with full non-inductive current drive, including similar to 50% bootstrap current. A record duration of ITBs was achieved, up to 11 s, approaching the resistive time. For the first time, pressure and current profiles of AT regimes are controlled by a real-time feedback system, in separate experiments. Erosion and co-deposition studies with a quartz micro-balance show reduced co-deposition. Measured divertor thermal loads during disruptions in JET could modify ITER assumptions

Study of fast-ion transport induced by fishbones on JET

The impact of fishbone oscillations onto a confined fast-ion population is simulated for a JET plasma and benchmarked against experiment quantitatively with the help of neutron rate measurements. The transient drops in volume integrated neutron emission are found to be mainly caused by the spatial redistribution of the (neutral beam injected) fast-ion population confined in the plasma rather than by fast-ion loss. The simulations yield a quadratic dependence of the neutron drop on the fishbone amplitude. It is found that the simulations are able to correctly reproduce the magnitude of the experimentally observed drop in volume integrated neutron emission to within a factor 2. Furthermore, frequency chirping is found to be important. Omitting the fishbone frequency chirp in the simulations reduces the magnitude of the neutron rate drop (and hence fast-ion redistribution) to about half its original value

Non-resonant magnetic braking on JET and TEXTOR

The non-resonant magnetic braking effect induced by a non-axisymmetric magnetic perturbation is investigated on JET and TEXTOR. The collisionality dependence of the torque induced by the n = 1, where n is the toroidal mode number, magnetic perturbation generated by the error field correction coils on JET is observed. The observed torque is located mainly in the plasma core (normalized radius