Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old

A Ferroelectric Fast Reactive Tuner (FE-FRT) to Combat Microphonics

A prototype Fast Reactive Tuner (FRT) for superconducting cavities has been developed, which allows the frequency to be controlled by application of a potential difference across a newly developed ultra-low loss ferro-electric material residing within the tuner. The tuner operates at room temperature, outside of the cryostat and coupled to the cavity via an antenna and co-axial cable. This technique allows for active compensation of microphonics, eliminating the need to design over-coupled fundamental power couplers and thus significantly reducing RF power particularly for low beam current applications. Modelling; simulation; and stability analysis, of the tuner; cavity; measurement system; and feedback loop, have been performed in the frequency and time domain, and are compared to the latest experimental results. The potential benefits of applying this techniques to ERLs, which are seen as one of the major use cases, are detailed both in general and with regards to specific projects. Ideas and designs for an improved next generation FRT are also discussed

CERN’s SRF Test Stand for Cavity Performance Measurements

Recent deployment of a digital LLRF system within the cavity testing framework of CERN’s vertical test cryostats has permitted a full revamp of cavity performance validation. With both full continuous and pulse mode operation, steady state a transient RF behaviour can be effectively probed. Due to direct and integrated control and monitoring of environmental test conditions, standard and novel RF measurement procedures have been developed and integrated into the testing infrastructure, along with a coherent data flow of high granularity measurement data. We present an overview of this cavity measurement system and address the underlying architectural structure, data handling and integration of user interfaces. In addition we highlight the benefits of variety of RF cavity measurements that can now be accommodated in our large 2 K cryostats

A Ferroelectric Fast Reactive Tuner for Superconducting Cavities

A prototype FerroElectric Fast Reactive Tuner (FE-FRT) for superconducting cavities has been developed, which allows the frequency to be controlled by application of a potential difference across a ferroelectric residing within the tuner. This technique has now become practically feasible due to the recent development of a new extremely low loss ferroelectric material. In a world first, CERN has tested the prototype FE-FRT with a superconducting cavity, and frequency tuning has been successfully demonstrated. This is a significant first step in the development of an entirely new class of tuner. These will allow electronic control of cavity frequencies, by a device operating at room temperature, within timescales that will allow active compensation of microphonics. For many applications this could eliminate the need to use over-coupled fundamental power couplers, thus significantly reducing RF amplifier power

RF Performance Results of RF Double Quarter Wave Resonators for LHC High Luminosity Project

The LHC High Luminosity (HL-LHC) project includes, among other key items, the installation of superconducting crab cavities in the LHC machine. The Double Quarter Wave (DQW) crab cavity will be utilised to compensate for the effects of the vertical crossing angle. Two bare DQW series cavities were manufactured in Germany by RI Research Instruments and validated successfully at CERN through a cold test at 2K. Two DQW series cavities were produced in-house at CERN, integrated into a titanium helium tank, and equipped with RF ancillaries. This paper addresses the cavities preparation processes and summarizes the results of cryogenic tests of DQW cavities at CER

Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis

International audienceEnterovirus (EV) infection rarely results in life-threatening infection of the central nervous system. We report two unrelated children with EV30 and EV71 rhombencephalitis. One patient carries compound heterozygous TLR3 variants (loss-of-function F322fs2* and hypomorphic D280N), and the other is homozygous for an IFIH1 variant (loss-of-function c.1641+1G&gt;C). Their fibroblasts respond poorly to extracellular (TLR3) or intracellular (MDA5) poly(I:C) stimulation. The baseline (TLR3) and EV-responsive (MDA5) levels of IFN-β in the patients’ fibroblasts are low. EV growth is enhanced at early and late time points of infection in TLR3- and MDA5-deficient fibroblasts, respectively. Treatment with exogenous IFN-α2b before infection renders both cell lines resistant to EV30 and EV71, whereas post-infection treatment with IFN-α2b rescues viral susceptibility fully only in MDA5-deficient fibroblasts. Finally, the poly(I:C) and viral phenotypes of fibroblasts are rescued by the expression of WT TLR3 or MDA5. Human TLR3 and MDA5 are critical for cell-intrinsic immunity to EV, via the control of baseline and virus-induced type I IFN production, respectively

Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency

International audienceInborn errors of TLR3-dependent IFN-α/β– and IFN-λ–mediated immunity in the CNS can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-α/β and IFN-λ are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3′-UTR of the last exon of IFNAR1, who died of HSE at the age of 2 years. An older cousin died following vaccination against measles, mumps, and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other, less severe, viral illnesses. The encoded IFNAR1 protein is expressed on the cell surface but is truncated and cannot interact with the tyrosine kinase TYK2. The patient’s fibroblasts and EBV-B cells did not respond to IFN-α2b or IFN-β, in terms of STAT1, STAT2, and STAT3 phosphorylation or the genome-wide induction of IFN-stimulated genes. The patient’s fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-α2b or IFN-β. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This viral disease occurred in natural conditions, unlike those previously reported in other patients with IFNAR1 or IFNAR2 deficiency. This experiment of nature indicates that IFN-α/β are essential for anti–HSV-1 immunity in the CN