Delayed mucosal antiviral responses despite robust peripheral inflammation in fatal COVID-19

Background While inflammatory and immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished coronavirus disease 2019 (COVID-19) severity categories, and relate these to disease progression and peripheral inflammation. Methods We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalized with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0–5 days after symptom onset) or late (6–20 days after symptom onset) phase. Results Patients that survived severe COVID-19 showed interferon (IFN)-dominated mucosal immune responses (IFN-γ, CXCL10, and CXCL13) early in infection. These early mucosal responses were absent in patients who would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by interleukin 2 (IL-2), IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. Conclusions Defective early mucosal antiviral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials

Luminous red galaxies in hierarchical cosmologies

Luminous red galaxies (LRGs) are much rarer and more massive than L* galaxies. Coupled with their extreme colours, LRGs therefore provide a demanding testing ground for the physics of massive galaxy formation. We present the first self-consistent predictions for the abundance and properties of LRGs in hierarchical structure formation models. We test two published models which use quite different mechanisms to suppress the formation of massive galaxies: the Bower et al. model which invokes ‘active galactic nuclei (AGN) feedback’ to prevent gas from cooling in massive haloes and the Baugh et al. model which relies upon a ‘superwind’ to eject gas before it is turned into stars. Without adjusting any parameters, the Bower et al. model gives an excellent match to the observed luminosity function of LRGs in the Sloan Digital Sky Survey (with a median redshift of z= 0.24) and to their clustering; the Baugh et al. model is less successful in these respects. Both models fail to match the observed abundance of LRGs at z= 0.5 to better than a factor of ≈2. In the models, LRGs are typically bulge-dominated systems with stellar masses of ≈2 × 1011h−1M⊙ and velocity dispersions of σ∼ 250 km s−1. Around half of the stellar mass in the model LRGs is already formed by z∼ 2.2 and is assembled into one main progenitor by z∼ 1.5; on average, only 25 per cent of the mass of the main progenitor is added after z∼ 1. LRGs are predicted to be found in a wide range of halo masses, a conclusion which relies on properly taking into account the scatter in the formation histories of haloes. Remarkably, we find that the correlation function of LRGs is predicted to be a power law down to small pair separations, in excellent agreement with observational estimates. Neither the Bower et al. nor the Baugh et al. model is able to reproduce the observed radii of LRGs

Large-scale structure and dynamics of the most X-ray luminous galaxy cluster known - RX J1347-1145

We present photometric, spectroscopic and weak lensing analysis of the large-scale structure and dynamics of the most X-ray luminous galaxy cluster known, RX J1347−1145, at z= 0.451. We spectroscopically confirmed 47 new members with Low Dispersion Survey Spectrograph 3 (LDSS3) on the Magellan telescope. Together with previously known members, we measure a new velocity dispersion of 1163 ± 97 km s−1. The mass inferred from our velocity dispersion is M200= 1.16+0.32−0.27× 1015 M⊙, with r200= 1.85 Mpc, under the assumption of a singular isothermal sphere. We also present a weak lensing analysis using deep Canada–France–Hawaii Telescope (CFHT) data on this cluster, and find a deprojected mass of 1.47+0.46−0.43× 1015 M⊙ within r200, in excellent agreement with our dynamical estimate. Thus, our new dynamical mass estimate is consistent with that from weak lensing and X-ray studies in the literature, resolving a previously claimed discrepancy. We photometrically detect and spectroscopically confirm another massive cluster with σ= 780 ± 100 km s−1 and M200= 3.4+1.4−1.1× 1014 M⊙∼ 7 Mpc south-west of RX J1347−1145, which we refer to as RXJ1347−SW. Our spectroscopic survey reveals a possible excess of galaxies in velocity space in the region between RX J1347−1145 and RXJ1347−SW; comparing with simulations, this excess appears consistent with that expected from a large filamentary structure traced by galaxies connecting these two clusters

The 2dF-SDSS LRG and QSO survey: the QSO luminosity function at 0.4 \lt z \lt 2.6

We present the QSO luminosity function of the completed 2dF-SDSS LRG and QSO (2SLAQ) survey, based on QSOs photometrically selected from Sloan Digital Sky Survey imaging data and then observed spectroscopically using the 2dF instrument on the Anglo-Australian Telescope. We analyse 10637 QSOs in the redshift range 0.4<z<2.6 to a g-band flux limit of 21.85 (extinction corrected) and an absolute continuum magnitude of Mg(z=2)<-21.5. This sample covers an area of 191.9 deg^2. The binned QSO luminosity function agrees with that of the brighter SDSS main QSO sample, but extends ~2.5 mags fainter, clearly showing the flattening of the luminosity function towards faint absolute magnitudes. 2SLAQ finds an excess of QSOs compared to the 2dF QSO Redshift Survey at g>20.0, as found previously by Richards et al. (2005). The luminosity function is consistent with other previous, much smaller, samples produced to the depth of 2SLAQ. By combining the 2SLAQ and SDSS QSO samples we produce a QSO luminosity function with an unprecedented combination of precision and dynamic range. With this we are able to accurately constrain both the bright and faint ends of the QSO LF. While the overall trends seen in the evolution of the QSO LF appear similar to pure luminosity evolution, the data show very significant departures from such a model. Most notably we see clear evidence that the number density of faint QSOs peaks at lower redshift than bright QSOs: QSOs with Mg>-23 have space densities which peak at z2. By fitting simple luminosity function models in narrow Mg intervals we find that this downsizing is significant at the 99.98 per cent level (abridged).Comment: 20 pages, 18 figures. Accepted for publication in MNRAS. The data on which this paper is based can be accessed at http://www.2slaq.info