Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

High dimensional profiling identifies specific immune types along the recovery trajectories of critically ill COVID19 patients.

The COVID-19 pandemic poses a major burden on healthcare and economic systems across the globe. Even though a majority of the population develops only minor symptoms upon SARS-CoV-2 infection, a significant number are hospitalized at intensive care units (ICU) requiring critical care. While insights into the early stages of the disease are rapidly expanding, the dynamic immunological processes occurring in critically ill patients throughout their recovery at ICU are far less understood. Here, we have analysed whole blood samples serially collected from 40 surviving COVID-19 patients throughout their recovery in ICU using high-dimensional cytometry by time-of-flight (CyTOF) and cytokine multiplexing. Based on the neutrophil-to-lymphocyte ratio (NLR), we defined four sequential immunotypes during recovery that correlated to various clinical parameters, including the level of respiratory support at concomitant sampling times. We identified classical monocytes as the first immune cell type to recover by restoration of HLA-DR-positivity and the reduction of immunosuppressive CD163 + monocytes, followed by the recovery of CD8 + and CD4 + T cell and non-classical monocyte populations. The identified immunotypes also correlated to aberrant cytokine and acute-phase reactant levels. Finally, integrative analysis of cytokines and immune cell profiles showed a shift from an initially dysregulated immune response to a more coordinated immunogenic interplay, highlighting the importance of longitudinal sampling to understand the pathophysiology underlying recovery from severe COVID-19.

Author Correction: A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation.

Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.

An overview of state-of-the-art image restoration in electron microscopy.

In Life Science research, electron microscopy (EM) is an essential tool for morphological analysis at the subcellular level as it allows for visualization at nanometer resolution. However, electron micrographs contain image degradations such as noise and blur caused by electromagnetic interference, electron counting errors, magnetic lens imperfections, electron diffraction, etc. These imperfections in raw image quality are inevitable and hamper subsequent image analysis and visualization. In an effort to mitigate these artefacts, many electron microscopy image restoration algorithms have been proposed in the last years. Most of these methods rely on generic assumptions on the image or degradations and are therefore outperformed by advanced methods that are based on more accurate models. Ideally, a method will accurately model the specific degradations that fit the physical acquisition settings. In this overview paper, we discuss different electron microscopy image degradation solutions and demonstrate that dedicated artefact regularisation results in higher quality restoration and is applicable through recently developed probabilistic methods.

TGFßR signalling controls CD103+CD11b+ dendritic cell development in the intestine.

CD103+CD11b+ dendritic cells (DCs) are unique to the intestine, but the factors governing their differentiation are unclear. Here we show that transforming growth factor receptor 1 (TGFßR1) has an indispensable, cell intrinsic role in the development of these cells. Deletion of Tgfbr1 results in markedly fewer intestinal CD103+CD11b+ DCs and a reciprocal increase in the CD103-CD11b+ dendritic cell subset. Transcriptional profiling identifies markers that define the CD103+CD11b+ DC lineage, including CD101, TREM1 and Siglec-F, and shows that the absence of CD103+CD11b+ DCs in CD11c-Cre.Tgfbr1 fl/fl mice reflects defective differentiation from CD103-CD11b+ intermediaries, rather than an isolated loss of CD103 expression. The defect in CD103+CD11b+ DCs is accompanied by reduced generation of antigen-specific, inducible FoxP3+ regulatory T cells in vitro and in vivo, and by reduced numbers of endogenous Th17 cells in the intestinal mucosa. Thus, TGFßR1-mediated signalling may explain the tissue-specific development of these unique DCs.Developmental cues for the different dendritic cell (DC) subsets in the intestine are yet to be defined. Here the authors show that TGFßR1 signalling is needed for development of CD103+CD11b+ intestinal DCs from CD103-CD11b+ cells and that they contribute to the generation of Th17 and regulatory T cells.

Phenotyping asthma, rhinitis and eczema in MeDALL population-based birth cohorts: an allergic comorbidity cluster.

BACKGROUND: Asthma, rhinitis and eczema often co-occur in children, but their interrelationships at the population level have been poorly addressed. We assessed co-occurrence of childhood asthma, rhinitis and eczema using unsupervised statistical techniques. METHODS: We included 17 209 children at 4 years and 14 585 at 8 years from seven European population-based birth cohorts (MeDALL project). At each age period, children were grouped, using partitioning cluster analysis, according to the distribution of 23 variables covering symptoms 'ever' and 'in the last 12 months', doctor diagnosis, age of onset and treatments of asthma, rhinitis and eczema; immunoglobulin E sensitization; weight; and height. We tested the sensitivity of our estimates to subject and variable selections, and to different statistical approaches, including latent class analysis and self-organizing maps. RESULTS: Two groups were identified as the optimal way to cluster the data at both age periods and in all sensitivity analyses. The first (reference) group at 4 and 8 years (including 70% and 79% of children, respectively) was characterized by a low prevalence of symptoms and sensitization, whereas the second (symptomatic) group exhibited more frequent symptoms and sensitization. Ninety-nine percentage of children with comorbidities (co-occurrence of asthma, rhinitis and/or eczema) were included in the symptomatic group at both ages. The children's characteristics in both groups were consistent in all sensitivity analyses. CONCLUSION: At 4 and 8 years, at the population level, asthma, rhinitis and eczema can be classified together as an allergic comorbidity cluster. Future research including time-repeated assessments and biological data will help understanding the interrelationships between these diseases.