iScience

Post-acute sequelae of SARS-CoV-2 (SARS2) infection (PASC) is a heterogeneous condition, but the main viral drivers are unknown. Here, we use MENSA, Media Enriched with Newly Synthesized Antibodies, secreted exclusively from circulating human plasmablasts, to provide an immune snapshot that defines the underlying viral triggers. We provide proof-of-concept testing that the MENSA technology can capture the new host immune response to accurately diagnose acute primary and breakthrough infections w...

Alternative splicing (AS) and nonsense-mediated mRNA decay (NMD) are highly conserved cellular mechanisms that modulate gene expression. Here we introduce NMD pipeline that computes how splicing events introduce premature termination codons to mRNA transcripts via frameshift, then predicts the rate of PTC-dependent NMD. We utilize whole blood, deep RNA-sequencing data from critically ill patients to study gene expression in sepsis. Statistical significance was determined as adjusted p value < 0....

The pandemic spread of the potentially life-threatening disease COVID-19 requires a thorough understanding of the longitudinal dynamics of host responses. Temporal resolution of cellular features associated with a severe disease trajectory will be a pre-requisite for finding disease outcome predictors. Here, we performed a longitudinal multi-omics study using a two-centre German cohort of 13 patients (from Cologne and Kiel, cohort 1). We analysed the bulk transcriptome, bulk DNA methylome, and s...

Sepsis, the dysregulated host response to infection causing life-threatening organ dysfunction, is an unmet global health challenge. Here we apply high-throughput tandem mass spectrometry to delineate the plasma proteome for sepsis and comparator groups (non-infected critical illness, post-operative inflammation and healthy volunteers) involving 2622 samples and 4553 liquid chromatography-mass spectrometry analyses in a single batch, at 100 samples/day. We show how this scale of data can establi...

SARS-CoV-2 remains an acute threat to human health, endangering hospital capacities worldwide. Many studies have aimed at informing pathophysiologic understanding and identification of disease indicators for risk assessment, monitoring, and therapeutic guidance. While findings start to emerge in the general population, observations in high-risk patients with complex pre-existing conditions are limited. To this end, we biomedically characterized quantitative proteomics in a hospitalized cohort o...

IntroductionInfection with SARS-CoV-2 leads to coronavirus disease 2019 (COVID-19), which can result in acute respiratory distress syndrome and multiple organ failure. However, its comprehensive influence on pathological immune responses in the respiratory epithelium and peripheral immune cells is not yet fully understood. MethodsIn this study, we integrated multiple public scRNA-seq datasets of nasopharyngeal swab and peripheral blood results to investigate the gene regulatory networks (GRNs) ...

The complex interplay between metal abundance, transport mechanisms, cell distribution, and tumor progression-related biological pathways (e.g., metabolism, collagen remodeling) remains poorly understood. Traditionally, genes and metals have been studied in isolation, limiting insights into their interactions. Recent advances in spatial transcriptomics and elemental profiling now enable comprehensive exploration of tissue-wide metal-gene interactions, though integration remains challenging. In t...

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Neutrophil extracellular traps (NETs) have been implicated in the pathogenesis of sepsis, yet the precise role of NET-related genes (NRGs) remains unclear. This study employed a multiomic Mendelian randomization (MR) approach, leveraging genetic variants as instrumental variables to investigate the relationships between NRGs and sepsis risk. We systematically identified 69 NRGs based on literature...

Antimicrobial peptides (AMPs) are essential components of the innate immune system, exhibiting diverse mechanisms of action. This study investigates the roles of cathelicidin (LL-37), alpha-defensins, and the S100 proteins S100A8 and S100A9 in systemic inflammation associated with sepsis, severe COVID-19, and acute pancreatitis using whole-blood bulk RNA-sequencing data. Gene co-expression network analysis revealed that during septic shock and severe COVID-19, cathelicidin and alpha-defensins ac...

Precision medicine requires the translation of basic biological understanding to medical insights, mainly applied to characterization of each unique patient. In many clinical settings, this requires tools that can be broadly used to identify pathology and risks. Patients often present to the intensive care unit with broad phenotypes, including multiple organ dysfunction syndrome (MODS) resulting from infection, trauma, or other disease processes. Etiology and outcomes are unique to individuals, ...

Myeloid dysregulation is involved in severe Acute Respiratory Distress Syndrome (ARDS), but the mechanistic understanding is still incomplete. We analyzed endotracheal aspirate (ETA) scRNA-seq data from 40 intubated patients (both COVID-19 and non-COVID-19) in the COMET cohort, to uncover cell types and gene programs associated with ARDS mortality. In cell-type-agnostic analyses, we identified neutrophils as a critical cell type prognostic for ARDS mortality. Subsequent analyses uncovered a mort...

BackgroundWhole blood gene expression analysis is essential for understanding molecular host responses and identifying markers of disease severity. Self-collected finger-prick capillary blood provides a promising alternative to venous sampling, yet its application to transcriptomics is still underexplored. MethodsCOVERAGE-Immuno sub-study is an ancillary study of the COVERAGE France platform trial (NCT04356495), a randomized controlled trial of COVID-19 early treatment in at risk patients with ...

RationaleNeutrophils are important in the pathophysiology of COVID19 but the molecular changes contributing to altered neutrophil phenotypes following SARS-CoV-2 infection are not fully understood. ObjectivesTo use quantitative mass spectrometry-based proteomics to explore neutrophil phenotypes following acute SARS-CoV-2 infection and during recovery. MethodsProspective observational study of hospitalised patients with PCR-confirmed SARS-CoV-2 infection (May 2020-December 2020). Patients were ...

BackgroundPelvic organ prolapse (POP) represents a major health care burden in women but its underlying pathophysiological mechanisms have not been elucidated. ObjectiveTo integrate the results from a large scale exome chip study with published genetic and expression data into a molecular landscape of POP. Design, setting, and participantsThe exome chip study was conducted in 526 women with POP and 960 healthy controls. To corroborate the findings, we analysed differential gene expression data...

Precision medicine offers a promising pathway for improving therapeutic responses to pandemics like COVID-19. This study utilises independent patient cohorts from Florence and Liege, collected under the DRAGON consortium, to classify molecular phenotypes associated with COVID-19 through topological analysis of whole blood gene expression. Samples from 173 patients were collected, and RNA was sequenced using the Novaseq platform. Molecular phenotypes were identified through topological analysis o...

PurposeSepsis-associated immunothrombosis significantly contributes to high mortality, yet the role of N-glycosylation in this process remains poorly understood. This study aimed to comprehensively profile the plasma N-glycosylation landscape in sepsis and elucidate how its specific reprogramming in the complement and coagulation cascades influences immunothrombotic balance and patient outcomes. MethodsWe performed in-depth 4D-DIA proteomic and N-glycomic analyses on plasma from 43 sepsis patie...

A fundamental problem for disease treatment is that while antibiotics are a powerful counter to bacteria, they are ineffective against viruses. To ensure a given individual receives optimal treatment given their disease state and to reduce over-prescription of antibiotics leading to antimicrobial resistance, the host response can be measured to distinguish between the two states. To establish a predictive biomarker panel of disease state we conducted a meta-analysis of human blood infection stud...

Glucocorticoids (GCs) are used as anti-inflammatory and immunosuppressive drugs in many immune mediated diseases, but their use in sepsis and shock is controversial. This is caused in part by a lack of information regarding the responding cell types and GC-regulated genes in vivo. We used public blood transcriptomic datasets and GC-induced query genes to obtain 2 robust gene expression correlation signatures of GC induction, either in the absence or in the presence of severe inflammation. GC sig...

In susceptible patients, COVID-19 causes life-threatening disease driven by immune-mediated inflammatory lung injury. We have previously shown that multiple common host genetic variants are significantly associated with susceptibility to critical Covid-19, 1;2;3 and in one case, we demonstrated that such variants can inform development of new, effective drug treatment1;4. Here we report an association analysis of whole-genome sequences (WGS) from 11,423 cases from the GenOMICC study and 60,628 c...

Sepsis is the bodys dysfunctional response to infection associated with organ failure. Delays in diagnosis have a substantial impact on survival. Herein, samples from 586 in-house patients were used in conjunction with machine learning and cross-validation to narrow a gene expression signature of immune cell reprogramming to predict clinical deterioration in patients with suspected sepsis within the first 24 hours (h) of clinical presentation using just six genes (Sepset). The accuracy of the te...