Delineating sex-specific circulating host response signatures associated with COVID-19 severity and mortality.

Male SARS-CoV-2-infected patients have higher hospitalization rates, ICU admissions, and mortality compared to females, yet with unclear underlying mechanisms. We investigated the influence of biological sex on COVID-19 severity and patient outcomes. We profiled 41 circulating host response markers and identified differentially regulated proteins based on disease severity using covariates, such as sex, age, BMI, diabetes, and corticosteroid administration.

Standardizing designed and emergent quantitative features in microphysiological systems.

Microphysiological systems (MPSs) are cellular models that replicate aspects of organ and tissue functions in vitro. In contrast with conventional cell cultures, MPSs often provide physiological mechanical cues to cells, include fluid flow and can be interlinked (hence, they are often referred to as microfluidic tissue chips or organs-on-chips). Here, by means of examples of MPSs of the vascular system, intestine, brain and heart, we advocate for the development of standards that allow for comparisons of quantitative physiological features in MPSs and humans.

Inflammatory Protein Profiles in Plasma of Candidaemia Patients and the Contribution of Host Genetics to Their Variability.

Circulatory inflammatory proteins play a significant role in anti- host immune defence. However, little is known about the genetic variation that contributes to the variability of inflammatory responses in response to . To systematically characterize inflammatory responses in infection, we profiled 91 circulatory inflammatory proteins in peripheral blood mononuclear cells (PBMCs) stimulated with yeast isolated from 378 individuals of European origin from the 500 Functional Genomics (500FG) cohort of the Human Functional Genomics Project (HFGP) and Lifelines Deep cohort.

Uncoupling of IL-6 signaling and LC3-associated phagocytosis drives immunoparalysis during sepsis.

Immune deactivation of phagocytes is a central event in the pathogenesis of sepsis. Herein, we identify a master regulatory role of IL-6 signaling on LC3-associated phagocytosis (LAP) and reveal that uncoupling of these two processes during sepsis induces immunoparalysis in monocytes/macrophages. In particular, we demonstrate that activation of LAP by the human fungal pathogen Aspergillus fumigatus depends on ERK1/2-mediated phosphorylation of p47phox subunit of NADPH oxidase.

Leukocyte-Released Mediators in Response to Both Bacterial and Fungal Infections Trigger IFN Pathways, Independent of IL-1 and TNF-α, in Endothelial Cells.

In sepsis, dysregulated immune responses to infections cause damage to the host. Previous studies have attempted to capture pathogen-induced leukocyte responses. However, the impact of mediators released after pathogen-leukocyte interaction on endothelial cells, and how endothelial cell responses vary depending on the pathogen-type is lacking.

Functional Annotation of Genetic Loci Associated With Sepsis Prioritizes Immune and Endothelial Cell Pathways.

Due to limited sepsis patient cohort size and extreme heterogeneity, only one significant locus and suggestive associations at several independent loci were implicated by three genome-wide association studies. However, genes from such suggestive loci may also provide crucial information to unravel genetic mechanisms that determine sepsis heterogeneity. Therefore, in this study, we made use of integrative approaches to prioritize genes and pathways affected by sepsis associated genetic variants.

A Functional Genomics Approach to Understand Variation in Cytokine Production in Humans.

As part of the Human Functional Genomics Project, which aims to understand the factors that determine the variability of immune responses, we investigated genetic variants affecting cytokine production in response to ex vivo stimulation in two independent cohorts of 500 and 200 healthy individuals. We demonstrate a strong impact of genetic heritability on cytokine production capacity after challenge with bacterial, fungal, viral, and non-microbial stimuli. In addition to 17 novel genome-wide significant cytokine QTLs (cQTLs), our study provides a comprehensive picture of the genetic variants that influence six different cytokines in whole blood, blood mononuclear cells, and macrophages.