Biology subjects

Braun, E.

Publications and source records attributed to Braun, E..

24 records · Page 2Linked to original sources

bioRxiv2020

IFITM proteins promote SARS-CoV-2 infection in human lung cells

Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) are thought to restrict numerous viral pathogens including severe acute respiratory syndrome coronaviruses (SARS-CoVs). However, most evidence comes from single-round pseudovirus infection studies of cells that overexpress IFITMs. Here, we verified that artificial overexpression of IFITMs blocks SARS-CoV-2 infection. Strikingly, however, endogenous IFITM expression was essential for efficient infection of genuine SARS-CoV-2 in human lung cells. Our results indicate that the SARS-CoV-2 Spike protein interacts with IFITMs and hijacks them for efficient viral entry. IFITM proteins were expressed and further induced by interferons in human lung, gut, heart and brain cells. Intriguingly, IFITM-derived peptides and targeting antibodies inhibited SARS-CoV-2 entry and replication in human lung cells, cardiomyocytes and gut organoids. Our results show that IFITM proteins are important cofactors for SARS-CoV-2 infection of human cell types representing in vivo targets for viral transmission, dissemination and pathogenesis and suitable targets for therapeutic approaches.

microbiology↗

bioRxiv2020

Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, creates an urgent need for identifying molecular mechanisms that mediate viral entry, propagation, and tissue pathology. Cell membrane bound angiotensin-converting enzyme 2 (ACE2) and associated proteases, transmembrane protease serine 2 (TMPRSS2) and Cathepsin L (CTSL), were previously identified as mediators of SARS-CoV2 cellular entry. Here, we assess the cell type-specific RNA expression of ACE2, TMPRSS2, and CTSL through an integrated analysis of 107 single-cell and single-nucleus RNA-Seq studies, including 22 lung and airways datasets (16 unpublished), and 85 datasets from other diverse organs. Joint expression of ACE2 and the accessory proteases identifies specific subsets of respiratory epithelial cells as putative targets of viral infection in the nasal passages, airways, and alveoli. Cells that co-express ACE2 and proteases are also identified in cells from other organs, some of which have been associated with COVID-19 transmission or pathology, including gut enterocytes, corneal epithelial cells, cardiomyocytes, heart pericytes, olfactory sustentacular cells, and renal epithelial cells. Performing the first meta-analyses of scRNA-seq studies, we analyzed 1,176,683 cells from 282 nasal, airway, and lung parenchyma samples from 164 donors spanning fetal, childhood, adult, and elderly age groups, associate increased levels of ACE2, TMPRSS2, and CTSL in specific cell types with increasing age, male gender, and smoking, all of which are epidemiologically linked to COVID-19 susceptibility and outcomes. Notably, there was a particularly low expression of ACE2 in the few young pediatric samples in the analysis. Further analysis reveals a gene expression program shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues, including genes that may mediate viral entry, subtend key immune functions, and mediate epithelial-macrophage cross-talk. Amongst these are IL6, its receptor and co-receptor, IL1R, TNF response pathways, and complement genes. Cell type specificity in the lung and airways and smoking effects were conserved in mice. Our analyses suggest that differences in the cell type-specific expression of mediators of SARS-CoV-2 viral entry may be responsible for aspects of COVID-19 epidemiology and clinical course, and point to putative molecular pathways involved in disease susceptibility and pathogenesis.

bioinformatics↗

bioRxiv2020

Topological defects in the nematic order of actin fibers as organization centers of Hydra morphogenesis

Animal morphogenesis arises from the complex interplay between multiple mechanical and biochemical processes with mutual feedback. Developing an effective, coarse-grained description of morphogenesis is essential for understanding how these processes are coordinated across scales to form robust, functional outcomes. Here we show that the nematic order of the supra-cellular actin fibers in regenerating Hydra defines a slowly-varying field, whose dynamics provide an effective description of the morphogenesis process. We show that topological defects in this field, which are long-lived yet display rich dynamics, act as organization centers with morphological features developing at defect sites. These observations suggest that the nematic orientation field can be considered a "mechanical morphogen" whose dynamics, in conjugation with various biochemical and mechanical signaling processes, result in the robust emergence of functional patterns during morphogenesis.

biophysics↗

bioRxiv2019

Electric-induced reversal of morphogenesis in Hydra regeneration

Morphogenesis involves the dynamic interplay of biochemical, mechanical and electrical processes. Here we ask: to what extent can the course of morphogenesis be modulated and controlled by an external electric field? We show that above a critical amplitude, an external electric field can halt morphogenesis in Hydra regeneration. Moreover, above this critical amplitude, the electric field can even lead to reversal dynamics: a fully developed Hydra folds back into its incipient spheroid morphology. The potential to renew morphogenesis is re-exposed when the field is reduced back to amplitudes below criticality. These dynamics are accompanied by modulations of the Wnt3 activity, a central component of the head organizer in Hydra. Reversal of morphogenesis is shown to be triggered by enhanced epithelial electrical excitations, accompanied by intensified calcium activity, indicating that electrical processes play an instructive role to a level that can direct developmental trajectories. Reversal of morphogenesis by external fields, calls for extending its framework beyond programmatic, forward-driven, hierarchical processes.

biophysics↗

bioRxiv2019

Metabolic Cost of Rapid Adaptation of Single Yeast Cells Under Unforeseen Challenge

Cells can rapidly adapt to changing environments through non-genetic processes; however, the metabolic cost of such adaptation has never been considered. Here we demonstrate metabolic coupling in a remarkable, rapid adaptation process (10-3cells/hour) by simultaneously measuring metabolism and division of thousands of individual Saccharomyces cerevisiae cells using a droplet microfluidic system. Following a severe challenge, most cells, while not dividing, continue to metabolize, displaying a remarkably wide diversity of metabolic trajectories from which adaptation events can be anticipated. Adaptation requires the consumption of a characteristic amount of energy, indicating that it is an active process. The demonstration that metabolic trajectories predict a priori adaptation events provides the first evidence of tight energetic coupling between metabolism and regulatory reorganization in adaptation.\n\nOne Sentence SummaryDemonstration of the tight coupling between metabolic activity and regulatory processes during rapid adaptation at the single-cell level.

systems biology↗

bioRxiv2018

Molecular architecture of the mouse nervous system

The mammalian nervous system executes complex behaviors controlled by specialised, precisely positioned and interacting cell types. Here, we used RNA sequencing of half a million single cells to create a detailed census of cell types in the mouse nervous system. We mapped cell types spatially and derived a hierarchical, data-driven taxonomy. Neurons were the most diverse, and were grouped by developmental anatomical units, and by the expression of neurotransmitters and neuropeptides. Neuronal diversity was driven by genes encoding cell identity, synaptic connectivity, neurotransmission and membrane conductance. We discovered several distinct, regionally restricted, astrocytes types, which obeyed developmental boundaries and correlated with the spatial distribution of key glutamate and glycine neurotransmitters. In contrast, oligodendrocytes showed a loss of regional identity, followed by a secondary diversification. The resource presented here lays a solid foundation for understanding the molecular architecture of the mammalian nervous system, and enables genetic manipulation of specific cell types.

neuroscience↗