FGF receptor kinase inhibitors exhibit broad antiviral activity by targeting Src family kinases.

The development of antiviral strategies is a key task of biomedical research, but broad-spectrum virus inhibitors are scarce. Here we show that fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors reduce infection of several cell types with DNA and RNA viruses by blocking early stages of infection, but not viral cell association. Unexpectedly, their antiviral activity was largely independent of FGFR kinase inhibition.

Selective autophagy impedes KSHV entry after recruiting the membrane damage sensor galectin-8 to virus-containing endosomes.

Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic γ-herpesvirus. Autophagy during KSHV entry has remained unexplored. We show that LC3 lipidation as a hallmark of autophagy is induced shortly after KSHV entry.

Metagenomic study of lake microbial mats reveals protease-inhibiting antiviral peptides from a core microbiome member.

In contrast to the large body of work on bioactive natural products from individually cultivated bacteria, the chemistry of environmental microbial communities remains largely elusive. Here, we present a comprehensive bioinformatic and functional study on a complex and interaction-rich ecosystem, algal-bacterial (microbial) mats of Lake Chilika in India, Asia's largest brackish water body. We report the bacterial compositional dynamics over the mat life cycle, >1,300 reconstructed environmental genomes harboring >2,200 biosynthetic gene clusters (BGCs), the successful cultivation of a widespread core microbiome member belonging to the genus , heterologous reconstitution of two silent biosynthetic pathways, and new compounds with potent protease inhibitory and antiviral activities.

Dynamin independent endocytosis is an alternative cell entry mechanism for multiple animal viruses.

Mammalian receptor-mediated endocytosis (RME) often involves at least one of three isoforms of the large GTPase dynamin (Dyn). Dyn pinches-off vesicles at the plasma membrane and mediates uptake of many viruses, although some viruses directly penetrate the plasma membrane. RME is classically interrogated by genetic and pharmacological interference, but this has been hampered by undesired effects.

Stepwise virus assembly in the cell nucleus revealed by spatiotemporal click chemistry of DNA replication.

Biomolecular assemblies are fundamental to life and viral disease. The spatiotemporal coordination of viral replication and assembly is largely unknown. Here, we developed a dual-color click chemistry procedure for imaging adenovirus DNA (vDNA) replication in the cell nucleus.

Preexisting cell state rather than stochastic noise confers high or low infection susceptibility of human lung epithelial cells to adenovirus.

Viruses display large variability across all stages of their life cycle, including entry, gene expression, replication, assembly, and egress. We previously reported that the immediate early adenovirus (AdV) E1A transcripts accumulate in human lung epithelial A549 cancer cells with high variability, mostly independent of the number of incoming viral genomes, but somewhat correlated to the cell cycle state at the time of inoculation. Here, we leveraged the classical Luria-Delbrück fluctuation analysis to address whether infection variability primarily arises from the cell state or stochastic noise.

A versatile automated pipeline for quantifying virus infectivity by label-free light microscopy and artificial intelligence.

Virus infectivity is traditionally determined by endpoint titration in cell cultures, and requires complex processing steps and human annotation. Here we developed an artificial intelligence (AI)-powered automated framework for ready detection of virus-induced cytopathic effect (DVICE). DVICE uses the convolutional neural network EfficientNet-B0 and transmitted light microscopy images of infected cell cultures, including coronavirus, influenza virus, rhinovirus, herpes simplex virus, vaccinia virus, and adenovirus.

Gutless Helper-Dependent and First-Generation HAdV5 Vectors Have Similar Mechanical Properties and Common Transduction Mechanisms.

Delivering vectorized information into cells with the help of viruses has been of high interest to fundamental and applied science, and bears significant therapeutic promise. Human adenoviruses (HAdVs) have been at the forefront of gene delivery for many years, and the subject of intensive development resulting in several generations of agents, including replication-competent, -defective or retargeted vectors, and recently also helper-dependent (HD), so-called gutless vectors lacking any viral protein coding information. While it is possible to produce HD-AdVs in significant amounts, physical properties of these virus-like particles and their efficiency of transduction have not been addressed.

Machine learning for cross-scale microscopy of viruses.

Despite advances in virological sciences and antiviral research, viruses continue to emerge, circulate, and threaten public health. We still lack a comprehensive understanding of how cells and individuals remain susceptible to infectious agents. This deficiency is in part due to the complexity of viruses, including the cell states controlling virus-host interactions.

Engineered Human Adenoviruses of Species B and C Report Early, Intermediate Early, and Late Viral Gene Expression.

Adenoviruses (AdVs) are being developed for oncolytic or vaccination therapy against existing and emerging conditions. Well-characterized replication-competent human and human primate AdVs expressing multiple payloads are desirable, but their replication in rodent models is limited. To score the timing of adenoviral gene expression in cell cultures, we developed fully replication-competent transcriptional reporter viruses for HAdV-C5, -B3, and -B35.

Label-free microscopy for virus infections.

Microscopy has been essential to elucidate micro- and nano-scale processes in space and time and has provided insights into cell and organismic functions. It is widely employed in cell biology, microbiology, physiology, clinical sciences and virology. While label-dependent microscopy, such as fluorescence microscopy, provides molecular specificity, it has remained difficult to multiplex in live samples.

Vascular dysfunction in COVID-19 patients: update on SARS-CoV-2 infection of endothelial cells and the role of long non-coding RNAs.

Although COVID-19 is primarily a respiratory disease, it may affect also the cardiovascular system. COVID-19 patients with cardiovascular disorder (CVD) develop a more severe disease course with a significantly higher mortality rate than non-CVD patients. A common denominator of CVD is the dysfunction of endothelial cells (ECs), increased vascular permeability, endothelial-to-mesenchymal transition, coagulation, and inflammation.

High-content, arrayed compound screens with rhinovirus, influenza A virus and herpes simplex virus infections.

Viruses are genetically and structurally diverse, and outnumber cells by orders of magnitude. They can cause acute and chronic infections, suppress, or exacerbate immunity, or dysregulate survival and growth of cells. To identify chemical agents with pro- or antiviral effects we conducted arrayed high-content image-based multi-cycle infection screens of 1,280 mainly FDA-approved compounds with three human viruses, rhinovirus (RV), influenza A virus (IAV), and herpes simplex virus (HSV) differing in genome organization, composition, presence of an envelope, and tropism.

Methylene blue, Mycophenolic acid, Posaconazole, and Niclosamide inhibit SARS-CoV-2 Omicron variant BA.1 infection of human airway epithelial organoids.

Sublineages of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Omicron variants continue to amass mutations in the spike (S) glycoprotein, which leads to immune evasion and rapid spread of the virus across the human population. Here we demonstrate the susceptibility of the Omicron variant BA.1 (B.

Sequence-Specific Features of Short Double-Strand, Blunt-End RNAs Have RIG-I- and Type 1 Interferon-Dependent or -Independent Anti-Viral Effects.

Pathogen-associated molecular patterns, including cytoplasmic DNA and double-strand (ds)RNA trigger the induction of interferon (IFN) and antiviral states protecting cells and organisms from pathogens. Here we discovered that the transfection of human airway cell lines or non-transformed fibroblasts with 24mer dsRNA mimicking the cellular micro-RNA (miR)29b-1* gives strong anti-viral effects against human adenovirus type 5 (AdV-C5), influenza A virus X31 (H3N2), and SARS-CoV-2. These anti-viral effects required blunt-end complementary RNA strands and were not elicited by corresponding single-strand RNAs.

Adenovirus entry: Stability, uncoating, and nuclear import.

Adenoviruses (AdVs) are widespread in vertebrates. They infect the respiratory and gastrointestinal tracts, the eyes, heart, liver, and kidney, and are lethal to immunosuppressed people. Mastadenoviruses infecting mammals comprise several hundred different types, and many specifically infect humans.

Identification of broad anti-coronavirus chemical agents for repurposing against SARS-CoV-2 and variants of concern.

Endemic human coronaviruses (hCoVs) 229E and OC43 cause respiratory disease with recurrent infections, while severe acute respiratory syndrome (SARS)-CoV-2 spreads across the world with impact on health and societies. Here, we report an image-based multicycle infection procedure with α-coronavirus hCoV-229E-eGFP in an arrayed chemical library screen of 5440 clinical and preclinical compounds. Toxicity counter selection and challenge with the β-coronaviruses OC43 and SARS-CoV-2 in tissue culture and human airway epithelial explant cultures (HAEEC) identified four FDA-approved compounds with oral availability.

A viral ubiquitination switch attenuates innate immunity and triggers nuclear import of virion DNA and infection.

Antiviral defense and virus exclusion from the cell nucleus restrict foreign nucleic acid influx and infection. How the genomes of DNA viruses evade cytosolic pattern recognition and cross the nuclear envelope is incompletely understood. Here, we show that the virion protein V of adenovirus functions as a linchpin between the genome and the capsid, thereby securing particle integrity.

The RGD-binding integrins αvβ6 and αvβ8 are receptors for mouse adenovirus-1 and -3 infection.

Mammalian adenoviruses (AdVs) comprise more than ~350 types including over 100 human (HAdVs) and just three mouse AdVs (MAdVs). While most HAdVs initiate infection by high affinity/avidity binding of their fiber knob (FK) protein to either coxsackievirus AdV receptor (CAR), CD46 or desmoglein (DSG)-2, MAdV-1 (M1) infection requires arginine-glycine-aspartate (RGD) binding integrins. To identify the receptors mediating MAdV infection we generated five novel reporter viruses for MAdV-1/-2/-3 (M1, M2, M3) transducing permissive murine (m) CMT-93 cells, but not B16 mouse melanoma cells expressing mCAR, human (h) CD46 or hDSG-2.

Two years into COVID-19 - Lessons in SARS-CoV-2 and a perspective from papers in FEBS Letters.

The 2019 outbreak of coronavirus disease (COVID-19) in Wuhan (Hubei province of China) has given rise to a pandemic spread of virus, more than 240 million incidences and a death toll larger than 5 million people. COVID-19 has set off large efforts in research, therapy and patient care, as well as public and private debates in every imaginable form. A number of scientists used the publication platforms provided by the Federation of the European Biochemical Societies (FEBS) to present their research data, reviews, opinions and other contributions relating to COVID-19 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Virus Infection Variability by Single-Cell Profiling.

Cell-to-cell variability of infection has long been known, yet it has remained one of the least understood phenomena in infection research. It impacts on disease onset and development, yet only recently underlying mechanisms have been studied in clonal cell cultures by single-virion immunofluorescence microscopy and flow cytometry. In this review, we showcase how single-cell RNA sequencing (scRNA-seq), single-molecule RNA-fluorescence in situ hybridization (FISH), and copper(I)-catalyzed azide-alkyne cycloaddition (click) with alkynyl-tagged viral genomes dissect infection variability in human and mouse cells.

On-chip transporting arresting and characterizing individual nano-objects in biological ionic liquids.

Understanding and controlling the individual behavior of nanoscopic matter in liquids, the environment in which many such entities are functioning, is both inherently challenging and important to many natural and man-made applications. Here, we transport individual nano-objects, from an assembly in a biological ionic solution, through a nanochannel network and confine them in electrokinetic nanovalves, created by the collaborative effect of an applied ac electric field and a rationally engineered nanotopography, locally amplifying this field. The motion of so-confined fluorescent nano-objects is tracked, and its kinetics provides important information, enabling the determination of their particle diffusion coefficient, hydrodynamic radius, and electrical conductivity, which are elucidated for artificial polystyrene nanospheres and subsequently for sub-100-nm conjugated polymer nanoparticles and adenoviruses.

Microscopy deep learning predicts virus infections and reveals mechanics of lytic-infected cells.

Imaging across scales reveals disease mechanisms in organisms, tissues, and cells. Yet, particular infection phenotypes, such as virus-induced cell lysis, have remained difficult to study. Here, we developed imaging modalities and deep learning procedures to identify herpesvirus and adenovirus (AdV) infected cells without virus-specific stainings.