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Int J Mol Sci ; 23(12)2022 Jun 18.
Article in English | MEDLINE | ID: covidwho-2282707


The intestinal microbiota is known to influence local immune homeostasis in the gut and to shape the developing immune system towards elimination of pathogens and tolerance towards self-antigens. Even though the lung was considered sterile for a long time, recent evidence using next-generation sequencing techniques confirmed that the lower airways possess their own local microbiota. Since then, there has been growing evidence that the local respiratory and intestinal microbiota play a role in acute and chronic pediatric lung diseases. The concept of the so-called gut-lung axis describing the mutual influence of local microbiota on distal immune mechanisms was established. The mechanisms by which the intestinal microbiota modulates the systemic immune response include the production of short-chain fatty acids (SCFA) and signaling through pattern recognition receptors (PRR) and segmented filamentous bacteria. Those factors influence the secretion of pro- and anti-inflammatory cytokines by immune cells and further modulate differentiation and recruitment of T cells to the lung. This article does not only aim at reviewing recent mechanistic evidence from animal studies regarding the gut-lung axis, but also summarizes current knowledge from observational studies and human trials investigating the role of the respiratory and intestinal microbiota and their modulation by pre-, pro-, and synbiotics in pediatric lung diseases.

Gastrointestinal Microbiome , Lung Diseases , Microbiota , Animals , Child , Fatty Acids, Volatile , Gastrointestinal Microbiome/physiology , Humans , Lung
Viruses ; 14(3)2022 03 03.
Article in English | MEDLINE | ID: covidwho-1732235


Rocaglates are potent broad-spectrum antiviral compounds with a promising safety profile. They inhibit viral protein synthesis for different RNA viruses by clamping the 5'-UTRs of mRNAs onto the surface of the RNA helicase eIF4A. Apart from the natural rocaglate silvestrol, synthetic rocaglates like zotatifin or CR-1-31-B have been developed. Here, we compared the effects of rocaglates on viral 5'-UTR-mediated reporter gene expression and binding to an eIF4A-polypurine complex. Furthermore, we analyzed the cytotoxicity of rocaglates on several human immune cells and compared their antiviral activities in coronavirus-infected cells. Finally, the potential for developing viral resistance was evaluated by passaging human coronavirus 229E (HCoV-229E) in the presence of increasing concentrations of rocaglates in MRC-5 cells. Importantly, no decrease in rocaglate-sensitivity was observed, suggesting that virus escape mutants are unlikely to emerge if the host factor eIF4A is targeted. In summary, all three rocaglates are promising antivirals with differences in cytotoxicity against human immune cells, RNA-clamping efficiency, and antiviral activity. In detail, zotatifin showed reduced RNA-clamping efficiency and antiviral activity compared to silvestrol and CR-1-31-B, but was less cytotoxic for immune cells. Our results underline the potential of rocaglates as broad-spectrum antivirals with no indications for the emergence of escape mutations in HCoV-229E.

Antineoplastic Agents , Coronavirus , 5' Untranslated Regions , Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , Constriction , Humans
Nat Commun ; 12(1): 5536, 2021 09 20.
Article in English | MEDLINE | ID: covidwho-1428813


Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. The ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in different cell types including primary differentiated human bronchial epithelial cells, (partially) reverses the virus-induced translational shut-down, improves viability of infected cells and counteracts the CoV-mediated downregulation of IRE1α and the ER chaperone BiP. Proteome-wide analyses revealed specific pathways, protein networks and components that likely mediate the thapsigargin-induced antiviral state, including essential (HERPUD1) or novel (UBA6 and ZNF622) factors of ER quality control, and ER-associated protein degradation complexes. Additionally, thapsigargin blocks the CoV-induced selective autophagic flux involving p62/SQSTM1. The data show that thapsigargin hits several central mechanisms required for CoV replication, suggesting that this compound (or derivatives thereof) may be developed into broad-spectrum anti-CoV drugs.

Endoplasmic Reticulum Stress , SARS-CoV-2/physiology , Virus Replication/physiology , Animals , Autophagy/drug effects , Bronchi/pathology , COVID-19/pathology , COVID-19/virology , Cell Differentiation/drug effects , Cell Extracts , Cell Line , Cell Survival/drug effects , Chlorocebus aethiops , Coronavirus 229E, Human/physiology , Down-Regulation/drug effects , Endoplasmic Reticulum Chaperone BiP , Endoplasmic Reticulum Stress/drug effects , Endoplasmic Reticulum Stress/genetics , Endoplasmic Reticulum-Associated Degradation/drug effects , Epithelial Cells/drug effects , Epithelial Cells/virology , Heat-Shock Proteins/metabolism , Humans , Macrolides/pharmacology , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/physiology , Protein Biosynthesis/drug effects , Proteome/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reproducibility of Results , SARS-CoV-2/drug effects , Thapsigargin/pharmacology , Unfolded Protein Response/drug effects , Vero Cells , Virus Replication/drug effects