Type I interferons (IFN α/β) play a central role in innate immunity to respiratory viruses, including coronaviruses. Genetic defects in type I interferon signaling were reported in a significant proportion of critically ill CoOVID-19 patients. Extensive studies on interferon-induced intracellular signal transduction pathways led to the elucidation of the Jak-Stat pathway. Furthermore, advances in gene expression profiling by microarrays have revealed that type I interferon rapidly induced multiple transcription factor mRNA levels. In this study, transcription factor profiling in the transcriptome was used to gain novel insights into the role of inducible transcription factors in response to type I interferon signaling in immune cells and in lung epithelial cells after SARS-CoV-2 infection. Modeling the interferon-inducible transcription factor mRNA data in terms of distinct sub-networks based on biological functions such as antiviral response, immune modulation, and cell growth revealed enrichment of specific transcription factors in mouse and human immune cells. The evolutionarily conserved core type I interferon gene expression consists of the inducible transcriptional factor mRNA of the antiviral response sub-network and enriched in granulocytes. Analysis of the type I interferon-inducible transcription factor sub-networks as distinct protein-protein interaction pathways revealed insights into the role of critical hubs in signaling. Interrogation of multiple microarray datasets revealed that SARS-CoV-2 induced high levels of IFN-beta and interferon-inducible transcription factor mRNA in human lung epithelial cells. Transcription factor mRNA of the three major sub-networks regulating antiviral, immune modulation, and cell growth were differentially regulated in human lung epithelial cell lines after SARS-CoV-2 infection and in the tissue samples of COVID-19 patients. A subset of type I interferon-inducible transcription factors and inflammatory mediators were specifically enriched in the lungs and neutrophils of Covid-19 patients. The emerging complex picture of type I IFN transcriptional regulation consists of a rapid transcriptional switch mediated by the Jak-Stat cascade and a graded output of the inducible transcription factor activation that enables temporal regulation of gene expression.
<div> <p>A series of complexes between neutral Valine and methane that feature potential homopolar C-H∙∙∙H-C contacts were located on the MP2/aug-cc-pVTZ potential energy hypersurface. In order to better estimate the strength of this contacts, the interaction energies were improve by single-point calculations at different levels of theory (MP2, CCSD(T), SAPT2, SAPT2+3) together with Dunning’s basis sets (aug-cc-pVXZ; X=T,Q,5). Topological analysis of the electron density within the QTAIM framework, NCI plots and energy decomposition within the SAPT framework were used to discuss the nature of this interactions. The complexes whose monomers only interact though C-H∙∙∙H-C contacts indicate that these interactions are entirely due to dispersion forces, are not directional and are much stronger than expected (the interaction energies of the complexes range from -0.7 to -1.0 kcal/mol). This large value is remarkable considering the small size of the interacting groups herein considered (methane, and one or two Valine’s methyl groups), and indicates that in biological systems, where those interactions can be very numerous in the presence of multiple aliphatic amino acids, if those interactions are not properly model, magnitudes as ligand-receptor affinities, protein-protein interaction energies and protein stabilities might be grossly misestimated. Finally, since some of the computed complexes also include stronger interactions than homopolar C-H∙∙∙H-C contacts, we analyzed if the potential C-H∙∙∙H-C contacts in these complexes are really contributing to stabilize the complexes or are just a geometrical artifact arising from the maximization of stronger interactions.</p> </div>
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