scholarly journals Transcriptional Profiling and Machine Learning Unveil a Concordant Biosignature of Type I Interferon-Inducible Host Response Across Nasal Swab and Pulmonary Tissue for COVID-19 Diagnosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Cheng Zhang ◽  
Yi-Gang Feng ◽  
Chiwing Tam ◽  
Ning Wang ◽  
Yibin Feng
Keyword(s):  
Machine Learning ◽  
Lung Tissue ◽  
Host Response ◽  
Nasal Swab ◽  
Type I Interferon ◽  
False Negative ◽  
Transcriptional Profile ◽  
Diagnostic Methods ◽  
Transcriptional Level ◽  
Type I

BackgroundCOVID-19, caused by SARS-CoV-2 virus, is a global pandemic with high mortality and morbidity. Limited diagnostic methods hampered the infection control. Since the direct detection of virus mainly by RT-PCR may cause false-negative outcome, host response-dependent testing may serve as a complementary approach for improving COVID-19 diagnosis.ObjectiveOur study discovered a highly-preserved transcriptional profile of Type I interferon (IFN-I)-dependent genes for COVID-19 complementary diagnosis.MethodsComputational language R-dependent machine learning was adopted for mining highly-conserved transcriptional profile (RNA-sequencing) across heterogeneous samples infected by SARS-CoV-2 and other respiratory infections. The transcriptomics/high-throughput sequencing data were retrieved from NCBI-GEO datasets (GSE32155, GSE147507, GSE150316, GSE162835, GSE163151, GSE171668, GSE182569). Mathematical approaches for homological analysis were as follows: adjusted rand index-related similarity analysis, geometric and multi-dimensional data interpretation, UpsetR, t-distributed Stochastic Neighbor Embedding (t-SNE), and Weighted Gene Co-expression Network Analysis (WGCNA). Besides, Interferome Database was used for predicting the transcriptional factors possessing IFN-I promoter-binding sites to the key IFN-I genes for COVID-19 diagnosis.ResultsIn this study, we identified a highly-preserved gene module between SARS-CoV-2 infected nasal swab and postmortem lung tissue regulating IFN-I signaling for COVID-19 complementary diagnosis, in which the following 14 IFN-I-stimulated genes are highly-conserved, including BST2, IFIT1, IFIT2, IFIT3, IFITM1, ISG15, MX1, MX2, OAS1, OAS2, OAS3, OASL, RSAD2, and STAT1. The stratified severity of COVID-19 may also be identified by the transcriptional level of these 14 IFN-I genes.ConclusionUsing transcriptional and computational analysis on RNA-seq data retrieved from NCBI-GEO, we identified a highly-preserved 14-gene transcriptional profile regulating IFN-I signaling in nasal swab and postmortem lung tissue infected by SARS-CoV-2. Such a conserved biosignature involved in IFN-I-related host response may be leveraged for COVID-19 diagnosis.

scholarly journals RNA-Seq Based Transcriptome Analysis of the Type I Interferon Host Response upon Vaccinia Virus Infection of Mouse Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Bruno Hernáez ◽  
Graciela Alonso ◽  
Juan Manuel Alonso-Lobo ◽  
Alberto Rastrojo ◽  
Cornelius Fischer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Surface ◽  
Vaccinia Virus ◽  
Transcriptional Activation ◽  
Host Response ◽  
Type I Interferon ◽  
Cell Signalling ◽  
Transcriptional Level ◽  
Type I ◽  
Rna Seq

Vaccinia virus (VACV) encodes the soluble type I interferon (IFN) binding protein B18 that is secreted from infected cells and also attaches to the cell surface, as an immunomodulatory strategy to inhibit the host IFN response. By using next generation sequencing technologies, we performed a detailed RNA-seq study to dissect at the transcriptional level the modulation of the IFN based host response by VACV and B18. Transcriptome profiling of L929 cells after incubation with purified recombinant B18 protein showed that attachment of B18 to the cell surface does not trigger cell signalling leading to transcriptional activation. Consistent with its ability to bind type I IFN, B18 completely inhibited the IFN-mediated modulation of host gene expression. Addition of UV-inactivated virus particles to cell cultures altered the expression of a set of 53 cellular genes, including genes involved in innate immunity. Differential gene expression analyses of cells infected with replication competent VACV identified the activation of a broad range of host genes involved in multiple cellular pathways. Interestingly, we did not detect an IFN-mediated response among the transcriptional changes induced by VACV, even after the addition of IFN to cells infected with a mutant VACV lacking B18. This is consistent with additional viral mechanisms acting at different levels to block IFN responses during VACV infection.

scholarly journals The Latency-Associated Transcript Inhibits Apoptosis via Downregulation of Components of the Type I Interferon Pathway during Latent Herpes Simplex Virus 1 Ocular Infection

2019 ◽  
Vol 93 (10) ◽  
Author(s):  
Kati Tormanen ◽  
Sariah Allen ◽  
Kevin R. Mott ◽  
Homayon Ghiasi
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Type I Interferon ◽  
Gene Expression Pattern ◽  
Ocular Infection ◽  
Transcriptional Level ◽  
Type I ◽  
Human Pathology ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTThe herpes simplex virus (HSV-1) latency-associated transcript (LAT) has been shown to inhibit apoptosis via inhibiting activation of proapoptotic caspases. However, the mechanism of LAT control of apoptosis is unclear, because LAT is not known to encode a functional protein, and the LAT transcript is found largely in the nucleus. We hypothesized that LAT inhibits apoptosis by regulating expression of genes that control apoptosis. Consequently, we sought to establish the molecular mechanism of antiapoptosis functions of LAT at a transcriptional level during latent HSV-1 ocular infection in mice. Our results suggest the following. (i) LAT likely inhibits apoptosis via upregulation of several components of the type I interferon (IFN) pathway. (ii) LAT does not inhibit apoptosis via the caspase cascade at a transcriptional level or via downregulating Toll-like receptors (TLRs). (iii) The mechanism of LAT antiapoptotic effect is distinct from that of the baculovirus inhibitor of apoptosis (cpIAP) because replacement of LAT with the cpIAP gene resulted in a different gene expression pattern than in either LAT+or LAT−viruses. (iv) Replacement of LAT with the cpIAP gene does not cause upregulation of CD8 or markers of T cell exhaustion despite their having similar levels of latency, further supporting that LAT and cpIAP function via distinct mechanisms.IMPORTANCEThe HSV-1 latency reactivation cycle is the cause of significant human pathology. The HSV-1 latency-associated transcript (LAT) functions by regulating latency and reactivation, in part by inhibiting apoptosis. However, the mechanism of this process is unknown. Here we show that LAT likely controls apoptosis via downregulation of several components in the JAK-STAT pathway. Furthermore, we provide evidence that immune exhaustion is not caused by the antiapoptotic activity of the LAT.

scholarly journals The LymphotoxinβReceptor Is Essential for Upregulation of IFN-Induced Guanylate-Binding Proteins and Survival afterToxoplasma gondiiInfection

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Kristina Behnke ◽  
Ursula R. Sorg ◽  
Helmut E. Gabbert ◽  
Klaus Pfeffer
Keyword(s):  
Type I Interferon ◽  
Parasite Load ◽  
Mortality Rates ◽  
Host Responses ◽  
Interferon Response ◽  
Transcriptional Level ◽  
Type I ◽  
Type Ii ◽  
Wild Type ◽  
Guanylate Binding Protein

Lymphotoxinβreceptor (LTβR) signaling plays an important role in efficient initiation of host responses to a variety of pathogens, encompassing viruses, bacteria, and protozoans via induction of the type I interferon response. The present study reveals that afterToxoplasma gondiiinfection, LTβR−/−mice show a substantially reduced survival rate when compared to wild-type mice. LTβR−/−mice exhibit an increased parasite load and a more pronounced organ pathology. Also, a delayed increase of serum IL-12p40 and a failure of the protective IFNγresponse in LTβR−/−mice were observed. Serum NO levels in LTβR−/−animals rose later and were markedly decreased compared to wild-type animals. At the transcriptional level, LTβR−/−animals exhibited a deregulated expression profile of several cytokines known to play a role in activation of innate immunity inT. gondiiinfection. Importantly, expression of the IFNγ-regulated murine guanylate-binding protein (mGBP) genes was virtually absent in the lungs of LTβR−/−mice. This demonstrates clearly that the LTβR is essential for the induction of a type II IFN-mediated immune response againstT. gondii. The pronounced inability to effectively upregulate host defense effector molecules such as GBPs explains the high mortality rates of LTβR−/−animals afterT. gondiiinfection.

scholarly journals Integrated single-cell analysis unveils diverging immune features of COVID-19, influenza and other community-acquired pneumonia.

2021 ◽  
Author(s):  
Alex Schuurman ◽  
Tom Reijnders ◽  
Anno Saris ◽  
Ivan Ramirez-Moral ◽  
Michiel Schinkel ◽  
...  
Keyword(s):  
Single Cell ◽  
Host Response ◽  
Influenza A ◽  
Single Cell Analysis ◽  
Type I Interferon ◽  
Community Acquired Pneumonia ◽  
Type I ◽  
Cell Analysis ◽  
The Common ◽  
Peripheral Immune Response

Abstract The exact immunopathophysiology of community-acquired pneumonia (CAP) caused by SARS-CoV-2 (COVID-19) remains clouded by methodological heterogeneity and a lack of relevant disease controls. The absence of single-cell investigations in the broader population of patients with CAP renders it difficult to distinguish immune features unique to COVID-19 from the common characteristics of a dysregulated host response to pneumonia. We performed integrated single-cell transcriptomic and proteomic analyses in PBMCs from a matched cohort of eight patients with COVID-19, eight patients with CAP caused by Influenza A or other pathogens, and four non-infectious control subjects. Using this balanced, multi-omics approach we describe shared and diverging transcriptional and phenotypic patterns – including increased levels of type I interferon stimulated NK cells in COVID-19, cytotoxic CD8 T EMRA cells in both COVID-19 and influenza, and distinctive monocyte compositions between all groups – and thereby expand our understanding of the peripheral immune response in different etiologies of pneumonia.

Dual transcriptomics to determine interferon-gamma independent host response to intestinal Cryptosporidium parvum infection

2021 ◽  
Author(s):  
Gina M. Gallego-Lopez ◽  
Carolina Mendoza Cavazos ◽  
Andrés M. Tibabuzo Perdomo ◽  
Andrew L. Garfoot ◽  
Roberta M. O’Connor ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cryptosporidium Parvum ◽  
Chronic Infection ◽  
Host Response ◽  
Type I Interferon ◽  
Secondary Infection ◽  
Transcript Abundance ◽  
Type I ◽  
Transcriptomic Response ◽  
Dual Transcriptomics

Animals with a chronic infection of the parasite Toxoplasma gondii are protected against lethal secondary infection with other pathogens. Our group previously determined that soluble T. gondii antigens (STAg) can mimic this protection and be used as a treatment against several lethal pathogens. Because treatments are limited for the parasite Cryptosporidium parvum , we tested STAg as a C. parvum therapeutic. We determined that STAg treatment reduced C. parvum Iowa II oocyst shedding in IFNγ-KO mice. Murine intestinal sections were then sequenced to define the IFNγ independent transcriptomic response to C. parvum infection. Gene Ontology and transcript abundance comparisons showed host immune response and metabolism changes. Transcripts for type I interferon responsive genes were more abundant in C. parvum infected mice treated with STAg. Comparisons between PBS or STAg treatments showed no significant differences in C. parvum gene expression. C. parvum transcript abundance was highest in the ileum and mucin-like glycoproteins and the GDP-fucose transporter were among the most abundant. These results will assist the field in determining both host- and parasite-directed future therapeutic targets.

scholarly journals Contributions of Ubiquitin and Ubiquitination to Flaviviral Antagonism of Type I IFN

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 763
Author(s):  
Erika Hay-McCullough ◽  
Juliet Morrison
Keyword(s):  
Immune Response ◽  
Host Response ◽  
Type I Interferon ◽  
Antiviral Response ◽  
Cellular Protein ◽  
Type I ◽  
Type I Ifn ◽  
Cellular Regulation ◽  
Host Antiviral Response

Flaviviruses implement a broad range of antagonism strategies against the host antiviral response. A pivotal component of the early host response is production and signaling of type I interferon (IFN-I). Ubiquitin, a prevalent cellular protein-modifying molecule, is heavily involved in the cellular regulation of this and other immune response pathways. Viruses use ubiquitin and ubiquitin machinery to antagonize various steps of these pathways through diverse mechanisms. Here, we highlight ways in which flaviviruses use or inhibit ubiquitin to antagonize the antiviral IFN-I response.

scholarly journals Genes and regulatory mechanisms associated with experimentally-induced bovine respiratory disease identified using supervised machine learning methodology

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Matthew A. Scott ◽  
Amelia R. Woolums ◽  
Cyprianna E. Swiderski ◽  
Andy D. Perkins ◽  
Bindu Nanduri
Keyword(s):  
Machine Learning ◽  
Respiratory Disease ◽  
Lung Tissue ◽  
Bovine Respiratory Disease ◽  
Atp Synthesis ◽  
Parameter Tuning ◽  
Supervised Machine Learning ◽  
Type I ◽  
Linear Discriminant ◽  
Validation Parameters

AbstractBovine respiratory disease (BRD) is a multifactorial disease involving complex host immune interactions shaped by pathogenic agents and environmental factors. Advancements in RNA sequencing and associated analytical methods are improving our understanding of host response related to BRD pathophysiology. Supervised machine learning (ML) approaches present one such method for analyzing new and previously published transcriptome data to identify novel disease-associated genes and mechanisms. Our objective was to apply ML models to lung and immunological tissue datasets acquired from previous clinical BRD experiments to identify genes that classify disease with high accuracy. Raw mRNA sequencing reads from 151 bovine datasets (n = 123 BRD, n = 28 control) were downloaded from NCBI-GEO. Quality filtered reads were assembled in a HISAT2/Stringtie2 pipeline. Raw gene counts for ML analysis were normalized, transformed, and analyzed with MLSeq, utilizing six ML models. Cross-validation parameters (fivefold, repeated 10 times) were applied to 70% of the compiled datasets for ML model training and parameter tuning; optimized ML models were tested with the remaining 30%. Downstream analysis of significant genes identified by the top ML models, based on classification accuracy for each etiological association, was performed within WebGestalt and Reactome (FDR ≤ 0.05). Nearest shrunken centroid and Poisson linear discriminant analysis with power transformation models identified 154 and 195 significant genes for IBR and BRSV, respectively; from these genes, the two ML models discriminated IBR and BRSV with 100% accuracy compared to sham controls. Significant genes classified by the top ML models in IBR (154) and BRSV (195), but not BVDV (74), were related to type I interferon production and IL-8 secretion, specifically in lymphoid tissue and not homogenized lung tissue. Genes identified in Mannheimia haemolytica infections (97) were involved in activating classical and alternative pathways of complement. Novel findings, including expression of genes related to reduced mitochondrial oxygenation and ATP synthesis in consolidated lung tissue, were discovered. Genes identified in each analysis represent distinct genomic events relevant to understanding and predicting clinical BRD. Our analysis demonstrates the utility of ML with published datasets for discovering functional information to support the prediction and understanding of clinical BRD.

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