scholarly journals Profiling transcription factor sub-networks in type I interferon signaling and in response to SARS-CoV-2 infection

2021 ◽  
Author(s):  
Chilakamarti V. Ramana
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Immune Modulation ◽  
Type I Interferon ◽  
Lung Epithelial Cells ◽  
Type I ◽  
Interferon Signaling ◽  
Lung Epithelial

AbstractType 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.

scholarly journals Lung Epithelial Regulation of BCL2 Related Protein A1 (BCL2A1) by Coronaviruses (SARS-CoV) and Type I Interferon Signaling

2021 ◽  
Author(s):  
Ramana Chilakamarti
Keyword(s):  
Epithelial Cells ◽  
Human Lung ◽  
Type I Interferon ◽  
Respiratory Viruses ◽  
Lung Epithelial Cells ◽  
Type I ◽  
Related Protein ◽  
Interferon Signaling ◽  
Lung Epithelial ◽  
Human Lung Epithelial Cells

Highly pathogenic respiratory viruses such as 1918 influenza (HIN1) and coronavirus (SARS-CoV-2) induce significant lung injury with diffuse alveolar damage, capillary leak, and extensive cell death resulting in acute respiratory distress syndrome (ARDS). Direct effects of the virus, as well as host immune response such as proinflammatory cytokine production, contribute to programmed cell death or apoptosis. Alveolar lung epithelial type II (AT2) cells play a major role in the clearance of respiratory viruses, secretion of surfactant proteins and antimicrobial substances into the bronchoalveolar fluid as well as repair of lung injury. Gene expression in AT2 cells is regulated in a tissue and cell-specific manner and in a temporal fashion. The availability of tissue and cell-specific RNA datasets in Human Protein Atlas led to the identification of localized expression patterns of BCL-2 family members such as BCL2 related protein A1 (BCL2A1) in AT2 cells and immune cells of the lung. BCL2A1 expression was regulated by multiple stimuli including Toll-like receptor (TLR) ligands, interferons (IFNs), inflammatory cytokines, and inhibited by the steroid dexamethasone. In this study, regulation of BCL2A1 gene expression in human lung epithelial cells by several respiratory viruses and type I interferon signaling was investigated. SARS-CoV-2 infection significantly induced BCL2A1 expression in human lung epithelial cells within 24 hours that required the expression of Angiotensin-converting enzyme 2 (ACE2). BCL2A1 mRNA induction by SARS-CoV-2 was correlated with the induced expression of IFN-β and IFN-regulated transcription factor mRNA. BCL2A1 was induced by IFN-β treatment or by infection with influenza virus lacking the non-structural protein1(NS1) in NHBE cells. Furthermore, bioinformatics revealed that a subset of BCL-2 family members involved in the control of apoptosis and transcription such as BCL2A1, BCL2L14, BCL3, and BCL6 were regulated in the lung epithelial cells by coronaviruses and in the lung tissue samples of COVID-19 patients. Transcriptomic data also suggested that these genes were differentially regulated by the steroid drug dexamethasone.

scholarly journals Regulation of Lysosome-Associated Membrane Protein 3 (LAMP3) in Lung Epithelial Cells by Coronaviruses (SARS-CoV-1/2) and Type I Interferon Signaling

2021 ◽  
Author(s):  
Chilakamarti V. Ramana
Keyword(s):  
Epithelial Cells ◽  
Viral Entry ◽  
Human Lung ◽  
Type I Interferon ◽  
Respiratory Viruses ◽  
Lung Epithelial Cells ◽  
Type I ◽  
Type Ii ◽  
Interferon Signaling ◽  
Lung Epithelial

AbstractSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major risk factor for mortality and morbidity in critical care hospitals around the world. Lung epithelial type II cells play a major role in several physiological processes, including recognition and clearance of respiratory viruses as well as repair of lung injury in response to environmental toxicants. Gene expression profiling of lung epithelial type II-specific genes led to the identification of lysosomal-associated membrane protein 3 (LAMP3). Intracellular locations of LAMP3 include plasma membrane, endosomes, and lysosomes. These intracellular organelles are involved in vesicular transport and facilitate viral entry and release of the viral RNA into the host cell cytoplasm. In this study, regulation of LAMP3 expression in human lung epithelial cells by several respiratory viruses and type I interferon signaling was investigated. Coronaviruses including SARS-CoV-1 and SARS-CoV-2 significantly induced LAMP3 expression in lung epithelial cells within 24 hours after infection that required the presence of ACE2 viral entry receptor. Time-course experiments revealed that the induced expression of LAMP3 by SARS-CoV-2 was correlated with the induced expression of interferon-beta1 (IFNB1) and signal transducers and activator of transcription 1 (STAT1) mRNA levels. LAMP3 was also induced by direct IFN-beta treatment or by infection with influenza virus lacking the non-structural protein1(NS1) in NHBE bronchial epithelial cells. LAMP3 expression was induced in human lung epithelial cells by several respiratory viruses, including respiratory syncytial virus (RSV) and the human parainfluenza virus 3 (HPIV3). Location in lysosomes and endosomes as well as induction by respiratory viruses and type I Interferon suggests that LAMP3 may have an important role in inter-organellar regulation of innate immunity and a potential target for therapeutic modulation in health and disease. Furthermore, bioinformatics revealed that a subset of lung type II cell genes were differentially regulated in the lungs of COVID-19 patients.

scholarly journals Defining the Role of Type I Interferon Signaling in the Increased Accumulation of Versican in Lungs of Mice Exposed to Influenza Infection

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Jourdan Brune ◽  
Mary Chang ◽  
Jessica Felgenhauer ◽  
Brian Johnson ◽  
Megan Larmore ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Influenza Infection ◽  
Type I ◽  
Interferon Signaling

scholarly journals IL-35 subunit EBI3 alleviates bleomycin-induced pulmonary fibrosis via suppressing DNA enrichment of STAT3

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Donghong Chen ◽  
Guofeng Zheng ◽  
Qing Yang ◽  
Le Luo ◽  
Jinglian Shen
Keyword(s):  
Gene Expression ◽  
Pulmonary Fibrosis ◽  
Regulatory Mechanism ◽  
Lung Epithelial Cells ◽  
Wild Type ◽  
Qrt Pcr ◽  
Lung Epithelial ◽  
Gene Expression Analyses ◽  
Human And Mouse

Abstract Background IL-35 subunit EBI3 is up-regulated in pulmonary fibrosis tissues. In this study, we investigated the pathological role of EBI3 in pulmonary fibrosis and dissected the underlying molecular mechanism. Methods Bleomycin-induced pulmonary fibrosis mouse model was established, and samples were performed gene expression analyses through RNAseq, qRT-PCR and Western blot. Wild type and EBI3 knockout mice were exposed to bleomycin to investigate the pathological role of IL-35, via lung function and gene expression analyses. Primary lung epithelial cells were used to dissect the regulatory mechanism of EBI3 on STAT1/STAT4 and STAT3. Results IL-35 was elevated in both human and mouse with pulmonary fibrosis. EBI3 knockdown aggravated the symptoms of pulmonary fibrosis in mice. EBI3 deficiency enhanced the expressions of fibrotic and extracellular matrix-associated genes. Mechanistically, IL-35 activated STAT1 and STAT4, which in turn suppressed DNA enrichment of STAT3 and inhibited the fibrosis process. Conclusion IL-35 might be one of the potential therapeutic targets for bleomycin-induced pulmonary fibrosis.

scholarly journals Mouse Model of SARS-CoV-2 Reveals Inflammatory Role of Type I Interferon Signaling

2020 ◽  
Author(s):  
Benjamin Goldman-Israelow ◽  
Eric Song ◽  
Tianyang Mao ◽  
Peiwen Lu ◽  
Amit Meir ◽  
...  
Keyword(s):  
Mouse Model ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Signaling

scholarly journals Role of the Intracellular Domain of the Human Type I Interferon Receptor 2 Chain (IFNAR2c) in Interferon Signaling

2000 ◽  
Vol 275 (31) ◽  
pp. 23981-23985 ◽  
Author(s):  
Dean Russell-Harde ◽  
T. Charis Wagner ◽  
M. R. Sandhya Rani ◽  
David Vogel ◽  
Oscar Colamonici ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Type I ◽  
Interferon Signaling ◽  
Intracellular Domain ◽  
Human Type ◽  
Interferon Receptor

scholarly journals Role of p38α Map Kinase in Type I Interferon Signaling

2003 ◽  
Vol 279 (2) ◽  
pp. 970-979 ◽  
Author(s):  
Yongzhong Li ◽  
Antonella Sassano ◽  
Beata Majchrzak ◽  
Dilip K. Deb ◽  
David E. Levy ◽  
...  
Keyword(s):  
Map Kinase ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Signaling ◽  
P38α Map Kinase

scholarly journals Role of NLRs in the Regulation of Type I Interferon Signaling, Host Defense and Tolerance to Inflammation

2021 ◽  
Vol 22 (3) ◽  
pp. 1301
Author(s):  
Ioannis Kienes ◽  
Tanja Weidl ◽  
Nora Mirza ◽  
Mathias Chamaillard ◽  
Thomas A. Kufer
Keyword(s):  
Viral Infections ◽  
Type I Interferon ◽  
Tissue Injury ◽  
Interferon Response ◽  
Type I ◽  
Interferon Signaling ◽  
Microbial Products ◽  
Interferon Responses

Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection.

Sign in / Sign up

Export Citation Format

Share Document