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

Cv, Ramana

doi:10.1101/2021.01.25.428122

Cited by 5 publications

(10 citation statements)

References 87 publications

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“…We have recently reported high levels of free (active) LIGHT in serum of COVID-19 patients and that these higher levels correlate with severity of disease 15 . These results were independently confirmed by Arunachalam et al 16 and others 17,18 . We therefore sought to assess the effectiveness of the human LIGHT neutralizing antibody, CERC-002, as a treatment for CRS and ARDS in COVID-19 patients.…”

Section: Introductionsupporting

confidence: 63%

CERC-002, a human anti-LIGHT mAb reduces respiratory failure and death in hospitalized COVID-19 ARDS patients

Anderson

et al. 2021

Preprint

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Background Severe COVID-19 infection is associated with dysregulated immune response which, in a substantial minority of patients, results in cytokine release syndrome (CRS) and acute respiratory distress syndrome (ARDS). Inhibition of cytokines or cytokine-associated signal transduction is a promising strategy to ameliorate ARDS associated with CRS. We and others have previously shown that serum free LIGHT (TNFSF14) levels are markedly elevated in patients with COVID-19 pneumonia/ARDS10,11, suggesting that LIGHT neutralization may offer therapeutic benefit to COVID-19 ARDS patients. Methods We conducted a randomized, double-blind, placebo-controlled, multi-center, proof-of-concept clinical trial of CERC-002 in adults with mild to moderate ARDS associated with COVID-19 (n=83). Enrolled patients received a single dose of CERC-002 or placebo, in addition to standard of care that included high dose corticosteroids. The primary efficacy endpoint was alive and free of respiratory failure status through Day 28. Secondary outcomes included alive status at Day 28, free of invasive ventilation through Day 28, and serum free LIGHT levels. Results In patients hospitalized with COVID-19 associated pneumonia and mild to moderate (ARDS), CERC-002 increased the rate of alive and free of respiratory failure status through Day 28 as compared to placebo (83.9% vs 64.5%; p=0.044). Efficacy was highest in the prespecified subgroup of patients 60 years old and older (76.5% vs 47.1%; p=0.042), the population most vulnerable to severe complications and death with COVID-19 infection. Through both the initial 28-day and 60-day follow-up periods, reductions of approximately 50% in mortality were observed for CERC-002 compared to placebo (7.7% vs 14.3% at Day 28 and 10.8% vs 22.5% at Day 60). Importantly, this improvement was incremental to standard of care including high dose steroids and remdesivir 88.0% and 57.8%, respectively). In addition, serum LIGHT levels but not IL-6 levels were markedly reduced in patients treated with CERC-002. Conclusions The data presented herein demonstrate that CERC-002 markedly reduces the risk of respiratory failure and death incremental to standard of care including high dose corticosteroids and reduces LIGHT levels in patients with COVID-19 ARDS. (ClinicalTrials.gov number NCT04412057).

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Section: Introductionsupporting

confidence: 63%

CERC-002, a human anti-LIGHT mAb reduces respiratory failure and death in hospitalized COVID-19 ARDS patients

Anderson

et al. 2021

Preprint

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“…There Stat1 homodimer binding to another regulatory element known as gamma-activated sequence (GAS) located near transcription start site (TSS) of interferon-stimulated genes (45). Transcription factor binding site data in the promoter region of LAMP3 revealed that there were no ISRE or GAS elements within the 1.5 Kb upstream of the transcription start site.…”

Section: Regulation Of Lamp3 Expression By Interferonsmentioning

confidence: 99%

“…Expression data in Interferon resource (Interferome) revealed that LAMP3 was regulated by type I and type II interferon but not type II interferon (data not shown). Transcriptional regulation by type 1 interferons is mediated by Stat, Stat2, and IRF9 trimeric complex binding to a regulatory element known as interferon-stimulated response element (ISRE) or Stat1 homodimer binding to another regulatory element known as gamma-activated sequence (GAS) located near transcription start site (TSS) of interferon-stimulated genes (45). Transcription factor binding site data in the promoter region of LAMP3 revealed that there were no ISRE or GAS elements within the 1.5 Kb upstream of the transcription start site.…”

Section: Regulation Of Lamp3 Expression By Interferonsmentioning

confidence: 99%

“…However, promoter analysis and chromatin immunoprecipitation experiments are required to confirm the role of interferon response elements and the binding of STAT proteins in LAMP3 gene regulation. Alternatively, novel regulatory elements and transcription factors may be involved in interferon regulation of LAMP3 gene (45). Bioinformatic analysis revealed that alterations in cell cycle and antiviral genes were responsible for a majority of cervical cancers and LAMP3 as a regulator of antiviral gene expression (46).…”

Section: Regulation Of Lamp3 Expression By Interferonsmentioning

confidence: 99%

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

Ramana

2021

Preprint

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Severe 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.

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“…In contrast, in NHBE bronchial epithelial cells IFN-β rapidly and transiently induced BCL2A1 mRNA levels within 4-6 hours and the levels declined by 12 hours (Figure 11A). Transcriptional regulation by type 1 interferons is mediated by STAT1, STAT2, and IRF9 binding to regulatory elements known as interferon-stimulated response element (ISRE) or STAT1 and STAT3 homo-or heterodimers binding to another regulatory element known as gamma-activated sequence (GAS) located near transcription start site (TSS) of interferon-stimulated genes (52,53).…”

Section: Regulation Of Bcl2a1 Expression By Type I Interferon Signalingmentioning

confidence: 99%

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

Ramana

2021

Preprint

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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.

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

Cited by 5 publications

References 87 publications

CERC-002, a human anti-LIGHT mAb reduces respiratory failure and death in hospitalized COVID-19 ARDS patients

CERC-002, a human anti-LIGHT mAb reduces respiratory failure and death in hospitalized COVID-19 ARDS patients

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

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

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