Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor–κB and characterized by increased tumor necrosis factor–α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.

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Genetic relationships between A20/TNFAIP3, chronic inflammation and autoimmune disease

Biochemical Society Transactions ◽

10.1042/bst0391086 ◽

2011 ◽

Vol 39 (4) ◽

pp. 1086-1091 ◽

Cited By ~ 69

Author(s):

Lars Vereecke ◽

Rudi Beyaert ◽

Geert van Loo

Keyword(s):

Chronic Inflammation ◽

Inflammatory Responses ◽

Genetic Relationships ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Regulatory Factor ◽

Genomic Locus ◽

Autoimmune Pathology ◽

Factor Α ◽

Necrosis Factor

A20 [also known as TNFAIP3 (tumour necrosis factor α-induced protein 3)] restricts and terminates inflammatory responses through modulation of the ubiquitination status of central components in NF-κB (nuclear factor κB), IRF3 (interferon regulatory factor 3) and apoptosis signalling cascades. The phenotype of mice with full or conditional A20 deletion illustrates that A20 expression is essential to prevent chronic inflammation and autoimmune pathology. In addition, polymorphisms within the A20 genomic locus have been associated with multiple inflammatory and autoimmune disorders, including SLE (systemic lupus erythaematosis), RA (rheumatoid arthritis), Crohn's disease and psoriasis. A20 has also been implicated as a tumour suppressor in several subsets of B-cell lymphomas. The present review outlines recent findings that illustrate the effect of A20 defects in disease pathogenesis and summarizes the identified A20 polymorphisms associated with different immunopathologies.

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Impaired type I interferon activity and exacerbated inflammatory responses in severe Covid-19 patients

10.1101/2020.04.19.20068015 ◽

2020 ◽

Cited By ~ 70

Author(s):

Jérôme Hadjadj ◽

Nader Yatim ◽

Laura Barnabei ◽

Aurélien Corneau ◽

Jeremy Boussier ◽

...

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Responses ◽

High Risk Population ◽

Type I ◽

Interferon Stimulated Genes ◽

Tnf Α ◽

Interferon Activity ◽

Anti Inflammatory ◽

Global Threat ◽

Necrosis Factor

AbstractBackgroundCoronavirus disease 2019 (Covid-19) is a major global threat that has already caused more than 100,000 deaths worldwide. It is characterized by distinct patterns of disease progression implying a diverse host immune response. However, the immunological features and molecular mechanisms involved in Covid-19 severity remain so far poorly known.MethodsWe performed an integrated immune analysis that included in-depth phenotypical profiling of immune cells, whole-blood transcriptomic and cytokine quantification on a cohort of fifty Covid19 patients with a spectrum of disease severity. All patient were tested 8 to 12 days following first symptoms and in absence of anti-inflammatory therapy.ResultsA unique phenotype in severe and critically ill patients was identified. It consists in a profoundly impaired interferon (IFN) type I response characterized by a low interferon production and activity, with consequent downregulation of interferon-stimulated genes. This was associated with a persistent blood virus load and an exacerbated inflammatory response that was partially driven by the transcriptional factor NFĸB. It was also characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling as well as increased innate immune chemokines.ConclusionWe propose that type-I IFN deficiency in the blood is a hallmark of severe Covid-19 and could identify and define a high-risk population. Our study provides a rationale for testing IFN administration combined with adapted anti-inflammatory therapy targeting IL-6 or TNF-α in most severe patients. These data also raise concern for utilization of drugs that interfere with the IFN pathway.

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Synergistic induction of nuclear factor-κB by transforming growth factor-β and tumour necrosis factor-α is mediated by protein kinase A-dependent RelA acetylation

Biochemical Journal ◽

10.1042/bj20080781 ◽

2008 ◽

Vol 417 (2) ◽

pp. 583-591 ◽

Cited By ~ 20

Author(s):

Hajime Ishinaga ◽

Hirofumi Jono ◽

Jae Hyang Lim ◽

Kensei Komatsu ◽

Xiangbin Xu ◽

...

Keyword(s):

Transforming Growth Factor ◽

Inflammatory Responses ◽

Transforming Growth Factor Β ◽

Nuclear Factor Κb ◽

Binding Activity ◽

Dna Binding Activity ◽

Tnf Α ◽

Factor Α ◽

Tgf Β1 ◽

Necrosis Factor

The TGF-β (transforming growth factor-β) pathway represents an important signalling pathway involved in regulating diverse biological processes, including cell proliferation, differentiation and inflammation. Despite the critical role for TGF-β in inflammatory responses, its role in regulating NF-κB (nuclear factor-κB)-dependent inflammatory responses still remains unknown. In the present study we show that TGF-β1 synergizes with proinflammatory cytokine TNF-α (tumour necrosis factor-α) to induce NF-κB activation and the resultant inflammatory response in vitro and in vivo. TGF-β1 synergistically enhances TNF-α-induced NF-κB DNA binding activity via induction of RelA acetylation. Moreover, synergistic enhancement of TNF-α-induced RelA acetylation and DNA-binding activity by TGF-β1 is mediated by PKA (protein kinase A). Thus the present study reveals a novel role for TGF-β in inflammatory responses and provides new insight into the regulation of NF-κB by TGF-β signalling.

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