Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium

AbstractCoronavirus disease 2019 (COVID-19) outcomes vary from asymptomatic infection to death. This disparity may reflect different airway levels of the SARS-CoV-2 receptor, ACE2, and the spike protein activator, TMPRSS2. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci (eQTL) for both ACE2 and TMPRSS2, that vary in frequency across world populations. Importantly, we find TMPRSS2 is part of a mucus secretory network, highly upregulated by T2 inflammation through the action of interleukin-13, and that interferon response to respiratory viruses highly upregulates ACE2 expression. Finally, we define airway responses to coronavirus infections in children, finding that these infections upregulate IL6 while also stimulating a more pronounced cytotoxic immune response relative to other respiratory viruses. Our results reveal mechanisms likely influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

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Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium

Nature Communications ◽

10.1038/s41467-020-18781-2 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 3

Author(s):

Satria P. Sajuthi ◽

Peter DeFord ◽

Yingchun Li ◽

Nathan D. Jackson ◽

Michael T. Montgomery ◽

...

Keyword(s):

Airway Epithelium ◽

Host Responses ◽

Interferon Response ◽

Host Proteins ◽

Factors Affecting ◽

Mediated Effects ◽

Emerging Virus ◽

Airway Responses

Abstract Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

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Autophagy is involved in adipogenic differentiation by repressesing proteasome-dependent PPARγ2 degradation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00640.2012 ◽

2013 ◽

Vol 305 (4) ◽

pp. E530-E539 ◽

Cited By ~ 46

Author(s):

Chongben Zhang ◽

Yingke He ◽

Mitsuhara Okutsu ◽

Lai Chun Ong ◽

Yi Jin ◽

...

Keyword(s):

High Fat Diet ◽

Animal Studies ◽

Adipogenic Differentiation ◽

Daily Injection ◽

Related Gene ◽

High Fat ◽

Pharmacological Interventions ◽

Diet Induced Obesity

Animal studies have shown that autophagy is essential in the process of obesity. Here, we performed daily injection of the autophagy inhibitor chloroquine (CQ) in mice and found that systemic administration of CQ blocks high-fat diet-induced obesity. To investigate the potential underlying molecular mechanism, we employed genetic and pharmacological interventions in cultured preadipocytes to investigate the role of autophagy in the control of the expression of the adipogenic regulator peroxisome proliferatior-activated receptor-γ (PPARγ). We show that adipogenic differentiation of 3T3-L1 preadipocytes is associated with activation of autophagy and increased PPARγ2 protein level. Treatment with CQ, shRNA-mediated knockdown, or genetic engineering-induced deletion of autophagy-related gene 5 (Atg5) promoted proteasome-dependent PPARγ2 degradation and attenuated adipogenic differentiation. Therefore, activated autophagy increases PPARγ2 stability and promotes adipogenic differentiation, and inhibition of autophagy may prevent high-fat diet-induced obesity and the consequential type 2 diabetes.

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