SARS CoV 2 Nsp5 Protein Causes Acute Lung Inflammation, a Dynamical Mathematical Model

Bensussen, Antonio; Díaz, José Garres; Buylla, Elena R. Álvarez

doi:10.21203/rs.3.rs-348638/v1

Cited by 2 publications

(2 citation statements)

References 46 publications

(86 reference statements)

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“…Indeed, epigenetic changes consistent with HDAC2 activity drives the cytokine storm that is responsible for much of the pathology seen in SARS-CoV-2 patients, with the degree of epigenetic change correlated to disease severity [44,[95][96][97]. NSP5 is thought to drive much of the cytokine response in the infected lung via HDAC2, and indeed, HDAC2 is required for the upregulation of many pro-inflammatory molecules in endothelial and myeloid cells undergoing SARS-CoV-2 infection [98][99][100]. HDAC inhibitors exhibit potent anti-inflammatory effects and therefore may antagonize many of the inflammatory pathways activated by SARS-CoV-2 [101,102].…”

Section: Discussionmentioning

confidence: 99%

SARS-COV-2 NSP5 Antagonizes MHC II Expresion by Subverting Histone Deacetylase 2

Taefehshokr

Lac

Vrieze

et al. 2023

Preprint

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The clearance of SARS-CoV-2 requires a multi-faceted immune response that is initiated by innate immune cells, with infection ultimately resolved by adaptive immune mechanisms. Induction of adaptive immunity to SARS-CoV-2 is dependent on the presentation of viral antigens on MHC II by professional antigen presenting cells such as dendritic cells and macrophages, to induce robust activation of CD4+ T cells. SARS-CoV-2 interferes with antigen presentation by downregulating MHC II on the antigen presenting cells of COVID-19 patients, but the molecular mechanism mediating this process is unelucidated. In this study, analysis of protein and gene expression in human antigen presenting cells reveals that the expression of MHC II is inhibited by the SARS-CoV-2 main protease, NSP5. Suppression of MHC II expression occurs via downregulation of the transcription factor CIITA, which is required for MHC II expression. This downregulation of CIITA is independent of NSP5's proteolytic activity, and rather, NSP5 delivers HDAC2 to the CIITA promoter via interactions with IRF3, Here, HDAC2 deacetylates and inactivates the CIITA promoter. This loss of CIITA expression prevents further expression of MHC II, with this suppression alleviated by ectopic expression of CIITA or knockdown of HDAC2. These results identify a novel mechanism by which SARS-CoV-2 can limit antigen presentation on MHC II, thereby delaying or weakening the subsequent adaptive immune response.

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Section: Discussionmentioning

confidence: 99%

SARS-COV-2 NSP5 Antagonizes MHC II Expresion by Subverting Histone Deacetylase 2

Taefehshokr

Lac

Vrieze

et al. 2023

Preprint

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“…The code used for each stochastic model presented in this work is available at the ZENODO repository ( 28 ).…”

Section: Methodsmentioning

confidence: 99%

Molecular tracking of insulin resistance and inflammation development on visceral adipose tissue

2023

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BackgroundVisceral adipose tissue (VAT) is one of the most important sources of proinflammatory molecules in obese people and it conditions the appearance of insulin resistance and diabetes. Thus, understanding the synergies between adipocytes and VAT-resident immune cells is essential for the treatment of insulin resistance and diabetes.MethodsWe collected information available on databases and specialized literature to construct regulatory networks of VAT resident cells, such as adipocytes, CD4+ T lymphocytes and macrophages. These networks were used to build stochastic models based on Markov chains to visualize phenotypic changes on VAT resident cells under several physiological contexts, including obesity and diabetes mellitus.ResultsStochastic models showed that in lean people, insulin produces inflammation in adipocytes as a homeostatic mechanism to downregulate glucose intake. However, when the VAT tolerance to inflammation is exceeded, adipocytes lose insulin sensitivity according to severity of the inflammatory condition. Molecularly, insulin resistance is initiated by inflammatory pathways and sustained by intracellular ceramide signaling. Furthermore, our data show that insulin resistance potentiates the effector response of immune cells, which suggests its role in the mechanism of nutrient redirection. Finally, our models show that insulin resistance cannot be inhibited by anti-inflammatory therapies alone.ConclusionInsulin resistance controls adipocyte glucose intake under homeostatic conditions. However, metabolic alterations such as obesity, enhances insulin resistance in adipocytes, redirecting nutrients to immune cells, permanently sustaining local inflammation in the VAT.

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SARS CoV 2 Nsp5 Protein Causes Acute Lung Inflammation, a Dynamical Mathematical Model

Cited by 2 publications

References 46 publications

SARS-COV-2 NSP5 Antagonizes MHC II Expresion by Subverting Histone Deacetylase 2

SARS-COV-2 NSP5 Antagonizes MHC II Expresion by Subverting Histone Deacetylase 2

Molecular tracking of insulin resistance and inflammation development on visceral adipose tissue

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