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

In the present work we propose a dynamical mathematical model of the lung cells inflammation process in response to SARS-CoV-2 infection. In this scenario the main protease Nsp5 enhances the inflammatory process, increasing the levels of NF kB, IL-6, Cox2, and PGE2 with respect to a reference state without the virus. In presence of the virus the translation rates of NF kB and IkB arise to a high constant value, and when the translation rate of IL-6 also increases above the threshold value of 7 pg mL−1 s−1 the model predicts a persistent over stimulated immune state with high levels of the cytokine IL-6. Our model shows how such over stimulated immune state becomes autonomous of the signals from other immune cells such as macrophages and lymphocytes, and does not shut down by itself. We also show that in the context of the dynamical model presented here, Dexamethasone or Nimesulide have little effect on such inflammation state of the infected lung cell, and the only form to suppress it is with the inhibition of the activity of the viral protein Nsp5. To that end, our model suggest that drugs like Saquinavir may be useful. In this form, our model suggests that Nsp5 is effectively a central node underlying the severe acute lung inflammation during SARS-CoV-2 infection. The persistent production of IL-6 by lung cells can be one of the causes of the cytokine storm observed in critical patients with COVID19. Nsp5 seems to be the switch to start inflammation, the consequent overproduction of the ACE2 receptor, and an important underlying cause of the most severe cases of COVID19.

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SARS-CoV-2 Nsp5 Protein Causes Acute Lung Inflammation: A Dynamical Mathematical Model

10.20944/preprints202012.0749.v2 ◽

2021 ◽

Author(s):

José Díaz ◽

Elena R. Álvarez-Buylla ◽

Antonio Bensussen

Keyword(s):

Mathematical Model ◽

Lung Inflammation ◽

Threshold Value ◽

Lung Cells ◽

Acute Lung Inflammation ◽

Translation Rate ◽

Immune State ◽

Central Node ◽

Main Protease ◽

Critical Patients

In the present work we propose a dynamical mathematical model of the lung cells inflammation process in response to SARS-CoV-2 infection. In this scenario the main protease Nsp5 enhances the inflammatory process, increasing the levels of NF kB, IL-6, Cox2, and PGE2 with respect to a reference state without the virus. In presence of the virus the translation rates of NF kB and IkB arise to a high constant value, and when the translation rate of IL-6 also increases above the threshold value of 7 pg mL-1 s-1 the model predicts a persistent over stimulated immune state with high levels of the cytokine IL-6. Our model shows how such over stimulated immune state becomes autonomous of the signals from other immune cells such as macrophages and lymphocytes, and does not shut down by itself. We also show that in the context of the dynamical model presented here, Dexamethasone or Nimesulide have little effect on such inflammation state of the infected lung cell, and the only form to suppress it is with the inhibition of the activity of the viral protein Nsp5.To that end, our model suggest that drugs like Saquinavir may be useful. In this form, our model suggests that Nsp5 is effectively a central node underlying the severe acute lung inflammation during SARS-CoV-2 infection. The persistent production of IL-6 by lung cells can be one of the causes of the cytokine storm observed in critical patients with COVID19. Nsp5 seems to be the switch to start inflammation, the consequent overproduction of the ACE2 receptor, and an important underlying cause of the most severe cases of COVID19.

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SARS-CoV-2 Nsp5 Protein Causes Acute Lung Inflammation: A Mathematical Model

10.20944/preprints202012.0749.v1 ◽

2020 ◽

Author(s):

José Díaz ◽

Elena R. Álvarez-Buylla ◽

Antonio Bensussen

Keyword(s):

Mathematical Model ◽

Lung Inflammation ◽

Threshold Value ◽

Point Of View ◽

Lung Cells ◽

Acute Lung Inflammation ◽

Translation Rate ◽

Immune State ◽

Critical Patients ◽

Nf Kappab

In the present work we propose a mathematical model of the process of inflammation in lung cells in response to SARS-CoV-2 infection from which a plausible scenario for the dynamics of this process arise. In this scenario the main protease Nsp5 enhances the inflammatory process, increasing the levels of NF kappaB, IL-6, Cox2, and PGE2 with respect to a reference state without the virus. When in presence of the virus the translation rates of NF kappaB and IkB are increased to a high constant value, and the translation rate of IL-6 is increased above the threshold value of 7 nM s-1, the model predicts a persistent over stimulated immune state with high levels of the cytokine IL-6. This over stimulated immune state becomes autonomous of the signals from other immune cells like macrophages and lymphocytes, and does not shut down by itself. Dexamethasone or Nimesulide have little effect on this state of the infected lung cell, and the only form to suppress it is with the inhibition of the activity of the viral protein Nsp5 with drugs like Saquinavir. In this form, our model suggests that Nsp5 is effectively the cause of the severe acute lung inflammation during SARS-CoV-2 infection. The persistent production of IL-6 by lung cells can be one of the causes of the cytokine storm observed in critical patients with COVID19. From an evolutive point of view, the use of Nsp5 as the switch to start inflammation, and the consequent overproduction of the ACE2 receptor, is the probable reason of the increased dangerousness of SARS-CoV-2 with respect to SARS-CoV.

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

10.21203/rs.3.rs-348638/v1 ◽

2021 ◽

Author(s):

Antonio Bensussen ◽

José Díaz ◽

Elena R. Álvarez Buylla

Keyword(s):

Mathematical Model ◽

Immune Cells ◽

Lung Inflammation ◽

Inflammatory Process ◽

Reference State ◽

Lung Cells ◽

Acute Lung Inflammation ◽

Immune State ◽

Main Protease ◽

External Signals

Abstract In the present work we propose a dynamical mathematical model of the lung cells inflammation process in response to SARS-CoV-2 infection. In this scenario, our model suggests that the main protease Nsp5 enhances the inflammatory process by increasing the levels of NF κB, IL-6, Cox2, and PGE2 with respect to a reference state without the virus. This overstimulated immune state becomes autonomous of the signals from other immune cells, and does not shut down by itself neither when the external signals are turned off. Our model suggests that Nsp5 is effectively the switch to start inflammation, the consequent overproduction of the ACE2 receptor, and an important underlying cause of the most severe cases of COVID19.

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Comparative docking of SARS-CoV-2 receptors antagonists from repurposing drugs

10.26434/chemrxiv.12044538.v4 ◽

2020 ◽

Author(s):

Micael Davi Lima de Oliveira ◽

Kelson Mota Teixeira de Oliveira

Keyword(s):

World Health Organisation ◽

World Health ◽

Lung Cells ◽

The Novel ◽

High Modulation ◽

Main Protease ◽

The World ◽

Novel Coronavirus ◽

Viral Receptors ◽

Theoretical Results

According to the World Health Organisation, until 16 June, 2020, the number of confirmed and notified cases of COVID-19 has already exceeded 7.9 million with approximately 434 thousand deaths worldwide. This research aimed to find repurposing antagonists, that may inhibit the activity of the main protease (Mpro) of the SARS-CoV-2 virus, as well as partially modulate the ACE2 receptors largely found in lung cells, and reduce viral replication by inhibiting Nsp12 RNA polymerase. Docking molecular simulations were performed among a total of 60 structures, most of all, published in the literature against the novel coronavirus. The theoretical results indicated that, in comparative terms, paritaprevir, ivermectin, ledipasvir, and simeprevir, are among the most theoretical promising drugs in remission of symptoms from the disease. Furthermore, also corroborate indinavir to the high modulation in viral receptors. The second group of promising drugs includes remdesivir and azithromycin. The repurposing drugs HCQ and chloroquine were not effective in comparative terms to other drugs, as monotherapies, against SARS-CoV-2 infection.

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Combined In Vitro and In Vivo Approaches to Propose a Putative Adverse Outcome Pathway for Acute Lung Inflammation Induced by Nanoparticles: A Study on Carbon Dots

Nanomaterials ◽

10.3390/nano11010180 ◽

2021 ◽

Vol 11 (1) ◽

pp. 180

Author(s):

Maud Weiss ◽

Jiahui Fan ◽

Mickaël Claudel ◽

Luc Lebeau ◽

Françoise Pons ◽

...

Keyword(s):

Carbon Dots ◽

Lung Inflammation ◽

Adverse Outcome ◽

Cellular Responses ◽

Target Cells ◽

Inflammasome Activation ◽

Adverse Outcome Pathway ◽

Acute Lung Inflammation

With the growth of nanotechnologies, concerns raised regarding the potential adverse effects of nanoparticles (NPs), especially on the respiratory tract. Adverse outcome pathways (AOP) have become recently the subject of intensive studies in order to get a better understanding of the mechanisms of NP toxicity, and hence hopefully predict the health risks associated with NP exposure. Herein, we propose a putative AOP for the lung toxicity of NPs using emerging nanomaterials called carbon dots (CDs), and in vivo and in vitro experimental approaches. We first investigated the effect of a single administration of CDs on mouse airways. We showed that CDs induce an acute lung inflammation and identified airway macrophages as target cells of CDs. Then, we studied the cellular responses induced by CDs in an in vitro model of macrophages. We observed that CDs are internalized by these cells (molecular initial event) and induce a series of key events, including loss of lysosomal integrity and mitochondrial disruption (organelle responses), as well as oxidative stress, inflammasome activation, inflammatory cytokine upregulation and macrophage death (cellular responses). All these effects triggering lung inflammation as tissular response may lead to acute lung injury.

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