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 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.
Highlights
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus is an intracellular infectious agent whose replication cycle depends on the host’s cell structures and functions
We propose a dynamical mathematical model that suggests that the three feedback loops mentioned above constitute a minimal circuit for the inflammatory process in the epithelial lung cells during SARS-CoV-2 infection (Figure 2), and we use an ordinary differential equations (ODEs) continuous model to explore the effect of Nsp5 in the qualitative dynamics of this circuit in which this viral protein acts as an enhancing perturbation in the phase space of this dynamical system (Díaz, 2020b) (Figure 2)
In the case of the ODEs κB, Cyclooxygenase 2 (Cox2), and prostaglandin E2 (PGE2), the concentration of Interleukin 6 (IL-6) is lower than is absence of the virus. (D) In the over stimulated immune state (OSIS), the presence of Nsp5 produces an enhanced production of Nuclear Factor κB (NF κB), Cox 2, PGE2 and IL-5
Summary
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus is an intracellular infectious agent whose replication cycle depends on the host’s cell structures and functions. It uses the translational apparatus of different types of infected cells to express its proteins (Nakagawa et al, 2016). SARS-CoV-2 causes the Coronavirus Disease 2019 (COVID19) that has infected over 241, 000, 000 persons and killed over 4,900,000 worldwide since the end of 2019. No specific and effective therapeutic drugs to defeat SARS-CoV-2 infection have been developed yet (Díaz, 2020a), several effective vaccines have been developed and are being applied. It is necessary to continue the search for effective therapeutic agents that complement the use of vaccines, to minimize the risk of death from COVID19.
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