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Human Phenotype

Transmission

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antibody (1)

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    COVID-19: In the Eye of the Cytokine Storm

    Authors: Roberto de la Rica; Marcio Borges; Marta Gonzalez-Freire

    id:10.20944/preprints202005.0157.v1 Date: 2020-05-09 Source: Preprints.org

    The dysregulated release of cytokines has been identified as one of the key factors behind poorer outcomes in COVID-19. This ‘cytokine storm ‘produces an excessive inflammatory and immune response, especially in the lungs, leading to acute respiratory distress HP respiratory distress MESHD (ARDS), pulmonary edema HP pulmonary edema MESHD and multi-organ failure MESHD. Alleviating this inflammatory state is crucial to improve prognosis. Pro-inflammatory factors play a central role in COVID-19 severity, especially in patients with comorbidities In these situations, an overactive, untreated immune response can be deadly, suggesting that mortality in COVID-19 cases is likely due to this virally driven hyperinflammation. Administering immunomodulators has not yielded conclusive improvements in other pathologies characterized by dysregulated inflammation MESHD such as sepsis HP sepsis MESHD, SARS-CoV-1 and MERS. The success of these drugs at reducing COVID-19-driven inflammation MESHD is still anecdotal and comes with serious risks. It is also imperative to screen the elderly TRANS for risk factors that predispose them to severe COVID-19. Immunosenescence and comorbidities should be taken into consideration. In this review, we summarize the latest data available about the role of the cytokine storm in COVID-19 disease severity as well as potential therapeutic approaches to ameliorate it. We also examine the role of inflammation MESHD in other diseases often comorbid with COVID-19, such as aging, sepsis HP sepsis MESHD, and pulmonary disorders MESHD. Finally, we identify gaps in our knowledge and suggest priorities for future research aimed at stratifying patients according to risk as well as personalizing therapies in the context of COVID19-driven hyperinflammation.

    Supramolecular Organization Predicts Protein Nanoparticle Delivery to Neutrophils for Acute Lung Inflammation MESHD Diagnosis and Treatment

    Authors: Jacob W Myerson; Priyal N Patel; Nahal Habibi; Landis R Walsh; Yi-Wei Lee; David C Luther; Laura T Ferguson; Michael H Zaleski; Marco E Zamora; Oscar A. Marcos-Contreras; Patrick M Glassman; Ian Johnston; Elizabeth D Hood; Tea Shuvaeva; Jason V Gregory; Raisa Y Kiseleva; Jia Nong; Kathryn M Rubey; Colin F Greineder; Samir Mitragotri; George S Worthen; Vincent M Rotello; Joerg Lahann; Vladimir R Muzykantov; Jacob S Brenner

    doi:10.1101/2020.04.15.037564 Date: 2020-04-18 Source: bioRxiv

    Acute lung inflammation MESHD has severe morbidity, as seen in COVID-19 patients. Lung inflammation MESHD is accompanied or led by massive accumulation of neutrophils in pulmonary capillaries ("margination"). We sought to identify nanostructural properties that predispose nanoparticles to accumulate in pulmonary marginated neutrophils, and therefore to target severely inflamed lungs. We designed a library of nanoparticles and conducted an in vivo screen of biodistributions in naive mice and mice treated with lipopolysaccharides. We found that supramolecular organization of protein in nanoparticles predicts uptake in inflamed lungs. Specifically, nanoparticles with agglutinated protein (NAPs) efficiently home to pulmonary neutrophils, while protein nanoparticles with symmetric structure (e.g. viral capsids) are ignored by pulmonary neutrophils. We validated this finding by engineering protein-conjugated liposomes that recapitulate NAP targeting to neutrophils in inflamed lungs. We show that NAPs can diagnose acute lung injury MESHD in SPECT imaging and that NAP-like liposomes can mitigate neutrophil extravasation and pulmonary edema HP pulmonary edema MESHD arising in lung inflammation MESHD. Finally, we demonstrate that ischemic MESHD ex vivo human lungs selectively take up NAPs, illustrating translational potential. This work demonstrates that structure-dependent interactions with neutrophils can dramatically alter the biodistribution of nanoparticles, and NAPs have significant potential in detecting and treating respiratory conditions arising from injury or infections MESHD.

    Kinins and Cytokines in COVID-19: A Comprehensive Pathophysiological Approach

    Authors: Frank van de Veerdonk; Mihai G. Netea; Marcel van Deuren; Jos W.M. van der Meer; Quirijn de Mast; Roger J. Bruggemann; Hans van der Hoeven

    id:10.20944/preprints202004.0023.v1 Date: 2020-04-03 Source: Preprints.org

    Most striking observations in COVID-19 patients are the hints on pulmonary edema HP pulmonary edema MESHD (also seen on CT scans as ground glass opacities), dry cough MESHD cough HP, fluid restrictions to prevent more severe hypoxia MESHD, the huge PEEP that is needed while lungs are compliant, and the fact that anti-inflammatory therapies are not powerful enough to counter the severity of the disease. We propose that the severity of the disease and many deaths MESHD are due to a local vascular problem due to activation of B1 receptors on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2, a cell membrane bound molecule with enzymatic activity that next to its role in RAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the bradykinin receptor type 1 (B1). In contrast to bradykinin receptor 2 (B2), the B1 receptor on endothelial cells is upregulated by proinflammatory cytokines. Without ACE2 acting as a guardian to inactivate the ligands of B1, the lung environment is prone for local vascular leakage leading to angioedema HP angioedema MESHD. Angioedema HP Angioedema MESHD is likely a feature already early in disease, and might explain the typical CT scans and the feeling of people that they drown. In some patients, this is followed by a clinical worsening of disease around day 9 due to the formation antibodies SERO directed against the spike (S)-antigen of the corona-virus that binds to ACE2 that could contribute to disease by enhancement of local immune cell influx and proinflammatory cytokines leading to damage. In parallel, inflammation MESHD induces more B1 expression, and possibly via antibody SERO-dependent enhancement of viral infection MESHD leading to continued ACE2 dysfunction in the lung because of persistence of the virus. In this viewpoint we propose that a bradykinin-dependent local lung angioedema HP angioedema MESHD via B1 and B2 receptors is an important feature of COVID-19, resulting in a very high number of ICU admissions. We propose that blocking the B1 and B2 receptors might have an ameliorating effect on disease caused by COVID-19. This kinin-dependent pulmonary edema HP pulmonary edema MESHD is resistant to corticosteroids or adrenaline and should be targeted as long as the virus is present. In addition, this pathway might indirectly be responsive to anti-inflammatory agents or neutralizing strategies for the anti-S- antibody SERO induced effects, but by itself is likely to be insufficient MESHD to reverse all the pulmonary edema HP pulmonary edema MESHD. Moreover, we provide a suggestion of how to ventilate in the ICU in the context of this hypothesis.

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