Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19

Narasaraju, Teluguakula; Tang, Benjamin; Herrmann, Martin; Muller, Sylviane; Chow, Vincent; Radic, Marko

doi:10.3389/fphar.2020.00870

Cited by 109 publications

(95 citation statements)

References 87 publications

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“…[171][172][173] Neutrophilia and NET-associated host damage are known to occur in severe SARS-CoV-2 infection, so inhibitors of the pathway are currently in clinical trials: histone citrullination, neutrophil elastase, and gasdermin D inhibitors to prevent release and DNases to degrade chromatin after release. [174,175] Complement inhibition would likely similarly reduce the risks of hypercoagulability and other immune-mediated inflammation associated with COVID-19, but effects may vary widely between sexes and ages. [176,177] Redox-active centers including proteins involved in selenocysteine synthesis are additionally depleted in cleavages likely because of their involvement in avoiding cell death and innate immune response.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 3CLpro whole human proteome cleavage prediction and enrichment/depletion analysis

Prescott¹

2020

Preprint

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A novel coronavirus (SARS-CoV-2) has devastated the globe as a pandemic that has killed more than 800,000 people. Effective and widespread vaccination is still uncertain, so many scientific efforts have been directed towards discovering antiviral treatments. Many drugs are being investigated to inhibit the coronavirus main protease, 3CLpro, from cleaving its viral polyprotein, but few publications have addressed this protease's interactions with the host proteome or their probable contribution to virulence. Too few host protein cleavages have been experimentally verified to fully understand 3CLpro's global effects on relevant cellular pathways and tissues. Here, we set out to determine this protease's targets and corresponding potential drug targets. Using a neural network trained on coronavirus proteomes with a Matthews correlation coefficient of 0.983, we predict that a large proportion of the human proteome is vulnerable to 3CLpro, with 4,460 out of approximately 20,000 human proteins containing at least one predicted cleavage site. These cleavages are nonrandomly distributed and are enriched in the epithelium along the respiratory tract, brain, testis, plasma, and immune tissues and depleted in olfactory and gustatory receptors despite the prevalence of anosmia and ageusia in COVID-19 patients. Affected cellular pathways include cytoskeleton/motor/cell adhesion proteins, nuclear condensation and other epigenetics, host transcription and RNAi, coagulation, pattern recognition receptors, growth factor, lipoproteins, redox, ubiquitination, and apoptosis. This whole proteome cleavage prediction demonstrates the importance of 3CLpro in expected and nontrivial pathways affecting virulence, lead us to propose more than a dozen potential therapeutic targets against coronaviruses, and should therefore be applied to all viral proteases and experimentally verified.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 3CLpro whole human proteome cleavage prediction and enrichment/depletion analysis

Prescott¹

2020

Preprint

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“…Systemic viral infections are usually accompanied by lymphocytosis, which is the effect of the increase in the pool of T CD8+ lymphocytes specific for the antigen. However, when it comes to COVID-19, a reduction in the number of lymphocytes along with neutrophilia is observed [ 11 ]. Increased production of transforming growth factor β (TGF-β), which has strong immunosuppressive activity, may be the cause of lymphopenia.…”

Section: Immunopathogenesis Of Covid-19mentioning

confidence: 99%

Significance of NETs Formation in COVID-19

Janiuk

Jabłońska

Garley

2021

Cells

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Severe contagious respiratory disease—COVID-19—caused by the SARS-CoV-2 coronavirus, can lead to fatal respiratory failure associated with an excessive inflammatory response. Infiltration and spread of SARS-CoV-2 are based on the interaction between the virus’ structural protein S and the cell’s receptor–angiotensin-converting enzyme 2 (ACE2), with the simultaneous involvement of human trans-membrane protease, serine 2 (TMPRSS2). Many scientific reports stress the importance of elevated recruitment and activity of neutrophils, which can form extracellular neutrophil traps (NETs) playing a significant role in the mechanism of combating pathogens, in the pathogenesis of COVID-19. Excessive generation of NETs during prolonged periods of inflammation predisposes for the occurrence of undesirable reactions including thromboembolic complications and damage to surrounding tissues and organs. Within the present manuscript, we draw attention to the impact of NET generation on the severe course of COVID-19 in patients with concurrent cardiovascular and metabolic diseases. Additionally, we indicate the necessity to explore not only the cellular but also the molecular bases of COVID-19 pathogenesis, which may aid the development of dedicated therapies meant to improve chances for the successful treatment of patients. We also present new directions of research into medications that display NETs formation regulatory properties as potential significant therapeutic strategies in the progress of COVID-19.

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“…AZD5069 ( Nicholls et al, 2015 ; Cullberg et al, 2018 ), danirixin ( Madan et al, 2019 ; Lazaar et al, 2020 ), and navarixin (SCH527123) ( Holz et al, 2010 ; Todd et al, 2016 ) are available CXCR2 inhibitors that ameliorate neutrophil activation in pulmonary diseases including bronchiectasis, virus-associated lung infection, COPD and asthma. Therefore, they may represent valuable drugs for the treatment of ARDS in COVID-19 patients ( Narasaraju et al, 2020 ). However, the development of the CXCR2 antagonist QBM076 was terminated for safety reasons (NCT01972776).…”

Section: Drugs Targeting Neutrophils For Covid-19 Associated Ardsmentioning

confidence: 99%

Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease

et al. 2020

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This review describes targeting neutrophils as a potential therapeutic strategy for acute respiratory distress syndrome (ARDS) associated with coronavirus disease 2019 (COVID-19), a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neutrophil counts are significantly elevated in patients with COVID-19 and significantly correlated with disease severity. The neutrophil-to-lymphocyte ratio can serve as a clinical marker for predicting fatal complications related to ARDS in patients with COVID-19. Neutrophil-associated inflammation plays a critical pathogenic role in ARDS. The effector functions of neutrophils, acting as respiratory burst oxidants, granule proteases, and neutrophil extracellular traps, are linked to the pathogenesis of ARDS. Hence, neutrophils can not only be used as pathogenic markers but also as candidate drug targets for COVID-19 associated ARDS.

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Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19

Cited by 109 publications

References 87 publications

SARS-CoV-2 3CLpro whole human proteome cleavage prediction and enrichment/depletion analysis

SARS-CoV-2 3CLpro whole human proteome cleavage prediction and enrichment/depletion analysis

Significance of NETs Formation in COVID-19

Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease

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