Complement Inhibition in Coronavirus Disease (COVID)-19: A Neglected Therapeutic Option

Stahel, Philip F.; Barnum, Scott R.

doi:10.3389/fimmu.2020.01661

Cited by 36 publications

(37 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[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. Respiratory viruses differentially modulate redox pathways, balancing lysis-enhanced virion proliferation and dual oxidase 2 (DUOX2)-derived reactive oxygen species (ROS)-induced interferon response.…”

Section: Discussionmentioning

confidence: 99%

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

Prescott¹

2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Prescott¹

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…These results indicate a highly specific immune response in periphery. Indeed, Stahel and Barnum (2020) pointed out the importance of the complement system in the pathogenesis of COVID-19. Our results support the need for further studies to uncover the exact mechanism of the complement system in COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic dysregulations associated with SARS-CoV-2 infection in human nasopharyngeal and peripheral blood mononuclear cells

Melo

Bhuiyan

Gatua

et al. 2020

Preprint

View full text Add to dashboard Cite

IntroductionOver 24 million people have been infected globally with the novel coronavirus, SARS-CoV-2, with more than 820,000 succumbing to the resulting COVID-19 disease as of the end of August 2020. The molecular mechanisms underlying the pathogenesis of the disease are not completely elucidated. Thus, we aim to understand host response to SARS-CoV-2 infection by comparing samples collected from two distinct compartments (infection site and blood), obtained from COVID-19 subjects and healthy controls.MethodsWe used two publicly available gene expression datasets generated via RNA sequencing in two different samples; nasopharyngeal swabs and peripheral blood mononuclear cells (PBMCs). We performed a differential gene expression analysis between COVID-19 subjects and healthy controls in the two datasets and then functionally profiled their differentially expressed genes (DEGs). The genes involved in innate immunity were also determined.ResultsWe found a clear difference in the host response to SARS-CoV-2 infection between the two sample groups. In COVID-19 subjects, the nasopharyngeal sample group indicated upregulation of genes involved in cytokine activity and interferon signalling pathway, as well as downregulation of genes involved in oxidative phosphorylation and viral transcription. Host response in COVID-19 subjects for the PBMC group, involved upregulation of genes involved in the complement system and immunoglobulin mediated immune response. CXCL13, GABRE, IFITM3 were upregulated and HSPA1B was downregulated in COVID-19 subjects in both sample groups.ConclusionOur results indicate the host response to SARS-CoV-2 is compartmentalized and suggests potential biomarkers of response to SARS-CoV-2 infection.HighlightsTranscriptomic profiling from publicly available RNA-seq count data revealed a site-specific immune response in COVID-19.Host response was found cellular-mediated in nasopharyngeal samples and humoral-mediated in PBMCs samples.CXCL13, GABRE and IFITM3 commonly upregulated and HSPA1B downregulated in both sample groups highlights the potential of these molecules as markers of response to SARS-CoV-2 infection.

show abstract

“…Recently, the complement system has been shown to also be of importance in SARS-CoV-induced ARDS ( 24 , 49 ). A seminal murine study on SARS-CoV-infected mice proved the activation of the complement cascade already during the first post-infection day ( 50 ).…”

Section: Coronavirus Morphopathologymentioning

confidence: 99%

Inflammation, Thrombosis, and Destruction: The Three-Headed Cerberus of Trauma- and SARS-CoV-2-Induced ARDS

2020

View full text Add to dashboard Cite

Physical trauma can be considered an unrecognized "pandemic" because it can occur anywhere and affect anyone and represents a global burden. Following severe tissue trauma, patients frequently develop acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS) despite modern surgical and intensive care concepts. The underlying complex pathophysiology of life-threatening ALI/ARDS has been intensively studied in experimental and clinical settings. However, currently, the coronavirus family has become the focus of ALI/ ARDS research because it represents an emerging global public health threat. The clinical presentation of the infection is highly heterogeneous, varying from a lack of symptoms to multiple organ dysfunction and mortality. In a particular subset of patients, the primary infection progresses rapidly to ALI and ARDS. The pathophysiological mechanisms triggering and driving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)induced ALI/ARDS are still poorly understood. Although it is also generally unknown whether insights from trauma-induced ARDS may be readily translated to SARS-CoV-2-associated ARDS, it was still recommended to treat coronavirus-positive patients with ALI/ARDS with standard protocols for ALI/ARDS. However, this strategy was questioned by clinical scientists, because it was documented that some severely hypoxic SARS-CoV-2-infected patients exhibited a normal respiratory system compliance, a phenomenon rarely observed in ARDS patients with another underlying etiology. Therefore, coronavirus-induced ARDS was defined as a specific ARDS phenotype, which accordingly requires an adjusted therapeutic approach. These suggestions reflect previous attempts of classifying ARDS into different phenotypes that might overall facilitate ARDS diagnosis and treatment. Based on the clinical data from ARDS patients, two major phenotypes have been proposed: hyperand hypo-inflammatory. Here, we provide a comparative review of the pathophysiological pathway of trauma-/hemorrhagic shock-induced ARDS and coronavirus-induced ARDS, with an emphasis on the crucial key points in the pathogenesis of both these ARDS forms. Therefore, the manifold available data on trauma-/hemorrhagic shock-induced ARDS may help to better understand coronavirus-induced ARDS.

show abstract

Complement Inhibition in Coronavirus Disease (COVID)-19: A Neglected Therapeutic Option

Cited by 36 publications

References 38 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

Transcriptomic dysregulations associated with SARS-CoV-2 infection in human nasopharyngeal and peripheral blood mononuclear cells

Inflammation, Thrombosis, and Destruction: The Three-Headed Cerberus of Trauma- and SARS-CoV-2-Induced ARDS

Contact Info

Product

Resources

About