Early Differences in Cytokine Production by Severity of Coronavirus Disease 2019

Tjan, Lidya Handayani; Furukawa, Koichi; Nagano, Tatsuya; Kiriu, Tatsunori; Nishimura, Mitsuhiro; Arii, Jun; Hino, Yasuhisa; Iwata, Sachiyo; Nishimura, Yoshihiro; Mori, Yasuko

doi:10.1093/infdis/jiab005

Cited by 91 publications

(86 citation statements)

References 14 publications

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“…Likewise, we found increased up-regulation of the IL2 genes in vaccinated relative to unvaccinated macaques. A similar finding has been reported in humans where higher IL 2 levels distinguish mild/asymptomatic forms of COVID-19 disease from the moderate/severe forms [66]. Following viral challenge in our study (specifically, Day 5 to 7), we found down-regulation of IFNα2 genes in BAL cells recovered from vaccinated subjects relative to their unvaccinated controls.…”

Section: Discussionsupporting

confidence: 91%

A synthetic peptide CTL vaccine targeting nucleocapsid confers protection from SARS-CoV-2 challenge in rhesus macaques

Harris

Brasel

Massey

et al. 2021

Preprint

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BackgroundPersistent transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a COVID-19 pandemic. Several vaccines, evoking protective spike antibody responses, conceived in 2020, are being deployed in mass public health vaccination programs. Recent data suggests, however, that as sequence variation in the spike genome accumulates, some vaccines may lose efficacy.MethodsUsing a macaque model of SARS-CoV-2 infection, we tested the efficacy of a peptide-based vaccine targeting MHC Class I epitopes on the SARS-CoV-2 nucleocapsid protein. We administered biodegradable microspheres with synthetic peptides and adjuvants to rhesus macaques. Unvaccinated control and vaccinated macaques were challenged with 1 x 108 TCID50 units of SARS-CoV-2, followed by assessment of clinical symptoms, viral load, chest radiographs, sampling of peripheral blood and bronchoalveolar lavage (BAL) fluid for downstream analysis.ResultsVaccinated animals were free of pneumonia-like infiltrates characteristic of SARS-CoV-2 infection and presented with lower viral loads relative to controls. Gene expression in cells collected from BAL samples of vaccinated macaques revealed a unique signature associated with enhanced development of adaptive immune responses relative to control macaques.ConclusionsWe demonstrate that a room temperature stable peptide vaccine based on known immunogenic HLA Class I bound CTL epitopes from the nucleocapsid protein can provide protection against SARS-CoV-2 infection in non-human primates.Graphical Abstract

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Section: Discussionsupporting

confidence: 91%

A synthetic peptide CTL vaccine targeting nucleocapsid confers protection from SARS-CoV-2 challenge in rhesus macaques

Harris

Brasel

Massey

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Likewise, we found increased upregulation of the IL2 genes in vaccinated relative to unvaccinated macaques. A similar finding has been reported in humans, where higher IL 2 levels distinguish mild/asymptomatic forms of COVID-19 disease from the moderate/severe forms [ 66 ]. Following viral challenge in our study (specifically, days 5 to 7), we found downregulation of IFNα2 genes in BAL cells recovered from vaccinated subjects relative to unvaccinated controls.…”

Section: Discussionsupporting

confidence: 86%

A Synthetic Peptide CTL Vaccine Targeting Nucleocapsid Confers Protection from SARS-CoV-2 Challenge in Rhesus Macaques

et al. 2021

View full text Add to dashboard Cite

Background: Persistent transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a COVID-19 pandemic. Several vaccines, conceived in 2020, that evoke protective spike antibody responses are being deployed in mass public health vaccination programs. Recent data suggests, however, that as sequence variation in the spike genome accumulates, some vaccines may lose efficacy. Methods: Using a macaque model of SARS-CoV-2 infection, we tested the efficacy of a peptide-based vaccine targeting MHC class I epitopes on the SARS-CoV-2 nucleocapsid protein. We administered biodegradable microspheres with synthetic peptides and adjuvants to rhesus macaques. Unvaccinated control and vaccinated macaques were challenged with 1 × 108 TCID50 units of SARS-CoV-2, followed by assessment of clinical symptoms and viral load, chest radiographs, and sampling of peripheral blood and bronchoalveolar lavage (BAL) fluid for downstream analysis. Results: Vaccinated animals were free of pneumonia-like infiltrates characteristic of SARS-CoV-2 infection and presented with lower viral loads relative to controls. Gene expression in cells collected from BAL samples of vaccinated macaques revealed a unique signature associated with enhanced development of adaptive immune responses relative to control macaques. Conclusions: We demonstrate that a room temperature stable peptide vaccine based on known immunogenic HLA class I bound CTL epitopes from the nucleocapsid protein can provide protection against SARS-CoV-2 infection in nonhuman primates.

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“…Circulating levels of interleukin-6 (IL-6) are significantly elevated in patients with COVID-19 [ 12 , 26 , 27 ]. The levels of serum IL-6 were found increased in asymptomatic patients as well, although patients with moderate and severe symptoms had much higher elevation in IL-6 levels [ 28 ]. A recent meta-analysis indicates that elevated circulating levels of IL-6 correlate well with increased mortality of COVID-19 patients [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic application of estrogen for COVID-19: Attenuation of SARS-CoV-2 spike protein and IL-6 stimulated, ACE2-dependent NOX2 activation, ROS production and MCP-1 upregulation in endothelial cells

Youn

Zhang

et al. 2021

Redox Biology

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The outbreak of COVID-19 has remained uncontained with urgent need for robust therapeutics. Males are more susceptible than females, and more often to develop into severe cases with higher mortality. This predisposition is potentially linked to higher prevalence of cigarette smoking. Nonetheless, we found for the first time that cigarette smoking extract (CSE) had no effect on angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) expression in endothelial cells. The otherwise observed worse outcomes in smokers is likely linked to baseline respiratory diseases associated with chronic smoking. Instead, we hypothesized that estrogen mediated protection might underlie less severe disease in females. Of note, endothelial inflammation and barrier dysfunction are major mediators of disease progression, and development of acute respiratory distress syndrome (ARDS) and multi-organ failure in patients with COVID-19. Therefore, we investigated the protective effects of estrogen on endothelial cells against oxidative stress induced by interleukin-6 (IL-6) and SARS-CoV-2 spike protein (S protein). Indeed, 17β-estradiol completely reversed IL-6 and S protein-induced selective activation of NADPH oxidase isoform 2 (NOX2), reactive oxygen species (ROS) production, ACE2 upregulation and induction of pro-inflammatory gene monocyte chemoattractant protein-1 (MCP-1) in endothelial cells to effectively attenuate endothelial cell dysfunction. Of note, co-treatment with CSE had no additional effects on S protein stimulated endothelial oxidative stress, again indicating that current smoking status is likely unrelated to more severe disease in chronic smokers. These data indicate that estrogen may serve as a novel therapy for patients with COVID-19 via inhibition of initial viral responses and attenuation of cytokine storm induced endothelial dysfunction, to substantially alleviate severity of the disease and mortality, especially in men. Short-term application of estrogen may therefore be readily used in the clinical management of COVID-19 as a robust therapeutic option.

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Early Differences in Cytokine Production by Severity of Coronavirus Disease 2019

Cited by 91 publications

References 14 publications

A synthetic peptide CTL vaccine targeting nucleocapsid confers protection from SARS-CoV-2 challenge in rhesus macaques

A synthetic peptide CTL vaccine targeting nucleocapsid confers protection from SARS-CoV-2 challenge in rhesus macaques

A Synthetic Peptide CTL Vaccine Targeting Nucleocapsid Confers Protection from SARS-CoV-2 Challenge in Rhesus Macaques

Therapeutic application of estrogen for COVID-19: Attenuation of SARS-CoV-2 spike protein and IL-6 stimulated, ACE2-dependent NOX2 activation, ROS production and MCP-1 upregulation in endothelial cells

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