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1.
Mol Ther Nucleic Acids ; 29: 343-353, 2022 Sep 13.
Article in English | MEDLINE | ID: covidwho-1926813

ABSTRACT

We evaluated mRNA and miRNA in COVID-19 patients and elucidated the pathogenesis of COVID-19, including protein profiles, following mRNA and miRNA integration analysis. mRNA and miRNA sequencing was done on admission with whole blood of 5 and 16 healthy controls (HCs) and 10 and 31 critically ill COVID-19 patients (derivation and validation cohorts, respectively). Interferon (IFN)-α2, IFN-ß, IFN-γ, interleukin-27, and IFN-λ1 were measured in COVID-19 patients on admission (day 1, 181 critical/22 non-critical patients) and days 6-8 (168 critical patients) and in 19 HCs. In the derivation cohort, 3,488 mRNA and 31 miRNA expressions were identified among differentially expressed RNA expressions in the patients versus those in HCs, and 2,945 mRNA and 32 miRNA expressions in the validation cohort. Canonical pathway analysis showed the IFN signaling pathway to be most activated. The IFN-ß plasma level was elevated in line with increased severity compared with HCs, as were IFN-ß downstream proteins, such as interleukin-27. IFN-λ1 was higher in non-critically ill patients versus HCs but lower in critical than non-critical patients. Integration of mRNA and miRNA analysis showed activated IFN signaling. Plasma IFN protein profile revealed that IFN-ß (type I) and IFN-λ1 (type III) played important roles in COVID-19 disease progression.

2.
Frontiers in immunology ; 13, 2022.
Article in English | EuropePMC | ID: covidwho-1918620

ABSTRACT

Introduction Resistin is reported to form a cytokine network and cause endothelial damage. The pathogenesis of coronavirus disease 2019 (COVID-19) remains unknown, but the association between cytokine storm and endothelial damage is crucial. This study aimed to evaluate resistin in COVID-19 pathogenesis compared with sepsis. Materials and Methods First, we evaluated the association of plasma resistin levels and disease severity and clinical outcome in two large cohorts: a publicly available cohort including 306 COVID-19 patients in the United States (MGH cohort) and our original cohort including only intubated 113 patients in Japan (Osaka cohort 1). Second, to understand pathogenesis, we evaluate resistin, cytokines and endothelial cell adhesion molecules in COVID-19 compared with sepsis. Blood samples were collected from 62 ICU-treated COVID-19 patients and 38 sepsis patients on day 1 (day of ICU admission), days 2-3, days 6-8, and from 18 healthy controls (Osaka cohort 2). The plasma resistin, inflammatory cytokines (IL-6, IL-8, MCP-1 and IL-10) and endothelial cell adhesion molecules (ICAM-1 and VCAM-1) were compared between patients and control. Correlations among resistin, inflammatory cytokines and endothelial cell adhesion molecules were evaluated in COVID-19 and sepsis. Results In the MGH cohort, the day 1 resistin levels were associated with disease severity score. The non-survivors showed significantly greater resistin levels than survivors on days 1, 4 and 8. In the Osaka cohort 1, 28-day non-survivors showed significantly higher resistin levels than 28-day survivors on days 6-8. Patients with late recovery (defined as the day of weaning off mechanical ventilation >12 or death) had significantly higher resistin levels than those with early recovery on day 1 and days 6-8. In the Osaka cohort 2, plasma resistin levels were elevated in COVID-19 and sepsis patients compared to controls at all measurement points and were associated with inflammatory cytokines and endothelial cell adhesion molecules. Conclusion Resistin was elevated in COVID-19 patients and was associated with cytokines and endothelial cell adhesion molecules. Higher resistin levels were related to worse outcome.

3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-309868

ABSTRACT

Background: Resistin increases in septic subjects and is associated with severity and prognosis. Its role in Coronavirus disease 2019 (COVID-19) is unknown. We investigated relationships between resistin and the severity, prognosis and time to wean off mechanical ventilation (MV) in two cohorts. Methods: : Plasma resistin was available for 306 mild-to-critical COVID-19 patients on days 1, 4 and 8 from the Massachusetts General Hospital Emergency Department COVID-19 (MGH) cohort public proteomics data. The relationship between resistin and severity (World Health Organization COVID-19 outcomes) and the prognosis were evaluated. A cohort of 62 critical COVID-19 patients (Osaka cohort) was used to evaluate the relationship between resistin on days 1 (day of ICU admission), 2–3, 6–8 and 11–15 and the prognosis and time to wean off MV. Correlations among resistin, inflammatory cytokines and endothelial damage markers were evaluated. Results: : In the MGH cohort, day 1 resistin was associated with severity and predicted the prognosis in an ROC analysis (AUC, 0.739;95% CI, 0.659–0.819). Twenty-eight-day non-survivors showed significantly greater resistin levels than 28-day survivors on days 1, 4 and 8. In the Osaka cohort, a Cox proportional hazards model (time dependent) showed a significant relationship between resistin and time to wean off MV (crude hazard ratio, 0.702 [95% CI, 0.508–0.969]). Resistin formed a network with inflammatory cytokines and endothelial damage markers. Conclusions: : Resistin was associated with severity, prognosis and time to wean off MV in COVID-19 patients. Resistin formed a network with inflammatory cytokines and endothelial damage markers, suggesting its contribution to the pathogenesis of COVID-19.

4.
Frontiers in immunology ; 12, 2021.
Article in English | EuropePMC | ID: covidwho-1651875

ABSTRACT

Introduction Coronavirus disease 2019 (COVID-19) is a new viral disease. Uncontrolled inflammation called “cytokine storm” is reported to contribute to disease pathogenesis as well as sepsis. We aimed to identify cytokines related to the pathogenesis of COVID-19 through a proteomics analysis of 1463 plasma proteins, validate these cytokines, and compare them with sepsis. Materials and Methods In a derivation cohort of 306 patients with COVID-19, 1463 unique plasma proteins were measured on days 1, 4, and 8. Cytokines associated with disease severity and prognosis were derived. In a validation cohort of 62 COVID-19 patients and 38 sepsis patients treated in the intensive care unit [ICU], these derived cytokines were measured on days 1 (day of ICU admission), 2-3, and 6-8 (maximum: 3 time points/patient). Derived cytokines were compared with healthy controls and between COVID-19 and sepsis patients, and the associations with prognosis were evaluated. The time to wean off mechanical ventilation (MV) was evaluated only for COVID-19. Results IL-6, amphiregulin, and growth differentiation factor (GDF)-15 were associated with disease severity and prognosis in the derivation cohort. In the validation cohort, IL-6 and GDF-15 were elevated in COVID-19 and sepsis on day 1, and the levels of these cytokines were higher in sepsis than in COVID-19. IL-6 and GDF-15 were associated with prognosis in sepsis. Cox proportional hazards model with time as a dependent covariate showed a significant relationship between plasma GDF-15 level and time to wean off MV (hazard ratio, 0.549 [95% confidence level, 0.382–0.789]). The GDF-15 level at ICU admission predicted late recovery. Conclusion GDF-15 and IL-6 derived from proteomics analysis were related with disease severity of COVID-19. Their values were higher in sepsis than in COVID-19 and were associated with prognosis in sepsis. In COVID-19 patients treated in the ICU, GDF-15 was associated with the time to wean off MV and better predicted late recovery.

5.
Nat Commun ; 12(1): 3802, 2021 06 21.
Article in English | MEDLINE | ID: covidwho-1387351

ABSTRACT

SARS-CoV-2 has mutated during the global pandemic leading to viral adaptation to medications and vaccinations. Here we describe an engineered human virus receptor, ACE2, by mutagenesis and screening for binding to the receptor binding domain (RBD). Three cycles of random mutagenesis and cell sorting achieved sub-nanomolar affinity to RBD. Our structural data show that the enhanced affinity comes from better hydrophobic packing and hydrogen-bonding geometry at the interface. Additional disulfide mutations caused the fixing of a closed ACE2 conformation to avoid off-target effects of protease activity, and also improved structural stability. Our engineered ACE2 neutralized SARS-CoV-2 at a 100-fold lower concentration than wild type; we also report that no escape mutants emerged in the co-incubation after 15 passages. Therapeutic administration of engineered ACE2 protected hamsters from SARS-CoV-2 infection, decreased lung virus titers and pathology. Our results provide evidence of a therapeutic potential of engineered ACE2.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/pharmacology , COVID-19/drug therapy , Mutation , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , COVID-19/virology , Cells, Cultured , Cricetinae , Crystallography, X-Ray , Disease Models, Animal , Humans , Male , Molecular Dynamics Simulation , Protein Binding , Protein Engineering/methods , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism
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