ABSTRACT
COVID-19, caused by SARS-CoV-2, is associated with arterial and venous thrombosis, thereby increasing mortality. SARS-CoV-2 spike protein (SP), a viral envelope structural protein, is implicated in COVID-19-associated thrombosis. However, the underlying mechanisms remain unknown. Thymidine phosphorylase (TYMP), a newly identified prothrombotic protein, is upregulated in the plasma, platelets, and lungs of patients with COVID-19 but its role in COVID-19-associated thrombosis is not defined. In this study, we found that wild-type SARS-CoV-2 SP significantly promoted arterial thrombosis in K18-hACE2TG mice. SP-accelerated thrombosis was attenuated by inhibition or genetic ablation of TYMP. SP increased the expression of TYMP, resulting in the activation of signal transducer and activator of transcription 3 (STAT3) in BEAS-2B cells, a human bronchial epithelial cell line. A siRNA-mediated knockdown of TYMP inhibited SP-enhanced activation of STAT3. Platelets derived from SP-treated K18-hACE2TG mice also showed increased STAT3 activation, which was reduced by TYMP deficiency. Activated STAT3 is known to potentiate glycoprotein VI signaling in platelets. While SP did not influence ADP- or collagen-induced platelet aggregation, it significantly shortened activated partial thromboplastin time and this change was reversed by TYMP knockout. Additionally, platelet factor 4 (PF4) interacts with SP, which also complexes with TYMP. TYMP enhanced the formation of the SP/PF4 complex, which may potentially augment the prothrombotic and procoagulant effects of PF4. We conclude that SP upregulates TYMP expression, and TYMP inhibition or knockout mitigates SP-enhanced thrombosis. These findings indicate that inhibition of TYMP may be a novel therapeutic strategy for COVID-19-associated thrombosis.
Subject(s)
COVID-19 , Thrombosis , Blood Platelet Disorders , Venous ThrombosisABSTRACT
Background: Endotheliopathy is common pathologic findings in patients with acute and long COVID-19. It may be associated with disease severity and predispose to long-term complications. Plasma levels of a proteoglycan syndecan-1 are found to be significantly elevated in patients with COVID-19, but its roles in assessing the disease severity and predicting long-term outcome are not fully understood. Methods: 124 consecutive hospitalized patients with SARS-CoV2 infection were prospectively enrolled and blood samples were collected on admission (T1), 3-4 days following treatment (T2), and 1-2 days prior to discharge or death (T3). Plasma levels of syndecan-1 were determined using an immunosorbent assay; various statistical analyses were performed to determine the association between plasma syndecan-1 levels and disease severity or the 60-day mortality rate. Results: Compared with those in the healthy controls, plasma levels of syndecan-1 in patients with critical COVID-19 were significantly higher (p<0.0001). However, there was no statistically significant difference among patients with different disease severity (p>0.05), resulting from large individual variability. Longitudinal analysis demonstrated that while the levels fluctuated during hospitalization in all patients, plasma syndecan-1 levels were persistently elevated from baseline in critical COVID19 patients. Cox proportional hazard regression analyses revealed that elevated plasma levels of syndecan-1 (>260 ng/mL at T1, >1018 ng/mL at T2, and >461 ng/mL at T3) were significantly associated with the 60-day mortality rate. Conclusions: Endotheliopathy, marked by glycocalyx degradation and elevated plasma syndecan-1, occurs in nearly all hospitalized patients with SARS-CoV2 infection; the elevated plasma syndecan-1 is associated with increased mortality in COVID-19 patients.
Subject(s)
COVID-19 , Severe Acute Respiratory Syndrome , DeathABSTRACT
The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) that causes the coronavirus disease 2019 (COVID-19) has presented numerous challenges to global health. The vaccines, including lipid-based nanoparticle mRNA, inactivated virus and recombined protein, have been used to prevent SARS-CoV-2 infections in clinics and are immensely helpful against the epidemic. Here, we first present an oral mRNA vaccine based on bovine milk-derived exosomes (milk-exos), which encodes the SARS-CoV-2 receptor binding domain (RBD) as an immunogen. The results indicated that RBD mRNA delivered by milk-derived exosomes can produce secreted RBD peptide in 293 cells in vitro and stimulated neutralizing antibodies against RBD in mice. These results indicated that bovine milk-derived exosome-based mRNA vaccine could serve as a new strategy for preventing SARS-CoV-2 infection. Meanwhile, it also can work as a new oral delivery system for mRNA. Keywords: bovine milk-derived exosomes; SARS-CoV-2; receptor binding domain; mRNA; oral vaccines; neutralizing antibody
Subject(s)
Coronavirus Infections , Severe Acute Respiratory Syndrome , COVID-19ABSTRACT
(1) Background: Triglyceride to high density lipoprotein cholesterol (TG/HDL-c) ratio is crucial when researching metabolic and vascular diseases, and its involvement in COVID-19 was sparsely elaborated on. The purpose of the study was to explore if there were any associations between the TG/HDL-c ratio and COVID-19 prognosis; (2) Methods: A total of 262 COVID-19 patients were retrospectively investigated. The clinical features and baseline hematological parameters were recorded and analyzed; (3) Results: Compared with the survivors, the non-survivors of COVID-19 had significantly higher levels of white blood cells (4.7 vs. 13.0 ×109/L; P < 0.001), neutrophils (3.0 vs. 11.6×109/L; P < 0.001), C-reactive proteins (15.7 vs. 76.7 mg/L; P < 0.001) and TG/HDL-c ratio (1.4 vs. 2.5; P = 0.001). The receiver operating characteristics curve [area under the curve, 0.731; 95% confidence interval, 0.609–0.853; P = 0.001] suggested that the TG/HDL-c ratio could predict the mortality of COVID-19. Moreover, the TG/HDL-c ratio was positively correlated with white blood cells (r = 0.255, P < 0.001), neutrophils (r = 0.243, P < 0.001) and C-reactive proteins (r = 0.170, P < 0.006); (4) Conclusions: Our study demonstrated that TG/HDL-c ratio may potentially be a predictive marker for mortality in COVID-19 patients.
Subject(s)
COVID-19ABSTRACT
Corona Virus Disease 2019 (COVID-19), due to its extremely high infectivity, has been spreading rapidly around the world and bringing huge influence to socioeconomic development as well as people's daily life. Taking for example the virus transmission that may occur after college students return to school, we analyze the quantitative influence of the key factors on the virus spread, including crowd density and self-protection. One Campus Virus Infection and Control Simulation model (CVICS) of the novel coronavirus is proposed in this paper, fully considering the characteristics of repeated contact and strong mobility of crowd in the closed environment. Specifically, we build an agent-based infection model, introduce the mean field theory to calculate the probability of virus transmission, and micro-simulate the daily prevalence of infection among individuals. The experimental results show that the proposed model in this paper efficiently simulate how the virus spread in the dense crowd in frequent contact under closed environment. Furthermore, preventive and control measures such as self-protection, crowd decentralization and isolation during the epidemic can effectively delay the arrival of infection peak and reduce the prevalence, and finally lower the risk of COVID-19 transmission after the students return to school.
Subject(s)
COVID-19 , Virus DiseasesABSTRACT
The FDA has granted Remdesivir (RDV, GS-5734) an emergency use authorization on the basis of an acceleration of clinical recovery in hospitalized patients with COVID-19. Unfortunately, the drug must be administered intravenously, restricting its use to those with relatively advanced disease. RDV is also unstable in plasma and has a complex activation pathway which may contribute to its highly variable antiviral efficacy in SARS-CoV-2 infected cells. A potent orally bioavailable antiviral for early treatment of SARS-CoV-2 infection is needed. We focused on making simple orally bioavailable lipid analogs of Remdesivir nucleoside (RVn, GS-441524) that are processed to RVn-monophosphate, the precursor of the active RVn-triphosphate, by a single step intracellular cleavage. In addition to likely improved oral bioavailability and simpler metabolic activation, two of the three new lipid prodrugs of RVn had anti-SARS-CoV-2 activity 9 to 24 times greater than that of RDV in Vero E6 cells
Subject(s)
COVID-19 , Severe Acute Respiratory SyndromeABSTRACT
Background: The aim of the present study was to describe the clinical characteristics of patients with different levels of high-density lipoproteins (HDLs) and analyze the correlation between HDL levels and prognosis of coronavirus disease 2019 (COVID-19) patients. Methods In the clinical retrospective analysis, a total of 228 adult COVID-19 patients admitted to Public Health Treatment Center of Changsha, China from January 17 to March 14, 2020 were enrolled. Median with interquartile range and Mann-Whitney test were used to depict and analyze the clinical characteristics of patients. The Kaplan-Meier (KM) curve and cox regression were adopted to analyze the association between HDLs and severe events of COVID-19 patients. Results Median levels of high-density lipoprotein cholesterol (HDL-C) in adult COVID-19 patients were below normal range. Compared with patients with high HDL-C, patients with low HDL-C showed higher proportion of male (69.6% vs 45.6%, P = 0.004), higher levels of C-reactive protein (CRP) (median, 27.83 vs 12.56 mg/L, P = 0.000) and alanine aminotransferase (ALT) (median, 21.49 vs 18.81 U/L, P = 0.044), as well as higher proportion of severe events (37.0% vs 14.8%, P = 0.001). Moreover, they presented a higher risk of developing severe events compared with those with high HDL-C (Log Rank P