Association between mannose-binding lectin gene polymorphisms and susceptibility to severe acute respiratory syndrome coronavirus infection

BACKGROUND: Genetic determinants of susceptibility to severe acute respiratory syndrome coronavirus (SARS-CoV) infection remain unknown. We assessed whether mannose-binding lectin (MBL) gene polymorphisms were associated with susceptibility to SARS-CoV infection or disease severity in an ethnically homogeneous population born in northern China. METHODS: The frequencies of 1 mutation in codon 54 and 3 promoter polymorphisms at nt -550, -221, and 4 were ascertained in 352 patients with SARS and 392 control subjects, by means of polymerase chain reaction direct sequencing. RESULTS: Of 352 patients with SARS and 392 control subjects, 120 (34.4%) and 91 (23.2%) were carriers of the codon 54 variant, respectively (odds ratio [OR], 1.73 [95% confidence interval {CI}, 1.25-2.39]; P=.00086). A total of 123 (36.0%) of 352 patients with SARS and 100 (25.5%) of 392 control subjects had haplotype pairs associated with medium or low expression of MBL (OR, 1.67 [95% CI, 1.21-2.29]; P=.00187). The population-attributable fraction of patients with SARS that was associated with having the codon 54 variant was 20.1% (95% CI, 7.9%-32.3%). CONCLUSIONS: MBL gene polymorphisms were significantly associated with susceptibility to SARS-CoV infection; this might be explained by the reduced expression of functional MBL secondary to having the codon 54 variant.     

Protease-mediated enhancement of severe acute respiratory syndrome coronavirus infection

A unique coronavirus severe acute respiratory syndrome-coronavirus (SARS-CoV) was revealed to be a causative agent of a life-threatening SARS. Although this virus grows in a variety of tissues that express its receptor, the mechanism of the severe respiratory illness caused by this virus is not well understood. Here, we report a possible mechanism for the extensive damage seen in the major target organs for this disease. A recent study of the cell entry mechanism of SARS-CoV reveals that it takes an endosomal pathway. We found that proteases such as trypsin and thermolysin enabled SARS-CoV adsorbed onto the cell surface to enter cells directly from that site. This finding shows that SARS-CoV has the potential to take two distinct pathways for cell entry, depending on the presence of proteases in the environment. Moreover, the protease-mediated entry facilitated a 100- to 1,000-fold higher efficient infection than did the endosomal pathway used in the absence of proteases. These results suggest that the proteases produced in the lungs by inflammatory cells are responsible for high multiplication of SARS-CoV, which results in severe lung tissue damage. Likewise, elastase, a major protease produced in the lungs during inflammation, also enhanced SARS-CoV infection in cultured cells.     

Acute-on-chronic liver failure in patients with severe acute respiratory syndrome coronavirus 2 infection

The corona virus disease 2019(COVID-19) pandemic caused by the severe acute respiratory syndrome corona virus 2(SARS-CoV-2) has had a significant impact on the lives of millions of people,especially those with other concomitant diseases,such as chronic liver diseases.To date,seven corona viruses have been identified to infect humans.The main site of pathological action of these viruses is lung tissue.However,a substantial number of studies have proven that SARSCoV-2 shows affinity towards severa...     

Severe acute respiratory syndrome coronavirus infection in vaccinated ferrets

BACKGROUND: Development of vaccines to prevent severe acute respiratory syndrome (SARS) is limited by the lack of well-characterized animal models. Previous vaccine reports have noted robust neutralizing antibody and inflammatory responses in ferrets, resulting in enhanced hepatitis. METHODS: We evaluated the humoral immune response and pathological end points in ferrets challenged with the Urbani strain of SARS-associated coronavirus (SARS-CoV) after having received formalin-inactivated whole-virus vaccine or mock vaccine. RESULTS: Humoral responses were observed in ferrets that received an inactivated virus vaccine. Histopathological findings in lungs showed that infection of ferrets produced residual lung lesions not seen in both mock and vaccinated ferrets. SARS-CoV infection demonstrated bronchial and bronchiolar hyperplasia and perivascular cuffing in ferret lung tissue, as seen previously in infected mice. No evidence of enhanced disease was observed in any of the ferrets. All of the ferrets cleared the virus by day 14, 1 week earlier if vaccinated. CONCLUSIONS: The vaccine provided mild immune protection to the ferrets after challenge; however, there was no evidence of enhanced liver or lung disease induced by the inactivated whole-virus vaccine. The ferret may provide another useful model for evaluating SARS vaccine safety and efficacy.     

Small molecules targeting severe acute respiratory syndrome human coronavirus

Severe acute respiratory syndrome (SARS) is an infectious disease caused by a novel human coronavirus. Currently, no effective antiviral agents exist against this type of virus. A cell-based assay, with SARS virus and Vero E6 cells, was developed to screen existing drugs, natural products, and synthetic compounds to identify effective anti-SARS agents. Of >10,000 agents tested, approximately 50 compounds were found active at 10 microM; among these compounds, two are existing drugs (Reserpine 13 and Aescin 5) and several are in clinical development. These 50 active compounds were tested again, and compounds 2-6, 10, and 13 showed active at 3 microM. The 50% inhibitory concentrations for the inhibition of viral replication (EC(50)) and host growth (CC(50)) were then measured and the selectivity index (SI = CC(50)/EC(50)) was determined. The EC(50), based on ELISA, and SI for Reserpine, Aescim, and Valinomycin are 3.4 microM (SI = 7.3), 6.0 microM (SI = 2.5), and 0.85 microM (SI = 80), respectively. Additional studies were carried out to further understand the mode of action of some active compounds, including ELISA, Western blot analysis, immunofluorescence and flow cytometry assays, and inhibition against the 3CL protease and viral entry. Of particular interest are the two anti-HIV agents, one as an entry blocker and the other as a 3CL protease inhibitor (K(i) = 0.6 microM).     

Prognostic impact of atrial fibrillation in patients with severe acute respiratory syndrome coronavirus 2 infection

The prognostic impact of atrial fibrillation (AF) in patients with severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection has not been well evaluated. We estimated the prognostic implications of AF in SARS-CoV-2 confirmed patients.The OpenData4Covid19 (https://hira-covid19.net) project is a global research collaboration on coronavirus disease (COVID-19), hosted by the Ministry of Health and Welfare of Korea and the Health Insurance Review and Assessment Service of Korea. This dataset comprises all COVID-19-tested patients and their individual histories of medical service use from January 1, 2017 to May 15, 2020. All patients >19 years with confirmed SARS-CoV-2 infection were included. The primary endpoint was a composite of death and intensive care unit admission.In total, 7162 adults with SARS-CoV-2 infection were included in this study. The prevalence of AF was 1.8% (n = 130). Patients with AF had unfavorable characteristics, such as older age and higher prevalence of comorbidities. The primary endpoint was more common in patients with AF than in those without (33.9% vs 12.9%, P < .001). In the multivariable model, age (odds ratio [OR]: 1.035, 95% confidence interval [CI]: 1.030–1.040), female sex (OR: 0.618, 95% CI: 0.535–0.713), diabetes (OR: 1.341, 95% CI: 1.093–1.580), and chronic kidney disease (OR: 2.714, 95% CI: 1.541–4.777) were associated with the primary endpoint. However, AF was not an independent predictor of the primary endpoint (OR: 1.402, 95% CI: 0.932–2.108).Patients with AF and concomitant SARS-CoV-2 infection had more comorbidities and a worse prognosis. However, an independent association between AF and adverse clinical outcomes was not evident.     

Antibody avidity maturation during severe acute respiratory syndrome-associated coronavirus infection

The maturation of virus-specific immunoglobulin G avidity during severe acute respiratory syndrome-associated coronavirus infection was examined. The avidity indices were low (mean +/- SD, 30.8% +/- 11.6%) among serum samples collected < or =50 days after fever onset, intermediate (mean +/- SD, 52.1% +/- 14.1%) among samples collected between days 51 and 90, and high (mean +/- SD, 78.1% +/- 8.0%) among samples collected after day 90. Avidity indices of 40% and 55% could be considered as cutoff values for determination of recent (< or =50 days) and past (>65 days) infection, respectively. Measurement of antibody avidity can be used to differentiate primary infection from reexposure and to assess humoral responses to candidate vaccines.     

Neutralizing antibodies in patients with severe acute respiratory syndrome-associated coronavirus infection

BACKGROUND: Severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) is the principal etiologic agent of SARS. We analyzed serum samples obtained from 623 patients with SARS in Beijing, to determine whether infection with SARS-CoV can elicit neutralizing antibodies (NAbs). METHODS: We developed a highly sensitive and safe neutralization assay using the SARS-CoV pseudotyped virus and used this assay to determine the titers of the NAbs in serum samples from patients with SARS. RESULTS: We found that 85.9% of serum samples contained NAbs against SARS-CoV and that most of the NAb activities could be attributed to immunoglobulin G. The NAbs became detectable first at 5-10 days after the onset of symptoms, and their levels peaked at 20-30 days and then were sustained for >150 days. The serum samples could neutralize the pseudotype particles bearing the spike glycoproteins from different SARS-CoV strains, suggesting that the NAbs to SARS-CoV were broadly reactive. CONCLUSIONS: NAbs to SARS-CoV are broadly elicited in patients with SARS and, according to their kinetics, may correlate with viral load during the early stages of the disease. These results suggest that it is possible to develop effective vaccines against SARS and that NAbs provide a potential strategy for treating patients with SARS.     

Renin-angiotensin system blockers and severe acute respiratory syndrome coronavirus 2

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Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry

Severe acute respiratory syndrome (SARS) is caused by an emergent coronavirus (SARS-CoV), for which there is currently no effective treatment. SARS-CoV mediates receptor binding and entry by its spike (S) glycoprotein, and infection is sensitive to lysosomotropic agents that perturb endosomal pH. We demonstrate here that the lysosomotropic-agent-mediated block to SARS-CoV infection is overcome by protease treatment of target-cell-associated virus. In addition, SARS-CoV infection was blocked by specific inhibitors of the pH-sensitive endosomal protease cathepsin L. A cell-free membrane-fusion system demonstrates that engagement of receptor followed by proteolysis is required for SARS-CoV membrane fusion and indicates that cathepsin L is sufficient to activate membrane fusion by SARS-CoV S. These results suggest that SARS-CoV infection results from a unique, three-step process: receptor binding and induced conformational changes in S glycoprotein followed by cathepsin L proteolysis within endosomes. The requirement for cathepsin L proteolysis identifies a previously uncharacterized class of inhibitor for SARS-CoV infection.     

Immunological detection of severe acute respiratory syndrome coronavirus by monoclonal antibodies

In order to establish immunological detection methods for severe acute respiratory syndrome coronavirus (SARS-CoV), we established monoclonal antibodies directed against structural components of the virus. B cell hybridomas were generated from mice that were hyper-immunized with inactivated SARS-CoV virion. By screening 2,880 generated hybridomas, we established three hybridoma clones that secreted antibodies specific for nucleocapsid protein (N) and 27 clones that secreted antibodies specific for spike protein (S). Among these, four S-protein specific antibodies had in vitro neutralization activity against SARS-CoV infection. These monoclonal antibodies enabled the immunological detection of SARS-CoV by immunofluorescence staining, Western blot or immunohistology. Furthermore, a combination of monoclonal antibodies with different specificities allowed the establishment of a highly sensitive antigen-capture sandwich ELISA system. These monoclonal antibodies would be a useful tool for rapid and specific diagnosis of SARS and also for possible antibody-based treatment of the disease.     

新型冠状病毒与脑血管病的关系

自2019年12月起,2019冠状病毒病(COVID-19,又称新型冠状病毒肺炎)首先在武汉被发现,随后该病迅速蔓延至全国乃至其他国家。该病具有传播广、死亡及重症率高的特点,影响深远,引起国内外的广泛重视。而脑血管病同样为我国人群主要的慢性疾病,每年也可造成一定的死亡及致残风险。COVID-19的发病机制与脑血管病的危险因素以及脑血管病本身都有很密切的关系,易合并存在,引发院内感染。笔者根据COVID-19现有的资料结合以往相关疾病的临床经验对新型冠状病毒与脑血管疾病的关系做一归纳,以求更好地指导临床个体化诊疗。