严重急性呼吸综合征冠状病毒2 Omicron变异株研究进展

世界卫生组织(World Health Organization, WHO)于2021年11月26日将首次在南非报告的新型冠状病毒 B．1.1.529 变异株列为受关注变种(variant of concern, VOC),并将其命名为奥密克戎(Omicron)。该变异株存在约50个突变,仅在刺突蛋白区域就有至少30个突变,远远超过其他流行株的突变位点数量。根据对突变位点的分析以及初步实验证实,该毒株可能具有极强的传染性以及免疫逃逸能力。Omicron变异株会怎样影响新冠疫情的走向引起了各国的广泛关注,本文将从Omicron变异株的基本特征、检测、致病性、传染性、免疫逃逸等方面进行综述。     

Smoking enhances the expression of angiotensin-converting enzyme 2 involved in the efficiency of severe acute respiratory syndrome coronavirus 2 infection

Smoking is one of the risk factors most closely related to the severity of coronavirus disease 2019 (COVID-19). However, the relationship between smoking history and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity is unknown. In this study, we evaluated the ACE2 expression level in the lungs of current smokers, ex-smokers, and nonsmokers. The ACE2 expression level of ex-smokers who smoked cigarettes until recently (cessation period shorter than 6 months) was higher than that of nonsmokers and ex-smokers with a long history of nonsmoking (cessation period longer than 6 months). We also showed that the efficiency of SARS-CoV-2 infection was enhanced in a manner dependent on the angiotensin-converting enzyme 2 (ACE2) expression level. Using RNA-seq analysis on the lungs of smokers, we identified that the expression of inflammatory signaling genes was correlated with ACE2 expression. Notably, with increasing duration of smoking cessation among ex-smokers, not only ACE2 expression level but also the expression levels of inflammatory signaling genes decreased. These results indicated that smoking enhances the expression levels of ACE2 and inflammatory signaling genes. Our data suggest that the efficiency of SARS-CoV-2 infection is enhanced by smoking-mediated upregulation of ACE2 expression level.     

Antibody profile in symptomatic/asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected Saudi persons

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected persons could be symptomatic or asymptomatic. Asymptomatic and symptomatic patients can transmit SARS-CoV-2. This study aimed to study the humoral immune response in Saudis who are Covid-19 symptomatic and asymptomatic patients. We created three types of enzyme-linked immunosorbant assays (ELISAs) to reveal IgG and IgM antibodies (Abs) against SARS-CoV-2. The developed ELISAs were designed to detect Abs against SARS-CoV-2 N, S and N + S proteins. A number of Covid-19 symptomatic (1 5 3) and asymptomatic (84) RT–PCR-confirmed patient sera were used to evaluate the ELISAs and to determine the IgG and IgM antibody profile in those patients. The sensitivity and specificity of these ELISAs were evaluated using pre-Covid-19 pandemic serum samples. The results revealed the existence of anti-SARS-CoV-2 IgG and IgM Abs in Covid-19 symptomatic and asymptomatic Saudi persons. The use of SARS-CoV-2 N and S proteins in the same ELISA greatly increased the detectability of infection. In conclusion, the Covid-19 symptomatic and asymptomatic Saudi persons demonstrated both IgG and IgM antibody profile with higher titer in symptomatic patients. The use of N + S proteins as antibody capture antigens greatly increased the ELISA sensitivity.     

Glycogen synthase kinase-3: A putative target to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic

The coronavirus disease 19 (COVID-19) outbreak caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) had turned out to be highly pathogenic and transmittable. Researchers throughout the globe are still struggling to understand this strain's aggressiveness in search of putative therapies for its control. Crosstalk between oxidative stress and systemic inflammation seems to support the progression of the infection. Glycogen synthase kinase-3 (Gsk-3) is a conserved serine/threonine kinase that mainly participates in cell proliferation, development, stress, and inflammation in humans. Nucleocapsid protein of SARS-CoV-2 is an important structural protein responsible for viral replication and interferes with the host defence mechanism by the help of Gsk-3 protein. The viral infected cells show activated Gsk-3 protein that degrades the Nuclear factor erythroid 2-related factor (Nrf2) protein, resulting in excessive oxidative stress. Activated Gsk-3 also modulates CREB-DNA activity, phosphorylates NF-​κB, and degrades β-catenin, thus provokes systemic inflammation. Interaction between these two pathophysiological events, oxidative stress, and inflammation enhance mucous secretion, coagulation cascade, and hypoxia, which ultimately leads to multiple organs failure, resulting in the death of the infected patient. The present review aims to highlight the pathogenic role of Gsk-3 in viral replication, initiation of oxidative stress, and inflammation during SARS-CoV-2 infection. The review also summarizes the potential Gsk-3 pathway modulators as putative therapeutic interventions in combating the COVID-19 pandemic.     

SARS-CoV-2抗原表位分析及相关疫苗研发的进展与挑战

疫苗的接种被认为是阻止时下2019冠状病毒病(Corona Virus Disease 2019,COVID-19)疫情进一步蔓延的最有效手段.目前,国内外多个研究团队采用了不同的技术路线开展严重急性呼吸综合征冠状病毒2(Severe Acute Respiratory Syndrome Coronavirus 2,S...     

Dynamics of severe acute respiratory syndrome coronavirus 2 genome variants in the feces during convalescence

In response to the current coronavirus disease 2019 (COVID-19) pandemic, it is crucial to understand the origin, transmission, and evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which relies on close surveillance of genomic diversity in clinical samples. Although the mutation at the population level had been extensively investigated, how the mutations evolve at the individual level is largely unknown. Eighteen time-series fecal samples were collected from nine patients with COVID-19 during the convalescent phase. The nucleic acids of SARS-CoV-2 were enriched by the hybrid capture method. First, we demonstrated the outstanding performance of the hybrid capture method in detecting intra-host variants. We identified 229 intra-host variants at 182 sites in 18 fecal samples. Among them, nineteen variants presented frequency changes > 0.3 within 1–5 days, reflecting highly dynamic intra-host viral populations. Moreover, the evolution of the viral genome demonstrated that the virus was probably viable in the gastrointestinal tract during the convalescent period. Meanwhile, we also found that the same mutation showed a distinct pattern of frequency changes in different individuals, indicating a strong random drift. In summary, dramatic changes of the SARS-CoV-2 genome were detected in fecal samples during the convalescent period; whether the viral load in feces is sufficient to establish an infection warranted further investigation.     

Capivasertib restricts SARS-CoV-2 cellular entry: a potential clinical application for COVID-19

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to more than 150 million infections and about 3.1 million deaths up to date. Currently, drugs screened are urgently aiming to block the infection of SARS-CoV-2. Here, we explored the interaction networks of kinase and COVID-19 crosstalk, and identified phosphoinositide 3-kinase (PI3K)/AKT pathway as the most important kinase signal pathway involving COVID-19. Further, we found a PI3K/AKT signal pathway inhibitor capivasertib restricted the entry of SARS-CoV-2 into cells under non-cytotoxic concentrations. Lastly, the signal axis PI3K/AKT/FYVE finger-containing phosphoinositide kinase (PIKfyve)/PtdIns(3,5)P2 was revealed to play a key role during the cellular entry of viruses including SARS-CoV-2, possibly providing potential antiviral targets. Altogether, our study suggests that the PI3K/AKT kinase inhibitor drugs may be a promising anti-SARS-CoV-2 strategy for clinical application, especially for managing cancer patients with COVID-19 in the pandemic era.     

Predictive factors of mortality in patients treated with tocilizumab for acute respiratory distress syndrome related to coronavirus disease 2019 (COVID-19)

COVID-19 patients (n = 34) suffering from ARDS were treated with tocilizumab (TCZ). Outcome was classified in two groups: “Death” and “Recovery”. Predictive factors of mortality were studied. Mean age was 75.3, mean oxygen (O₂) requirements 10.4 l/min. At baseline, all patients had multiple biological abnormalities (lymphopenia, increased CRP, ferritin, fibrinogen, D-dimer and liver enzymes). 24 patients (70.5%) recovered after TCZ therapy and 10 died (29.5%). Deceased subjects differed from patients in whom treatment was effective with regard to more pronounced lymphopenia (0.6 vs 1.0 G/l; p = 0.037), lower platelet number (156 vs 314 G/l; p = 0.0001), lower fibrinogen serum level (0.6 vs 1.0 G/l; p = 0.03), higher aspartate-amino-transferase (108 vs 57 UI/l; p = 0.05) and greater O₂ requirements (11 vs 8 l/min; p = 0.003).     

A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients

In this study, we aimed to evaluate the diagnostic value of serological assay for SARS-CoV-2. A newly-developed ELISA assay for IgM and IgG antibodies against N protein of SARS-CoV-2 was used to screen the serums of 238 admitted hospital patients between February 6 and February 14, 2020 with confirmed or suspected SARS-CoV-2. SARS-CoV-2 RNA was detected on pharyngeal swab specimens using real time RT-PCR. 194 (81.5%) of the serums were detected to be antibody (IgM and/or IgG) positive, significantly higher than the positive rate of viral RNA (64.3%). There was no difference in the positive rate of antibodies between the confirmed patients (83.0%, 127/153) and the suspected patients (78.8%, 67/85), whose nucleic acid tests were negative. The antibody positive rates were very low in the first five days after initial onset of symptoms, and then rapidly increased as the disease progressed. After 10 days, the antibody positive rates jumped from below 50% to over 80%. However, the positive rates of viral RNA maintained above 60% in the first 11 days after initial onset of symptoms, and then rapidly decreased. Overall, the suspected patients were most likely infected by SARS-CoV-2. Before the 11th day after initial onset of symptoms, nucleic acid test is key for confirmation of viral infection. The combination of serological assay can greatly improve the diagnostic efficacy. After the 11th day post-disease onset, the diagnosis for viral infection should be majorly dependent on serological assay.     

Mesenchymal stromal cells as potential immunomodulatory players in severe acute respiratory distress syndrome induced by SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus-2 and the related coronavirus disease-19 (COVID-19) is a worldwide emerging situation, which was initially reported in December 2019 in Wuhan, China. Currently, more than 7258842 new cases, and more than 411879 deaths have been reported globally. This new highly transmitted coronavirus is responsible for the development of severe acute respiratory distress syndrome. Due to this disorder, a great number of patients are hospitalized in the intensive care unit followed by connection to extracorporeal membrane oxygenation for breath supporting and survival. Severe acute respiratory distress syndrome is mostly accompanied by the secretion of proinflammatory cytokines, including interleukin (IL)-2, IL-6, IL-7, granulocyte colony-stimulating factor (GSCF), interferon-inducible protein 10 (IP10), monocyte chemotactic protein-1 (MCP1), macrophage inflammatory protein 1A (MIP1A), and tumor necrosis factor alpha (TNF-α), an event which is known as “cytokine storm”. Further disease pathology involves a generalized modulation of immune responses, leading to fatal multiorgan failure. Currently, no specific treatment or vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been developed. Mesenchymal stromal cells (MSCs), which are known for their immunosuppressive actions, could be applied as an alternative co-therapy in critically-ill COVID-19 patients. Specifically, MSCs can regulate the immune responses through the conversion of Th1 to Th2, activation of M2 macrophages, and modulation of dendritic cells maturation. These key immunoregulatory properties of MSCs may be exerted either by produced soluble factors or by cell-cell contact interactions. To date, several clinical trials have been registered to assess the safety, efficacy, and therapeutic potential of MSCs in COVID-19. Moreover, MSC treatment may be effective for the reversion of ground-glass opacity of damaged lungs and reduce the tissue fibrosis. Taking into account the multifunctional properties of MSCs, the proposed stem-cell-based therapy may be proven significantly effective in critically-ill COVID-19 patients. The current therapeutic strategy may improve the patient’s overall condition and in parallel may decrease the mortality rate of the current disease.     

Potential targets of severe acute respiratory syndrome coronavirus 2 of clinical drug fluvoxamine: Docking and molecular dynamics studies to elucidate viral action

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued evolving for survival and adaptation by mutating itself into different variants of concern, including omicron. Several studies and clinical trials found fluvoxamine, an Food and Drug Administration-approved antidepressant drug, to be effective at preventing mild coronavirus disease 2019 (COVID-19) from progressing to severe diseases. However, the mechanism of fluvoxamine's direct antiviral action against COVID-19 is still unknown. Fluvoxamine was docked with 11 SARS-CoV-2 targets and subjected to stability, conformational changes, and binding free energy analyses to explore its mode of action. Of the targets, nonstructural protein 14 (NSP14), main protease (Mpro), and papain-like protease (PLpro) had the best docking scores with fluvoxamine. Consistent with the docking results, it was confirmed by molecular dynamics simulations that the NSP14 N7-MTase ((N7-guanine)-methyltransferase)–fluvoxamine, Mpro–fluvoxamine, and PLpro–fluvoxamine complexes are stable, with the lowest binding free energies of −105.1, −82.7, and − 38.5 kJ/mol, respectively. A number of hotspot residues involved in the interaction were also identified. These include Glu166, Asp187, His41, and Cys145 in Mpro, Gly163 and Arg166 in PLpro, and Glu302, Gly333, and Phe426 in NSP14, which could aid in the development of better antivirals against SARS-CoV-2.     

Postbiotics as potential promising tools for SARS-CoV-2 disease adjuvant therapy

The SARS-CoV-2 pandemic defines the global health tension of our time. There are several continuous efforts to find a definitive cure in this regard. According to some adverse effects and problems of customary SARS-CoV-2 disease therapies, bioactive compounds, for example probiotics-derived metabolites (postbiotics) have been accomplishing supreme importance by investigators for adjuvant cures in patients with SARS-CoV-2. Postbiotics inhibit angiotensin-converting enzyme 2 activity and stimulate the immune system. They also boost the SARS-CoV-2 disease treatment effectiveness and reduce its adverse effects in SARS-CoV-2 illness patients as a result of antiviral and anti-inflammatory effects. Furthermore, postbiotics having unique features such as high safety, high shelf life and stability to the gastrointestinal tract can be utilized as hopeful instruments for both adjuvant and inhibition strategies in SARS-CoV-2 patients with no earnest unfavourable adverse effects. The concept of postbiotics and their biocompatible characteristics are comprehensively discussed in the present review while highlighting the bilateral relationship between postbiotic biometabolites and respiratory tract infection with a special look at the potential biological role in the inactivation of SARS-CoV-2 and reduction of related inflammatory pathways.     

值得关切的严重急性呼吸综合征冠状病毒2型变异株

自2019年12月2019冠状病毒病暴发流行以来,严重急性呼吸综合征冠状病毒 2 型已经产生了1万个以上的变异株。其中有些可能获得更强的传染性,有的致病性得以提高,有的或许不能被现有的检测试剂检测出来,还有的也许能够逃逸疫苗的免疫保护作用。世界卫生组织于2021年5月31日发布了针对这些变异株的新的命名系统。本文对当前世界上流行较广的4个变异株进行综述,包括最近在广州市引起小暴发的δ变异株。     

Sequence analysis and structural prediction of the severe acute respiratory syndrome coronavirus nsp5

The non-structural proteins (nsp or replicase proteins) of coronaviruses are relatively conserved and can be effective targets for drugs. Few studies have been conducted into the function of the severe acute respiratory syndrome coronavirus (SARS-CoV) nsp5. In this study, bioinformatics methods were employed to predict the secondary structure and construct 3-D models of the SARS-CoV GD strain nsp5. Sequencing and sequential comparison was performed to analyze the mutation trend of the polymerase nsp5 gene during the epidemic process using a nucleotide-nucleotide basic local alignment search tool (BLASTN) and a protein-protein basic local alignment search tool (BLASTP). The results indicated that the nsp5 gene was steady during the epidemic process and the protein was homologous with other coronavirus nsp5 proteins. The protein encoded by the nsp5 gene was expressed in COS-7 cells and analyzed by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE). This study provided the foundation for further exploration of the protein‘s biological function, and contributed to the search for anti-SARS-CoV drugs.     

2019新型冠状病毒及其诊疗与防控:回顾与展望

2019新型冠状病毒的暴发持续至今,导致了世界各地数以百万计的感染个例,更夺去了数十万人的生命。世界卫生组织在2020年2月将此病毒引起的疾病定名为2019冠状病毒病(Coronavirus disease 2019,COVID-19),而国际病毒分类委员会也将此病毒命名为SARS-Co V-2。COVID-19的典型临床症状类似感冒,少数病人可发展为重症甚至死亡。21世纪以来,人类冠状病毒有3次大暴发,分别是2003年暴发的严重急性呼吸综合征(SARS)、2012年暴发的中东呼吸综合征(MERS)和本次的新型肺炎。自2003年以来,对SARS和MERS冠状病毒的研究从未间断,对其自然起源、致病机理、药物筛选及疫苗研发等已取得一定进展。鉴于SARS-Co V-2和SARS-Co V的基因组序列高度相似,以往对SARS-Co V的研究对深入探讨SARS-Co V-2生物学特性、诊断、治疗和防控有很强的借鉴性。文中通过回顾过往的研究进展,对比SARS-Co V和SARS-Co V-2的生物学特性,分析当前亟需的防控和诊疗措施,探讨疫苗研发所面对的一些难题,并展望疫情发展趋势及对本领域研究与开发的主要挑战,冀为我国和全世界有效控制COVID-19疫情提供参考。     

免疫系统：严重急性呼吸综合征冠状病毒2型感染后的一把双刃剑

免疫系统是人体内的一把双刃剑,它一方面能清除侵染的各类病原体,但另一方面其异常调控又能在人体中引发各类免疫性疾病,甚至导致死亡。本文将简要讨论人体免疫系统与新的冠状病毒﹝即严重急性呼吸综合征冠状病毒2型(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)〕感染的相互关系。一方面免疫系统能全方位地预防病毒感染,进化出一整套从分子到细胞、从短期到长期的病毒清除机制;另一方面,免疫系统又可能引发“细胞因子风暴”,给SARS-CoV-2的感染患者带来负面作用。本文还将讨论受到广泛关注的免疫相关的治疗策略,着重探讨抗体依赖的增强效应(antibody-dependent enhancement, ADE)可能给疫苗研发带来的困难与挑战。     

Mesenchymal stem cells as living anti-inflammatory therapy for COVID-19 related acute respiratory distress syndrome

Coronavirus disease 2019(COVID-19), a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2(SARS-Co V2), is growing at an exponential rate worldwide. Manifestations of this disease are heterogeneous; however, advanced cases often exhibit various acute respiratory distress syndrome-like symptoms, systemic inflammatory reactions, coagulopathy, and organ involvements. A common theme in advanced COVID-19 is unrestrained immune activation, classically referred to as a cytokine storm, as well as deficiencies in immune regulatory mechanisms such as T regulatory cells. While mesenchymal stem cells(MSCs) themselves are objects of cytokine regulation, they can secrete cytokines to modulate immune cells by inducing antiinflammatory regulatory Treg cells, macrophages and neutrophils; and by reducing the activation of T and B cells, dendritic and nature killer cells. Consequently, they have therapeutic potential for treating severe cases of COVID-19. Here we discuss the unique ability of MSCs, to act as a living antiinflammatory, which can rebalance the cytokine/immune responses to restore equilibrium. We also discuss current MSC trials and present different concepts for optimization of MSC therapy in patients with COVID-19 acute respiratory distress syndrome.     

新型冠状病毒的相关研究进展

2019年12月出现于湖北武汉的一种新型冠状病毒(SARS-CoV-2)感染所致肺炎疫情,给人类生命安全造成威胁。迄今为止,对2019年出现的SARS-CoV-2的研究仍处于起步阶段,本文就其相关研究进展进行综述,重点阐述了目前关于SARS-CoV-2的病原学与致病机制方面的研究成果,同时对其流行病学以及该病毒引发的肺炎临床特点加以总结,有助于读者及时了解SARS-CoV-2最新的研究动态,并为今后开展治疗药物及疫苗研发提供方向。