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BackgroundFollowing the launch of the global COVID-19 vaccination campaign, there have been increased reports of autoimmune diseases developing de novo following vaccination. These cases include rheumatoid arthritis, autoimmune hepatitis, immune thrombotic thrombocytopenia, and connective tissue diseases. Nevertheless, COVID-19 vaccines are considered safe for patients with autoimmune diseases and are strongly recommended.ObjectivesThe aim of this in silico analysis is to investigate the presence of protein epitopes encoded by the BNT-162b2 mRNA vaccine, one of the most commonly administered COVID-19 vaccines, that could elicit an aberrant adaptive immune response in predisposed individuals.MethodsThe FASTA sequence of the protein encoded by the BNT-162b2 vaccine was retrieved from http://genome.ucsc.edu and used as a key input to the Immune Epitope Database and Analysis Resource (www.iedb.org). Linear peptides with 90% BLAST homology were selected, and T-cell, B-cell, and MHC ligand assays without MHC restriction were searched and evaluated. HLA-disease associations were screened on the HLA-SPREAD platform (https://hla-spread.igib.res.in) by selecting only positive markers.ResultsA total of 183 epitopes were found, corresponding to 178 SARS-CoV-2 and 5 SARS-CoV spike epitopes, respectively. Results were obtained from 22 T-cell assays, 398 B-cell assays, and 2 MHC ligand assays. Complementary receptors included 1080 T-cell receptors and 0 B-cell receptors.Specifically, the IEDB_epitope:1329790 (NATNVVIKVCEFQFCNDPFLGVYY) was shown to bind to HLA-DRB1*15:02 and HLA-DRB1*15:03 alleles, whereas the IEDB_epitope:1392457 (TKCTLKSFTVEKGIYQTSNFRVQPT) was reported to bind to HLA-DRB1*07:01, HLA-DRB1*03:01, HLA-DRB3*01:01, and HLA-DRB4*01:01 alleles. The HLA alleles detected were found to be positively associated with various immunological disorders (Table 1).Table 1.MHC-restricted epitopes of the BNT-162b2 vaccine and potentially associated immunological conditionsEpitopeAssayMHC moleculeAssociated disease (population)NATNVVIKVCEFQFCNDPFLGVYY + OX(C10)cellular MHC/mass spectrometry ligand presentationHLA-DRB1*15:02Takayasu arteritis (Japanese) Arthritis (Taiwanese) Scleroderma (Japanese) Colitis (Japanese)HLA-DRB1*15:03Systemic lupus erythematosus (Mexican American)TKCTLKSFTVEKGIYQTSNFRVQPT + SCM(K2)as aboveHLA-DRB1*07:01Allergy, hypersensitivity (Caucasian)HLA-DRB1*03:01Type 1 diabetes (African) Sarcoidosis, good prognosis (Finnish)HLA-DRB3*01:01Graves' disease (Caucasian) Thymoma (Caucasian) Sarcoidosis (Scandinavian) Autoimmune hepatitis (Caucasian)HLA-DRB4*01:01Vitiligo (Saudi Arabian)ConclusionSimilar to the SARS-CoV-2 spike protein, the protein product of the BNT-162b2 mRNA vaccine contains immunogenic epitopes that may trigger autoimmune phenomena in predisposed individuals. Genotyping for HLA alleles may help identify at-risk individuals. However, further research is needed to elucidate the underlying mechanisms and potential clinical implications.References[1]Vita R, Mahajan S, Overton JA et al. The Immune Epitope Database (IEDB): 2018 update. Nucleic Acids Res. 2019 Jan 8;47(D1):D339-D343. doi: 10.1093/nar/gky1006.[2]Dholakia D, Kalra A, Misir BR et al. HLA-SPREAD: a natural language processing based resource for curating HLA association from PubMed s. BMC Genomics 23, 10 (2022). https://doi.org/10.1186/s12864-021-08239-0[3]Parker R, Partridge T, Wormald C et al. Mapping the SARS-CoV-2 spike glycoprotein-derived peptidome presented by HLA class II on dendritic cells. Cell Rep. 2021 May 25;35(8):109179. doi: 10.1016/j.celrep.2021.109179.[4]Knierman MD, Lannan MB, Spindler LJ et al. The Human Leukocyte Antigen Class II Immunopeptidome of the SARS-CoV-2 Spike Glycoprotein. Cell Rep. 2020 Dec 1;33(9):108454. doi: 10.1016/j.celrep.2020.108454.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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The aim of this study was to evaluate the impact of the most frequent Asn501 polar uncharged amino acid mutations upon important structural properties of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Surface Glycoprotein RBD–hACE2 (human angiotensin-converting enzyme 2) heterodimer. Mutations N501Y, N501T and N501S were considered and their impact upon complex solubility, secondary motifs formation and intermolecular hydrogen bonding interface was analyzed. Results and findings are reported based on 50 ns run in Gromacs molecular dynamics simulation software. Special attention is paid on the biomechanical shifts in the receptor-binding domain (RBD) [499-505]: ProThrAsn(Tyr)GlyValGlyTyr, having substituted Asparagine to Tyrosine at position 501. The main findings indicate that the N501S mutation increases SARS-CoV-2 S-protein RBD–hACE2 solubility over N501T, N501 (wild type): (Formula presented.), (Formula presented.). The N501Y mutation shifts (Formula presented.) -helix S-protein RBD [366-370]: SerValLeuTyrAsn into π-helix for t > 38.5 ns. An S-protein RBD [503-505]: ValGlyTyr shift from (Formula presented.) -helix into a turn is observed due to the N501Y mutation in t > 33 ns. An empirical proof for the presence of a Y501-binding pocket, based on RBD [499-505]: PTYGVGY (Formula presented.) 's RMSF peak formation is presented. There is enhanced electrostatic interaction between Tyr505 (RBD) phenolic -OH group and Glu37 (hACE2) side chain oxygen atoms due to the N501Y mutation. The N501Y mutation shifts the (Formula presented.) hydrogen bond into permanent polar contact;(Formula presented.);(Formula presented.). © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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Undoubtedly, vaccination can be one of the promising approaches to control infectious diseases such as the COVID-19 pandemic. Inactivated viral vaccines have a history of "vaccine-induced enhanced disease", which may occur when neutralizing antibodies bind to viral antigens without blocking or clearing the infection. This can cause additional inflammation through the mechanisms described for other respiratory pathogens and lead to acute respiratory distress syndrome. Since the structure and function of SARS-CoV-2 glycoproteins are well known, vaccine manufacturers appear to be careful when inactivating the virus to completely inactivate and maintain the viral epitopes necessary for protective immune induction. It seems that caution should be taken in the usage of inactivated vaccines in children to ensure they are safe and efficacious, vaccinated children should be well monitored and any symptoms should be reported immediately.
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This paper presents raw plant materials and their characteristic compounds which may affect the immune system. Plant-derived agents in specific doses affect the body's non-specific, antigen-independent defense system. They have immunostimulatory effects on the entire immune regulatory system. They can enhance the immune response through various factors such as macrophages, leukocytes, and granulocytes, as well as through mediators released by the cellular immune system. This paper was inspired by the threats caused by the COVID-19 pandemic. The proper functioning of the immune system is important in limiting the effects of viral infection and restoring the normal functioning of the body. This paper also emphasizes the importance of the skillful use of plant immunostimulants by potential patients, but also by those who prescribe drugs. It is important not only to choose the right plant drug but above all to choose the correct dose and duration of treatment.
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Asthma and COPD comorbidities are expected to exacerbate the clinical manifestations of COVID-19. However, many reported studies show that asthmatic patients infected with COVID-19 do not show severe clinical manifestations, and some are asymptomatic. This literature review aimed to describe COVID-19 in asthmatic patients along with the hypothesis that asthma is a protective factor against COVID-19 infection. Systemic corticosteroids have been shown to reduce the death/mortality rate in patients who are hospitalized due to COVID-19 infection. This is possibly due to the suppression of the immune system against a hyperinflammatory state which can result in further damage from SARS-CoV-2 infection. Mucus hypersecretion, which is one of the hallmarks of asthma, can prevent the SARS-CoV-2 virus from reaching the distal lung and can protect the lungs from pathological processes. The secreted mucus is rich in glycoproteins, such as MUC5AC, which act as the first line of defense against infection. Mucus hypersecretion in asthmatic patients may prevent SARS-CoV-2 from penetrating far enough to gain access to type-2 alveolar cells, which are the cells that predominantly express ACE2 in the lungs. In conclusion, comorbid asthma in patients infected with COVID-19 does not cause adverse clinical manifestations to appear, but on the contrary, it will have a protective effect on patients.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the cause of coronavirus disease 2019 (COVID-19), has affected millions of people globally. It is a very contagious disease with various clinical manifestations. However, even in asymptomatic patients, it is believed that this virus exposure induces cryptic antibodies as in symptomatic patients. This current study aims to assess the prevalence of SARS-CoV-2 seropositivity by detecting the antibodies specific to the receptor-binding domain (SRBD) of SARS-CoV-2 in the pre-vaccine population in Bali. We assessed specific antibody titers against trimeric spike glycoprotein (S) of SARS-CoV-2 using Roche Elecsys Anti-SARS-CoV-2 S immunoassay in the serum of 510 pre-vaccine subjects without a previous documented history of SARS-CoV-2 infection. The average age was 35.53 years with 56.7% of the subjects being male. Among 510 subjects, 190 (37.3%) subjects were detected to have SARS-CoV-2 SRBD antibody or be seropositive. The range of the antibody titer was zero to 250 U/mL with the average being 44.3 U/mL. The number of subjects who had anti-SARS-Cov-2 SRBD titer above 132 U/mL was 76 (14.9%);it was the minimal antibody titer needed to donate plasma for plasma convalescent therapy. This study revealed a pre-vaccination population, without a history of COVID-19 infection, with seropositivity to SARS-CoV-2, which indicates the underdiagnosis of COVID-19, especially in asymptomatic individuals.
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All coronaviruses are characterized by spike glycoproteins whose S1 subunits contain the receptor binding domain (RBD). The RBD anchors the virus to the host cellular membrane to regulate the virus transmissibility and infectious process. Although the protein/receptor interaction mainly depends on the spike's conformation, particularly on its S1 unit, their secondary structures are poorly known. In this paper, the S1 conformation was investigated for MERS-CoV, SARS-CoV, and SARS-CoV-2 at serological pH by measuring their Amide I infrared absorption bands. The SARS-CoV-2 S1 secondary structure revealed a strong difference compared to those of MERS-CoV and SARS-CoV, with a significant presence of extended ß-sheets. Furthermore, the conformation of the SARS-CoV-2 S1 showed a significant change by moving from serological pH to mild acidic and alkaline pH conditions. Both results suggest the capability of infrared spectroscopy to follow the secondary structure adaptation of the SARS-CoV-2 S1 to different environments.
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COVID-19 , Middle East Respiratory Syndrome Coronavirus , Humans , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Spectrum AnalysisABSTRACT
The emergence of the Covid-19 pandemic has drawn great attention to vulnerable people affected by major diseases. Among them, Alzheimer's disease (AD) is the most prevalent disease. However, a long-standing challenge is to achieve early diagnosis of AD by detecting biomarkers such as amyloid beta (Aβ42), thus avoiding the labor of specialized hospital personnel and the high cost of imaging examinations using positron emission tomography. In this paper, we report a straightforward approach to realize a non-invasive lab-around fiber (LaF) optical sensor for AD biomarker detection, which is based on a tilted fiber Bragg grating (TFBG) combined with a nanoscale metallic thin film. We successfully demonstrated the detection of Aβ42 in complex biological matrices with a detection limit of 5 pg/mL. Therefore, our TFBG-SPR biosensor platform enables large-scale early disease screening and has great potential for clinical applications in early AD diagnosis. © 2022 IEEE.
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Various antibody therapeutics has been developed for the treatment and suppression of the 2019 outbreak of novel coronavirus（SARS-CoV-2）infection. A major limitation in the development of SARS-CoV-2 neutralizing antibodies is the occurrence and spread of escape variants that have mutations in the spike glycoprotein. The coronaviruses are carried by various wild animals, domestic animals, and pets, and there have been cases of Severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus transmission from animals to people, resulting in a large spread of infection in people. There is also a possibility that cross-species transmission of SARS-CoV-2 may occur in the future. Considering these factors, the development of antibody therapeutics with broad cross-reactivity against SARS-CoV-2 variants and other coronaviruses is required.Alternate :抄録2019年に発生した新型コロナウイルス（SARS-CoV-2）感染症の治療や発症抑制のためにさまざまな抗体医薬の開発が進められている。SARS-CoV-2中和抗体の開発で大きな障壁となるのが、スパイク糖タンパク質に変異をもつ変異株の発生と感染拡大である。またコロナウイルスは多くの野生動物や家畜、愛玩動物が保有しており、これまでにも重篤呼吸器症候群コロナウイルスや中東呼吸器症候群コロナウイルスが動物からヒトへ伝播して大きく感染が広がったケースがある。SARS-CoV-2についても動物が起源であると考えられており、今後も種を越えた伝播が発生する可能性が考えられる。これらを踏まえて、SARS-CoV-2変異株や類縁コロナウイルスに対する交差反応性に優れた抗体医薬の開発が求められる。
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Coronavirus disease 2019 (COVID-19) is an acute respiratory infection. Its virus called SARS-COV-2 which is an RNA virus with high homology to the bat coronavirus. In this review study, first the molecular and cellular characteristics and the proliferation and replication of SARS-COV-2 are investigated. Then, by reviewing bioinformatics studies regarding protected domain analysis, homology modeling, and molecular docking, the biological role of some specific SARS-COV-2 proteins are examined. The results showed that the open reading frame 8 (ORF8) and surface glycoprotein could bind to porphyrin. At the same time, ORF1ab, ORF10, and ORF3a can attack the heme part of hemoglobin to dissociate iron and form porphyrin. This attack reduces hemoglobin ability to carry oxygen and carbon dioxide. As a result, lung cells become severely inflamed due to their inability to exchange carbon dioxide and oxygen, which leads to large ground-glass opacities on CT scan images. Based on the bioinformatics results, chloroquine can prevent ORF1ab, ORF3a, and ORF10 from attacking hemoglobin to form porphyrin and avoid the binding of ORF8 and surface glycoprotein to porphyrin, which effectively relieves the symptoms of acute respiratory syndrome. In the current pandemic, bioinformatics studies are of great importance for preventing the spread of COVID-19, developing drugs and vaccines, and clinical practice.
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Objective: To investigate the serum levels of human cartilage glycoprotein 39 (YKL-40), 25-hydroxy vitamin D3 [25-hydroxy vitamin D3, 25 (OH)D3] and high mobility group protein B1 (high mobility group protein B1, HMGB1) level changes in the diagnosis of neonatal pneumonia infection type and the application of disease assessment. Methods: A total of 105 children with NP who were admitted to the Department of Neonatology, Longhua District People's Hospital of Shenzhen from January to December 2020 were selected as the research objects. According to different infectious pathogens, they were divided into a bacterial pneumonia group of 40 cases and a non-bacterial pneumonia group of 65 cases. According to the severity of the disease, they could be divided into 69 cases of mild pneumonia group and 36 cases of severe pneumonia group, and 85 healthy newborns were selected as the control group during the same period. Serum levels of YKL-40, 25 (OH)D3 and HMGB1 were detected by enzyme-linked immunosorbent assay. ROC curve was used to analyze the differential diagnosis value of YKL-40, 25 (OH) D3 and HMGB1 for NP alone or in combination. Spearman rank correlation was used the relationship between serum YKL-40, 25 (OH) D3 and HMGB1 levels and the severity of the disease in children with NP was analyzed. Results: The serum levels of YKL-40 (46.39 +or- 8.36 ng/ml, 40.28 +or- 8.47 ng/ml)and HMGB1 (23.38 +or- 5.66 ng/ml, 17.32 +or- 4.18 ng/ml) in the bacterial pneumonia groups and non-bacterial pneumonia groups were significantly higher than those in the control group (30.49 +or- 6.35 ng/ml, 12.56 +or- 3.22 ng/ml), and the differences were statistically significant (F=939.480, 99.507, all P < 0.05), while bacterial and non-bacterial pneumonia groups serum 25 (OH) D3 (12.76 +or- 3.57 g/L, 18.33 +or- 4.21 g/L) levels were significantly lower than those in the control group (19.76 +or- 4.87 g/L), and the difference was statistically significant (F=225.752, P < 0.05). The serum levels of YKL-40 (52.56 +or- 9.68 ng/ml) and HMGB1 (26.74 +or- 4.57 ng/ml) in the severe group were significantly higher than those in the mild group (16.63 +or- 5.32 ng/ml, 9.63 +or- 2.38 ng/ml) and the control group (11.63 +or- 3.32 ng/ml, 6.34 +or- 2.06 ng/ml), the differences were all statistical significance (F=265.331, 55.426, all P < 0.05), and serum 25 (OH) D3 (9.76 +or- 3.54 g/L, 31.16 +or- 5.01 g/L)levels in the severe and mild were significantly lower than control groups (35.16 +or- 5.88 g/L) (F=55.426, P < 0.05) . The results of Spearman rank correlation analysis showed that the disease severity was positively correlated with serum YKL-40 and HMGB1 levels (r=0.727, 0.210, all P < 0.05), but negatively correlated with 25 (OH) D3 levels (r= -0.566, P < 0.05). The results of ROC curve analysis showed that the combined detection of YKL-40, 25 (OH) D3 and HMGB1 had the highest efficacy in diagnosing NP, the AUC was 0.912 (95%CI: 0.864-0.932), the sensitivity and specificity were 96.34%, 85.72%, respectively. In the single detection of each index, the differences in AUC were statistically significant (Z=0.746, 2.843, 3.662, all P < 0.05). The combined detection of the three had the highest diagnostic efficiency in distinguishing neonatal bacterial pneumonia from non-bacterial pneumonia, and its AUC was 0.894 (95%CI: 0.832-0.941), the sensitivity and specificity were 97.26%, 80.66%, respectively. Which was higher than the single test of each index, and the difference in AUC was statistically significant (Z=1.573, 3.228, 2.689, all P < 0.05). Conclusion: Serum levels of YKL-40, 25 (OH) D3 and HMGB1 had important clinical value in diagnosis of NP infection types and in reflecting the severity of children's disease, the combined detection of the three has better clinical diagnostic performance.
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Different serological assays were rapidly generated to study humoral responses against the SARS-CoV-2 Spike glycoprotein. Due to the intrinsic difficulty of working with SARS-CoV-2 authentic virus, most serological assays use recombinant forms of the Spike glycoprotein or its receptor binding domain (RBD). Cell-based assays expressing different forms of the Spike, as well as pseudoviral assays, are also widely used. To evaluate whether these assays recapitulate findings generated when the Spike is expressed in its physiological context (at the surface of the infected primary cells), we developed an intracellular staining against the SARS-CoV-2 nucleocapsid (N) to distinguish infected from uninfected cells. Human airway epithelial cells (pAECs) were infected with authentic SARS-CoV-2 D614G or Alpha variants. We observed robust cell-surface expression of the SARS-CoV-2 Spike at the surface of the infected pAECs using the conformational-independent anti-S2 CV3-25 antibody. The infected cells were also readily recognized by plasma from convalescent and vaccinated individuals and correlated with several serological assays. This suggests that the antigenicity of the Spike present at the surface of the infected primary cells is maintained in serological assays involving expression of the native full-length Spike.
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Cell Membrane/metabolism , Epithelial Cells/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Antibodies, Viral/immunology , Antibody-Dependent Cell Cytotoxicity , Bronchioles/cytology , Cells, Cultured , Coronavirus Nucleocapsid Proteins/metabolism , Epithelial Cells/virology , HEK293 Cells , Humans , Neutralization Tests , Phosphoproteins/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunologyABSTRACT
The emergence of the SARS-CoV-2 virus and the associated pandemic has affected the entire human population. Human susceptibility to the virus has highlighted a tremendous need for affordable diagnostic systems to manage the pandemic and monitor the effectiveness of vaccination. We have developed a simple and label-free electrochemical immunosensor for the detection of human anti-SARS-CoV-2 IgG antibodies, which consists of a supporting screen-printed carbon electrode (SPCE) modified with an electrodeposited polyaniline film and glutaraldehyde, allowing effective immobilization of the SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) as a biorecognition element. The impedimetric immunosensor showed a linear response over a wide concentration range of 0.01–10 μg mL−1, that is, 67 pM–6.7 nM, with a low detection limit of 25.9 pM. A dual working electrode configuration with a built-in negative control unit was demonstrated for practical field applications. The immunosensor was successfully used in a real serum sample from an infected patient and showed good reproducibility and fair agreement with ELISA. An optional amplification step with secondary goat anti-human IgG antibodies was demonstrated, resulting in an extended linear range and a detection limit as low as 0.93 pM.
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[...]we highlight ongoing investigational treatment approaches that are so relevant to the care of oncology patients during this extraordinary pandemic. While many therapeutic strategies are currently being evaluated as possible COVID-19 treatments, there are currently no highly effective antiviral therapies or vaccines available to combat this virus, and mortality in severe disease remains high.6 Risk factors for severe illness resulting from COVID-19 are age greater than 65 years, diabetes, chronic lung disease, and obesity,7 and cancer patients who contract COVID-19, in particular, have been shown to have worse outcomes.8 In the initial experience reported from Wuhan, China, 1% of cancer patients were noted to contract COVID-19, compared with just 0.29% incidence in the general population.8 This may be attributed to greater detection rates in more closely surveilled cancer patients, but it could also be associated with nosocomial exposures and diminished im mune defenses.8 Cancer patients were also observed to be at higher risk for the development of severe COVID-19, which may be due to generally advanced age, increased prevalence of tobacco use, and higher incidence of comorbid pulmonary disease.9 Liang et al also demonstrated that cancer patients were more likely to require intensive care or experience mortality as compared with other COVID-19 patients (39% vs 8%).9 Cancer treatment may also increase COVID-19 susceptibility. Lin et al recommend LMWH at 100 U/kg every 12 hours for at least 3 to 5 days.8 In addition, a study performed in Tongji Hospital in Wuhan reviewed 449 patients with severe COVID-19, with 94 patients receiving LMWH (40-60 mg/day) and 5 receiving unfractionated heparin (1000-15,000 U/day) for 7 days or longer;the results showed that the 28-day mortality for LMWH or unfractionated heparin users with a sepsis-induced coagulopathy score of ≥4 and D-dimers >6 times the upper limit of normal was lower than that of non-LMWH or unfractionated heparin users.14 This has led several institutions, including our own, to institute anticoagulation protocols based on various parameters such as D-dimer levels.17 Pathophysiology of COVID-19 Coronaviruses are large, single-stranded, positive-sense RNA strand that encapsulate within a membrane envelope surrounded by glycoprotein spikes, forming a crown-like appearance.18 Less-pathogenic endemic human coronaviruses such as OC43, HKU1, NL63, and 229E exist, causing seasonally, self-limited upper respiratory symptoms.19 In contrast, more severe respiratory symptoms are caused by zoonotic human coronaviruses, including severe acute respiratory distress syndrome coronavirus (SARSCoV) discovered in November 2002 in Guangdong, China;Middle Eastern respiratory syndrome-related coronavirus (MERS-CoV) identified in 2012 in Saudi Arabia;and COVID-19.18 The subfamily, Coronavirinae, is divided into 4 classes of coronaviruses: α, β, δ, and γ. ACE2 has been shown to promote anti-inflammatory and antifibrotic effects, and it protects these cells from ARDS.19 In SARS-CoV-2, ACE2 ectodomain can shed as a result of spikes from the viral glycoprotein, reducing the catalytic function of ACE2 and promoting ARDS.19 In addition, SARS-CoV-2 has been shown to reduce synthesis of interferon-α and interferon-β and to increase inflammatory cytokines and chemokines.20 In lung adenocarcinomas, ACE2 gene expression
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Coronaviruses are a leading cause of emerging life-threatening diseases, as evidenced by the ongoing coronavirus disease pandemic (COVID-19). According to complete genome sequence analysis reports, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19, has a sequence identity highly similar to the earlier severe acute respiratory syndrome coronavirus (SARS-CoV). The SARS-CoV-2 has the same mode of transmission, replication, and pathogenicity as SARS-CoV. The SARS-CoV-2 spike protein's receptor-binding domain (RBD) binds to host angiotensin-converting enzyme-2 (ACE2). The ACE2 is overexpressed in various cells, most prominently epithelial cells of the lung (surface of type 1 and 2 pneumocytes), intestine, liver, kidney, and nervous system. As a result, these organs are more vulnerable to SARS-CoV-2 infection. Furthermore, renin-angiotensin system (RAS) blockers, which are used to treat cardiovascular diseases, intensify ACE2 expression, leading to an increase in the risk of COVID-19. ACE2 hydrolyzes angioten-sin-II (carboxypeptidase) to heptapeptide angiotensin (1-7) and releases a C-terminal amino acid. By blocking the interaction of spike protein with ACE2, the SARS-CoV-2 entry into the host cell and inter-nalization can be avoided. The pathogenicity of SARS-CoV-2 could be reduced by preventing the RBD from attaching to ACE2-expressing cells. Therefore, inhibition or down-regulation of ACE2 in host cells represents a therapeutic strategy to fight against COVID-19. However, ACE2 plays an essential role in the physiological pathway, protecting against hypertension, heart failure, myocardial infarction, acute respiratory lung disease, and diabetes. Given the importance of ACE's homeostatic role, targeting of ACE2 should be realized with caution. Above all, focusing on the SARS-CoV-2 spike protein and the ACE2 gene in the host cell is an excellent way to avoid viral mutation and resistance. The current review summarises the sequence analysis, structure of coronavirus, ACE2, spike protein-ACE2 complex, essential structural characteristics of the spike protein RBD, and ACE2 targeted approaches for anti-coronaviral drug design and development.Copyright © 2022 Bentham Science Publishers.
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The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has serious consequences on global public health and social development. The binding of receptor binding domain (RBD) of spike protein to angiotensin converting enzyme 2 (ACE2) on the surface of SARS-CoV-2 host cell initiates the infection progress. Spike and ACE2 are both glycoproteins, the impact of glycosylation on protein structures and protein-protein interactions remains largely elusive. Characterizing the structural and dynamics of protein-protein binding progress will improve mechanism understanding of viral infection and facilitate targeted drug design. Structural mass spectrometry (MS) method is widely used in protein structural studies, providing complementary information to conventional biophysical methods, such as X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and cryo-electron microscopy (cryo-EM). Native mass spectrometry (native MS) is an emerging technology that enables the study of intact protein, non-covalent protein-protein, and protein-ligand complexes in their biological state, which can provide structural stability, binding stoichiometry, and spatial arrangement information. Here, native MS was used to examine the interaction between RBD and ACE2 as well as the impact of deglycosylation on the interaction stability of the RBD-ACE2 complex. The results revealed that both RBD and ACE2 are highly glycosylated, ACE2 presents as a dimer while RBD as a monomer, and they form a (RBD-ACE2)2 complex. The conditions of using PNGasc F to remove the N-glycan were optimized. At least two Oglycans including NcuAc(2) and GalNAcC 1) Gal( 1) NcuAc(2) or GlcNAcd ) Gal(l) NeuAc(2) were observed for the N-glycan removed RBD. Furthermore, the stability of the complexes formed by glycosylated and deglycosylated RBD with ACE2 was compared, and the results showed that the removal of N-glycan significantly drops the interaction stability of the RBD-ACE2 complex. Therefore, we recommend that glycosyla-tion should not be removed for structural and functional studies. Additional glycosyla-tion, structural and dynamics studies on Spike (including separated RBD) and ACE2 complexes would help us to understand the process of viral infection, advance drug design and vaccine developments. Nowadays, a comprehensive MS-based toolbox has been developed for the analysis of protein structure, function, and dynamics, including hydrogen-deuterium exchange MS (HDX-MS), native top-down (nTD) MS, cross-linking MS (XL-MS), and covalent labelling MS (CL-MS), etc. Through integrating structural MS methods, more detailed and comprehensive structural information about glycoproteins and their complexes will be uncovered. © 2022 Chinese Society for Mass Spectrometry. All rights reserved.
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The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has serious consequences on global public health and social development. The binding of receptor binding domain (RBD) of spike protein to angiotensin converting enzyme 2 (ACE2) on the surface of SARS-CoV-2 host cell initiates the infection progress. Spike and ACE2 are both glycoproteins, the impact of glycosylation on protein structures and protein-protein interactions remains largely elusive. Characterizing the structural and dynamics of protein-protein binding progress will improve mechanism understanding of viral infection and facilitate targeted drug design. Structural mass spectrometry (MS) method is widely used in protein structural studies, providing complementary information to conventional biophysical methods, such as X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and cryo-electron microscopy (cryo-EM). Native mass spectrometry (native MS) is an emerging technology that enables the study of intact protein, non-covalent protein-protein, and protein-ligand complexes in their biological state, which can provide structural stability, binding stoichiometry, and spatial arrangement information. Here, native MS was used to examine the interaction between RBD and ACE2 as well as the impact of deglycosylation on the interaction stability of the RBD-ACE2 complex. The results revealed that both RBD and ACE2 are highly glycosylated, ACE2 presents as a dimer while RBD as a monomer, and they form a (RBD-ACE2)2 complex. The conditions of using PNGasc F to remove the N-glycan were optimized. At least two Oglycans including NcuAc(2) and GalNAcC 1) Gal( 1) NcuAc(2) or GlcNAcd ) Gal(l) NeuAc(2) were observed for the N-glycan removed RBD. Furthermore, the stability of the complexes formed by glycosylated and deglycosylated RBD with ACE2 was compared, and the results showed that the removal of N-glycan significantly drops the interaction stability of the RBD-ACE2 complex. Therefore, we recommend that glycosyla-tion should not be removed for structural and functional studies. Additional glycosyla-tion, structural and dynamics studies on Spike (including separated RBD) and ACE2 complexes would help us to understand the process of viral infection, advance drug design and vaccine developments. Nowadays, a comprehensive MS-based toolbox has been developed for the analysis of protein structure, function, and dynamics, including hydrogen-deuterium exchange MS (HDX-MS), native top-down (nTD) MS, cross-linking MS (XL-MS), and covalent labelling MS (CL-MS), etc. Through integrating structural MS methods, more detailed and comprehensive structural information about glycoproteins and their complexes will be uncovered. © 2022 Chinese Society for Mass Spectrometry. All rights reserved.
ABSTRACT
Coarse-grained (CG) modeling has defined a well-established approach to accessing greater space and time scales inaccessible to the computationally expensive all-atomic (AA) molecular dynamics (MD) simulations. Popular methods of CG follow a bottom-up architecture to match properties of fine-grained or experimental data whose development is a daunting challenge for requiring the derivation of a new set of parameters in potential calculation. We proposed a novel physics-informed machine learning (PIML) framework for a CG model and applied it, as a verification, for modeling the SARS-CoV-2 spike glycoprotein. The PIML in the proposed framework employs a force-matching scheme with which we determined the force-field parameters. Our PIML framework defines its trainable parameters as the CG force-field parameters and predicts the instantaneous forces on each CG bead, learning the force field parameters to best match the predicted forces with the reference forces. Using the learned interaction parameters, CGMD validation simulations reach the microsecond time scale with stability, at a simulation speed 40,000 times faster than the conventional AAMD. Compared with the traditional iterative approach, our framework matches the AA reference structure with better accuracy. The improved efficiency enhances the timeliness of research and development in producing long-term simulations of SARS-CoV-2 and opens avenues to help illuminate protein mechanisms and predict its environmental changes.
ABSTRACT
Patients suffering severe COVID-19 show an aggressive and excessive immune response against the SARS-CoV-2 coronavirus, known as a cytokine storm. If left untreated these patients face the risk of tissue damage, multi-organ failure and death. A high relative abundance of Prevotella copri has been reported in patients with newly diagnosed rheumatoid arthritis (RA). On the other hand, it has been observed that Prevotella histicola can modulate the inflammatory manifestations of autoimmune diseases like multiple sclerosis, and it is now being evaluated as a monoclonal microbial treatment in COVID-19. We observed that pre-treatment with P. histicola decreased NF-kB activation, while pre-treatment with P. histicola and P. copri decreased IRF activation in monocytes upon SARS-CoV-2 glycoprotein. Our findings suggest that exposure of blood immune cells, such as monocytes, to commensal species of Prevotella may reduce the inflammatory response to SARS-CoV-2 glycoprotein. Besides treatments targeting the viral infection, other treatments such as immunomodulation by bacteria aiming to reduce or regulate the inflammatory process in COVID-19 to avoid the development of related complications may be considered.
ABSTRACT
A novel coronavirus strain has been testing the capabilities of our modern world and suffocating health care systems, while bringing together scientist's researches and governmental powers, to fight off its robust viral disease. A new zoonotic pathogenic member of the human coronaviruses, that was first documented in Wuhan, China, has crossed the species barrier to infect humans and caused an outbreak of viral pneumonia. In this brief review, we'll discuss the virology of SARS-CoV-2, the virus that causes COVID-19, covering the general structure of the virus, its genetics and its process of replication. SARS-CoV-2 gets into the cell through the recognition of the angiotensin-converting enzyme 2 (ACE2) receptors by the spike glycoprotein, with the aid of the priming protein transmembrane serine protease 2 (TMPRSS2), which is important for its activation, and replicates as a result of a complex process that involves RNA synthesis, proofreading and capping.