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Wei L, Song L, Dunker AK, Foster JA, Uversky VN, Goh GKM. A Comparative Experimental and Computational Study on the Nature of the Pangolin-CoV and COVID-19 Omicron. Int J Mol Sci 2024; 25:7537. [PMID: 39062780 PMCID: PMC11277539 DOI: 10.3390/ijms25147537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 06/28/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
The relationship between pangolin-CoV and SARS-CoV-2 has been a subject of debate. Further evidence of a special relationship between the two viruses can be found by the fact that all known COVID-19 viruses have an abnormally hard outer shell (low M disorder, i.e., low content of intrinsically disordered residues in the membrane (M) protein) that so far has been found in CoVs associated with burrowing animals, such as rabbits and pangolins, in which transmission involves virus remaining in buried feces for a long time. While a hard outer shell is necessary for viral survival, a harder inner shell could also help. For this reason, the N disorder range of pangolin-CoVs, not bat-CoVs, more closely matches that of SARS-CoV-2, especially when Omicron is included. The low N disorder (i.e., low content of intrinsically disordered residues in the nucleocapsid (N) protein), first observed in pangolin-CoV-2017 and later in Omicron, is associated with attenuation according to the Shell-Disorder Model. Our experimental study revealed that pangolin-CoV-2017 and SARS-CoV-2 Omicron (XBB.1.16 subvariant) show similar attenuations with respect to viral growth and plaque formation. Subtle differences have been observed that are consistent with disorder-centric computational analysis.
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Affiliation(s)
- Lai Wei
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100089, China;
| | - Lihua Song
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100089, China;
| | - A. Keith Dunker
- Center for Computational Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - James A. Foster
- Department of Biological Sciences, University of Idaho, Moscow, ID 83844, USA;
- Institute for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, ID 83844, USA
| | - Vladimir N. Uversky
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA;
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Dhulipala S, Uversky VN. Looking at the Pathogenesis of the Rabies Lyssavirus Strain Pasteur Vaccins through a Prism of the Disorder-Based Bioinformatics. Biomolecules 2022; 12:1436. [PMID: 36291645 PMCID: PMC9599798 DOI: 10.3390/biom12101436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/30/2022] [Accepted: 10/04/2022] [Indexed: 11/28/2022] Open
Abstract
Rabies is a neurological disease that causes between 40,000 and 70,000 deaths every year. Once a rabies patient has become symptomatic, there is no effective treatment for the illness, and in unvaccinated individuals, the case-fatality rate of rabies is close to 100%. French scientists Louis Pasteur and Émile Roux developed the first vaccine for rabies in 1885. If administered before the virus reaches the brain, the modern rabies vaccine imparts long-lasting immunity to the virus and saves more than 250,000 people every year. However, the rabies virus can suppress the host's immune response once it has entered the cells of the brain, making death likely. This study aimed to make use of disorder-based proteomics and bioinformatics to determine the potential impact that intrinsically disordered protein regions (IDPRs) in the proteome of the rabies virus might have on the infectivity and lethality of the disease. This study used the proteome of the Rabies lyssavirus (RABV) strain Pasteur Vaccins (PV), one of the best-understood strains due to its use in the first rabies vaccine, as a model. The data reported in this study are in line with the hypothesis that high levels of intrinsic disorder in the phosphoprotein (P-protein) and nucleoprotein (N-protein) allow them to participate in the creation of Negri bodies and might help this virus to suppress the antiviral immune response in the host cells. Additionally, the study suggests that there could be a link between disorder in the matrix (M) protein and the modulation of viral transcription. The disordered regions in the M-protein might have a possible role in initiating viral budding within the cell. Furthermore, we checked the prevalence of functional disorder in a set of 37 host proteins directly involved in the interaction with the RABV proteins. The hope is that these new insights will aid in the development of treatments for rabies that are effective after infection.
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Affiliation(s)
- Surya Dhulipala
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Vladimir N. Uversky
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
- USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
- Protein Research Group, Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, 142290 Pushchino, Moscow Region, Russia
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A Study on the Nature of SARS-CoV-2 Using the Shell Disorder Models: Reproducibility, Evolution, Spread, and Attenuation. Biomolecules 2022; 12:biom12101353. [PMID: 36291562 PMCID: PMC9599796 DOI: 10.3390/biom12101353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/19/2022] [Accepted: 09/20/2022] [Indexed: 12/03/2022] Open
Abstract
The basic tenets of the shell disorder model (SDM) as applied to COVID-19 are that the harder outer shell of the virus shell (lower PID—percentage of intrinsic disorder—of the membrane protein M, PIDM) and higher flexibility of the inner shell (higher PID of the nucleocapsid protein N, PIDN) are correlated with the contagiousness and virulence, respectively. M protects the virion from the anti-microbial enzymes in the saliva and mucus. N disorder is associated with the rapid replication of the virus. SDM predictions are supported by two experimental observations. The first observation demonstrated lesser and greater presence of the Omicron particles in the lungs and bronchial tissues, respectively, as there is a greater level of mucus in the bronchi. The other observation revealed that there are lower viral loads in 2017-pangolin-CoV, which is predicted to have similarly low PIDN as Omicron. The abnormally hard M, which is very rarely seen in coronaviruses, arose from the fecal–oral behaviors of pangolins via exposure to buried feces. Pangolins provide an environment for coronavirus (CoV) attenuation, which is seen in Omicron. Phylogenetic study using M shows that COVID-19-related bat-CoVs from Laos and Omicron are clustered in close proximity to pangolin-CoVs, which suggests the recurrence of interspecies transmissions. Hard M may have implications for long COVID-19, with immune systems having difficulty degrading viral proteins/particles.
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Goh GKM, Dunker AK, Foster JA, Uversky VN. Shell Disorder Models Detect That Omicron Has Harder Shells with Attenuation but Is Not a Descendant of the Wuhan-Hu-1 SARS-CoV-2. Biomolecules 2022; 12:631. [PMID: 35625559 PMCID: PMC9139003 DOI: 10.3390/biom12050631] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 04/17/2022] [Accepted: 04/20/2022] [Indexed: 02/01/2023] Open
Abstract
Before the SARS-CoV-2 Omicron variant emergence, shell disorder models (SDM) suggested that an attenuated precursor from pangolins may have entered humans in 2017 or earlier. This was based on a shell disorder analysis of SARS-CoV-1/2 and pangolin-Cov-2017. The SDM suggests that Omicron is attenuated with almost identical N (inner shell) disorder as pangolin-CoV-2017 (N-PID (percentage of intrinsic disorder): 44.8% vs. 44.9%-lower than other variants). The outer shell disorder (M-PID) of Omicron is lower than that of other variants and pangolin-CoV-2017 (5.4% vs. 5.9%). COVID-19-related CoVs have the lowest M-PIDs (hardest outer shell) among all CoVs. This is likely to be responsible for the higher contagiousness of SARS-CoV-2 and Omicron, since hard outer shell protects the virion from salivary/mucosal antimicrobial enzymes. Phylogenetic study using M reveals that Omicron branched off from an ancestor of the Wuhan-Hu-1 strain closely related to pangolin-CoVs. M, being evolutionarily conserved in COVID-19, is most ideal for COVID-19 phylogenetic study. Omicron may have been hiding among burrowing animals (e.g., pangolins) that provide optimal evolutionary environments for attenuation and increase shell hardness, which is essential for fecal-oral-respiratory transmission via buried feces. Incoming data support SDM e.g., the presence of fewer infectious particles in the lungs than in the bronchi upon infection.
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Affiliation(s)
| | - A. Keith Dunker
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - James A. Foster
- Department of Biological Sciences, University of Idaho, Moscow, ID 83844, USA;
- Institute for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, ID 83844, USA
| | - Vladimir N. Uversky
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA;
- Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, 142290 Moscow Region, Russia
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Goh GKM, Dunker AK, Foster JA, Uversky VN. Computational, Experimental, and Clinical Evidence of a Specific but Peculiar Evolutionary Nature of (COVID-19) SARS-CoV-2. J Proteome Res 2022; 21:874-890. [PMID: 35142523 PMCID: PMC8864774 DOI: 10.1021/acs.jproteome.2c00001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Indexed: 11/30/2022]
Abstract
The shell disorder models have predicted that SARS-CoV-2 is of a specific but peculiar evolutionary nature. All coronaviruses (CoVs) closely related to SARS-CoV-2 have been found to have the hardest outer shells (M protein) among CoVs. This hard shell (low M percentage of intrinsic disorder (PID)) is associated with burrowing animals, for example, pangolins, and is believed to be responsible for the high contagiousness of SARS-CoV-2 because it will be more resistant to antimicrobial enzymes found in saliva/mucus. Incoming clinical and experimental data do support this along with a prediction based on another aspect of the shell (N, inner shell) disorder models that SARS-CoV-1 is more virulent than SARS-CoV-2 because SARS-CoV-2 produces fewer virus copies in vital organs even if large amounts of infections particles are shed orally and nasally. A phylogenetic study using M reveals a closer relationship of SARS-CoV to pangolin-CoVs than the bat-RaTG13 found in Yunnan, China. Previous studies may have been confused by recombinations that were poorly handled. The shell disorder models suggest that a pangolin-CoV strain may have entered the human population in 2017 or before as an attenuated virus, which could explain why SARS-CoV is found to be highly adapted to humans.
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Affiliation(s)
| | - A. Keith Dunker
- Center for Computational Biology and Bioinformatics,
Indiana University School of Medicine, Indianapolis, Indiana
46202, United States
| | - James A. Foster
- Department of Biological Sciences,
University of Idaho, Moscow, Idaho 83844, United
States
- Institute for Bioinformatics and Evolutionary Studies,
University of Idaho, Moscow, Idaho 83844, United
States
| | - Vladimir N. Uversky
- Department of Molecular Medicine, USF Health Byrd
Alzheimer’s Research Institute, Morsani College of Medicine,
University of South Florida, Tampa, Florida 33620,
United States
- Laboratory of New Methods in Biology, Institute for
Biological Instrumentation of the Russian Academy of Sciences, Federal
Research Center “Pushchino Scientific Center for Biological Research of the
Russian Academy of Sciences”, Pushchino, Moscow Region 142290,
Russia
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6
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Tenchov R, Zhou QA. Intrinsically Disordered Proteins: Perspective on COVID-19 Infection and Drug Discovery. ACS Infect Dis 2022; 8:422-432. [PMID: 35196007 PMCID: PMC8887652 DOI: 10.1021/acsinfecdis.2c00031] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Indexed: 12/23/2022]
Abstract
Since the beginning of the COVID-19 pandemic caused by SARS-CoV-2, millions of patients have been diagnosed and many of them have died from the disease worldwide. The identification of novel therapeutic targets are of utmost significance for prevention and treatment of COVID-19. SARS-CoV-2 is a single-stranded RNA virus with a 30 kb genome packaged into a membrane-enveloped virion, transcribing several tens of proteins. The belief that the amino acid sequence of proteins determines their 3D structure which, in turn, determines their function has been a central principle of molecular biology for a long time. Recently, it has been increasingly realized, however, that there is a large group of proteins that lack a fixed or ordered 3D structure, yet they exhibit important biological activities─so-called intrinsically disordered proteins and protein regions (IDPs/IDRs). Disordered regions in viral proteins are generally associated with viral infectivity and pathogenicity because they endow the viral proteins the ability to easily and promiscuously bind to host proteins; therefore, the proteome of SARS-CoV-2 has been thoroughly examined for intrinsic disorder. It has been recognized that, in fact, the SARS-CoV-2 proteome exhibits significant levels of structural order, with only the nucleocapsid (N) structural protein and two of the nonstructural proteins being highly disordered. The spike (S) protein of SARS-CoV-2 exhibits significant levels of structural order, yet its predicted percentage of intrinsic disorder is still higher than that of the spike protein of SARS-CoV. Noteworthy, however, even though IDPs/IDRs are not common in the SARS-CoV-2 proteome, the existing ones play major roles in the functioning and virulence of the virus and are thus promising drug targets for rational antiviral drug design. Presented here is a COVID-19 perspective on the intrinsically disordered proteins, summarizing recent results on the SARS-CoV-2 proteome disorder features, their physiological and pathological relevance, and their prominence as prospective drug target sites.
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Affiliation(s)
- Rumiana Tenchov
- CAS, a division of the American Chemical Society,
Columbus, Ohio 43210, United States
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7
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Sen S, Dey A, Bandhyopadhyay S, Uversky VN, Maulik U. Understanding structural malleability of the SARS-CoV-2 proteins and relation to the comorbidities. Brief Bioinform 2021; 22:6304388. [PMID: 34143202 DOI: 10.1093/bib/bbab232] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 05/13/2021] [Accepted: 05/27/2021] [Indexed: 12/11/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of the coronavirus disease (COVID-19), is a part of the $\beta $-Coronaviridae family. The virus contains five major protein classes viz., four structural proteins [nucleocapsid (N), membrane (M), envelop (E) and spike glycoprotein (S)] and replicase polyproteins (R), synthesized as two polyproteins (ORF1a and ORF1ab). Due to the severity of the pandemic, most of the SARS-CoV-2-related research are focused on finding therapeutic solutions. However, studies on the sequences and structure space throughout the evolutionary time frame of viral proteins are limited. Besides, the structural malleability of viral proteins can be directly or indirectly associated with the dysfunctionality of the host cell proteins. This dysfunctionality may lead to comorbidities during the infection and may continue at the post-infection stage. In this regard, we conduct the evolutionary sequence-structure analysis of the viral proteins to evaluate their malleability. Subsequently, intrinsic disorder propensities of these viral proteins have been studied to confirm that the short intrinsically disordered regions play an important role in enhancing the likelihood of the host proteins interacting with the viral proteins. These interactions may result in molecular dysfunctionality, finally leading to different diseases. Based on the host cell proteins, the diseases are divided in two distinct classes: (i) proteins, directly associated with the set of diseases while showing similar activities, and (ii) cytokine storm-mediated pro-inflammation (e.g. acute respiratory distress syndrome, malignancies) and neuroinflammation (e.g. neurodegenerative and neuropsychiatric diseases). Finally, the study unveils that males and postmenopausal females can be more vulnerable to SARS-CoV-2 infection due to the androgen-mediated protein transmembrane serine protease 2.
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Affiliation(s)
- Sagnik Sen
- Department of Computer Science and Engineering, Jadavpur University, Kolkata-32, West Bengal, India
| | - Ashmita Dey
- Department of Computer Science and Engineering, Jadavpur University, Kolkata-32, West Bengal, India
| | | | - Vladimir N Uversky
- Department of Molecular Medicine and Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America.,Laboratory of New Methods in Biology, Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences", Pushchino, Moscow region, 142290 Russia
| | - Ujjwal Maulik
- Department of Computer Science and Engineering, Jadavpur University, Kolkata-32, West Bengal, India
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Mishra BK, Keshri AK, Saini DK, Ayesha S, Mishra BK, Rao YS. Mathematical model, forecast and analysis on the spread of COVID-19. CHAOS, SOLITONS, AND FRACTALS 2021; 147:110995. [PMID: 33935381 PMCID: PMC8079075 DOI: 10.1016/j.chaos.2021.110995] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 04/17/2021] [Accepted: 04/20/2021] [Indexed: 05/31/2023]
Abstract
Pandemic COVID-19 which has infected more than 35,027,546 people and death more than 1,034,837 people in 235 countries as on October 05, 2020 has created a chaos across the globe. In this paper, we develop a compartmental epidemic model to understand the spreading behaviour of the disease in human population with a special case of Bhilwara, a desert town in India where successful control measures TTT (tracking, testing and treatment) was adopted to curb the disease in the very early phase of the spread of the disease in India. Local and global asymptotic stability is established for endemic equilibrium. Extensive numerical simulations with real parametric values are performed to validate the analytical results. Trend analysis of fatality rate, infection rate, and impact of lockdown is performed for USA, European countries, Russia, Iran, China, Japan, S. Korea with a comparative assessment by India. Kruskal - Wallis test is performed to test the null hypothesis for infected cases during the four lockdown phases in India. It has been observed that there is a significant difference at both 95% and 99% confidence interval in the infected cases, recovered cases and the case fatality rate during all the four phases of the lockdown.
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Affiliation(s)
| | - Ajit Kumar Keshri
- Department of Computer Science & Engineering, Birla Institute of Technology, Mesra, Ranchi, India
| | - Dinesh Kumar Saini
- Department of Computer and Communication Engineering, Manipal University Jaipur, India
| | - Syeda Ayesha
- Department of Financial Management, Wollongong University, Dubai, UAE
| | | | - Yerra Shankar Rao
- Department of Mathematics, Gandhi Institute of Excellent Technocrats, Ghangapatana, Bhubaneswar, India
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9
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Schiavina M, Pontoriero L, Uversky VN, Felli IC, Pierattelli R. The highly flexible disordered regions of the SARS-CoV-2 nucleocapsid N protein within the 1-248 residue construct: sequence-specific resonance assignments through NMR. BIOMOLECULAR NMR ASSIGNMENTS 2021; 15:219-227. [PMID: 33660218 PMCID: PMC7928198 DOI: 10.1007/s12104-021-10009-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 02/15/2021] [Indexed: 05/04/2023]
Abstract
The nucleocapsid protein N from SARS-CoV-2 is one of the most highly expressed proteins by the virus and plays a number of important roles in the transcription and assembly of the virion within the infected host cell. It is expected to be characterized by a highly dynamic and heterogeneous structure as can be inferred by bioinformatics analyses as well as from the data available for the homologous protein from SARS-CoV. The two globular domains of the protein (NTD and CTD) have been investigated while no high-resolution information is available yet for the flexible regions of the protein. We focus here on the 1-248 construct which comprises two disordered fragments (IDR1 and IDR2) in addition to the N-terminal globular domain (NTD) and report the sequence-specific assignment of the two disordered regions, a step forward towards the complete characterization of the whole protein.
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Affiliation(s)
- Marco Schiavina
- Magnetic Resonance Center - CERM, University of Florence, Via Luigi Sacconi 6, 50019, Sesto Fiorentino, FI, Italy
- Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, 50019, Sesto Fiorentino, FI, Italy
| | - Letizia Pontoriero
- Magnetic Resonance Center - CERM, University of Florence, Via Luigi Sacconi 6, 50019, Sesto Fiorentino, FI, Italy
- Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, 50019, Sesto Fiorentino, FI, Italy
| | - Vladimir N Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA
| | - Isabella C Felli
- Magnetic Resonance Center - CERM, University of Florence, Via Luigi Sacconi 6, 50019, Sesto Fiorentino, FI, Italy.
- Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, 50019, Sesto Fiorentino, FI, Italy.
| | - Roberta Pierattelli
- Magnetic Resonance Center - CERM, University of Florence, Via Luigi Sacconi 6, 50019, Sesto Fiorentino, FI, Italy.
- Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, 50019, Sesto Fiorentino, FI, Italy.
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10
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Alharbi SN, Alrefaei AF. Comparison of the SARS-CoV-2 (2019-nCoV) M protein with its counterparts of SARS-CoV and MERS-CoV species. JOURNAL OF KING SAUD UNIVERSITY. SCIENCE 2021; 33:101335. [PMID: 33432259 PMCID: PMC7787911 DOI: 10.1016/j.jksus.2020.101335] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/13/2020] [Accepted: 12/27/2020] [Indexed: 05/09/2023]
Abstract
Coronaviruses M proteins are well-represented in the major protein component of the viral envelope. During the viral assembly, they play an important role by association with all other viral structural proteins. Despite their crucial functions, very little information regarding the structures and functions of M proteins is available. Here we utilize bioinformatic tools from available sequences and 3D structures of SARS-CoV, SARS-CoV2, and MERS-CoV M proteins in order to predict potential B-cell epitopes and assessing antibody binding affinity. Such study aims to aid finding more effective vaccines and recognize neutralizing antibodies. we found some rather exciting differences between SARS-COV-2, SARS-Cov and MERS-CoV M proteins. Two SARS-CoV-2 peptides with significant antigen presentation scores for human cell surface proteins have been identified. The results reveal that N-terminal domains of M proteins of SARS-CoV and SARS-CoV2 are translocated (outside) whereas it is inside (cytoplasmic side) in MERS-CoV.
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Affiliation(s)
- Sultan Nafea Alharbi
- National Centre for Biotechnology, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia
| | - Abdulwahed Fahad Alrefaei
- Department of Zoology, King Saud University, College of Science, P. O. Box 2455, Riyadh 11451, Saudi Arabia
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11
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Goh GKM, Uversky VN. Shell disorder and the HIV vaccine mystery: lessons from the legendary Oswald Avery. J Biomol Struct Dyn 2021; 40:5702-5711. [PMID: 33410379 DOI: 10.1080/07391102.2020.1870562] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The search for a human immunodeficiency virus (HIV) vaccine has spanned nearly four decades without much success. A much needed paradigm shift can be found in the abnormally high levels of intrinsic disorder in the outer shells of HIVs, the hepatitis C virus (HCV), and herpes simplex viruses (HSVs), for which successful vaccines have not been established. On the other hand, this feature (high levels of intrinsic disorder in the outer shells) is completely absent in classic viruses for which effective vaccines are found, such as the rabies virus. The motions arising from the disordered outer shell result in the inability of antibodies to bind tightly to the polysaccharides on the viral surface proteins, and, therefore, induce inadequate immune response. Experiments conducted by the legendary Avery Oswald in the 1920s form the theoretical underpinning of this new model. Failures of the vaccines based on the HIV glycoprotein Gp120 and other vaccines can be traced back to the lack of understanding of the important roles of shell disorder in a "Trojan-horse" immune evasion mechanism utilized by the virus.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
| | - Vladimir N Uversky
- Department of Molecular Medicine, USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.,Laboratory of New Methods in Biology, Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences", Pushchino, Russia Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Russia
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12
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SanJuan-Reyes S, Gómez-Oliván LM, Islas-Flores H. COVID-19 in the environment. CHEMOSPHERE 2021; 263:127973. [PMID: 32829224 PMCID: PMC7426221 DOI: 10.1016/j.chemosphere.2020.127973] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/31/2020] [Accepted: 08/07/2020] [Indexed: 05/02/2023]
Abstract
In recent months, the presence of an emerging disease of infectious etiology has paralyzed everyone, already being a public health problem due to its high rate of infection, a life-threatening disease. The WHO has named it COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV2). New studies provide information of the role of the environment in COVID-19 transmission process, mortality related to this infectious disease and the impact on human health. The following review aims to analyze information on the implications of COVID-19 infection on human health and the impact of its presence on the environment, from its transmission capacity and the role of air pollutants and climatological factors to reducing the air pollution during confinement. Likewise, it provides a vision of the impact on the environment and human health of exposure to disinfectants and the presence of COVID-19 in wastewater, among other actions.
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Affiliation(s)
- Sindy SanJuan-Reyes
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma Del Estado de México, Paseo Colón Intersección Paseo Tollocan S/n, Col. Residencial Colón, 50120, Toluca, Estado de México, Mexico
| | - Leobardo Manuel Gómez-Oliván
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma Del Estado de México, Paseo Colón Intersección Paseo Tollocan S/n, Col. Residencial Colón, 50120, Toluca, Estado de México, Mexico.
| | - Hariz Islas-Flores
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma Del Estado de México, Paseo Colón Intersección Paseo Tollocan S/n, Col. Residencial Colón, 50120, Toluca, Estado de México, Mexico
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Lermyte F. Roles, Characteristics, and Analysis of Intrinsically Disordered Proteins: A Minireview. Life (Basel) 2020; 10:E320. [PMID: 33266184 PMCID: PMC7761095 DOI: 10.3390/life10120320] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 12/11/2022] Open
Abstract
In recent years, there has been a growing understanding that a significant fraction of the eukaryotic proteome is intrinsically disordered, and that these conformationally dynamic proteins play a myriad of vital biological roles in both normal and pathological states. In this review, selected examples of intrinsically disordered proteins are highlighted, with particular attention for a few which are relevant in neurological disorders and in viral infection. Next, the underlying causes for the intrinsic disorder are discussed, along with computational methods used to predict whether a given amino acid sequence is likely to adopt a folded or unfolded state in the solution. Finally, biophysical methods for the analysis of intrinsically disordered proteins will be discussed, as well as the unique challenges they pose in this context due to their highly dynamic nature.
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Affiliation(s)
- Frederik Lermyte
- Department of Chemistry, Technical University of Darmstadt, Alarich-Weiss-Straße 4, 64287 Darmstadt, Germany
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14
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Goh GKM, Dunker AK, Foster JA, Uversky VN. A Novel Strategy for the Development of Vaccines for SARS-CoV-2 (COVID-19) and Other Viruses Using AI and Viral Shell Disorder. J Proteome Res 2020; 19:4355-4363. [PMID: 33006287 PMCID: PMC7640981 DOI: 10.1021/acs.jproteome.0c00672] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Indexed: 12/29/2022]
Abstract
A model that predicts levels of coronavirus (CoV) respiratory and fecal-oral transmission potentials based on the shell disorder has been built using neural network (artificial intelligence, AI) analysis of the percentage of disorder (PID) in the nucleocapsid, N, and membrane, M, proteins of the inner and outer viral shells, respectively. Using primarily the PID of N, SARS-CoV-2 is grouped as having intermediate levels of both respiratory and fecal-oral transmission potentials. Related studies, using similar methodologies, have found strong positive correlations between virulence and inner shell disorder among numerous viruses, including Nipah, Ebola, and Dengue viruses. There is some evidence that this is also true for SARS-CoV-2 and SARS-CoV, which have N PIDs of 48% and 50%, and case-fatality rates of 0.5-5% and 10.9%, respectively. The underlying relationship between virulence and respiratory potentials has to do with the viral loads of vital organs and body fluids, respectively. Viruses can spread by respiratory means only if the viral loads in saliva and mucus exceed certain minima. Similarly, a patient is likelier to die when the viral load overwhelms vital organs. Greater disorder in inner shell proteins has been known to play important roles in the rapid replication of viruses by enhancing the efficiency pertaining to protein-protein/DNA/RNA/lipid bindings. This paper suggests a novel strategy in attenuating viruses involving comparison of disorder patterns of inner shells (N) of related viruses to identify residues and regions that could be ideal for mutation. The M protein of SARS-CoV-2 has one of the lowest M PID values (6%) in its family, and therefore, this virus has one of the hardest outer shells, which makes it resistant to antimicrobial enzymes in body fluid. While this is likely responsible for its greater contagiousness, the risks of creating an attenuated virus with a more disordered M are discussed.
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Affiliation(s)
| | - A. Keith Dunker
- Center
for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - James A. Foster
- Department
of Biological Sciences, University of Idaho, Moscow, Idaho 83844, United States
- Institute
for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, Idaho 83844, United States
| | - Vladimir N. Uversky
- Department
of Molecular Medicine, USF Health Byrd Alzheimer’s Research
Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida 33620, United States
- Laboratory
of New Methods in Biology, Institute for Biological Instrumentation
of the Russian Academy of Sciences, Federal
Research Center “Pushchino Scientific Center for Biological
Research of the Russian Academy of Sciences”, Pushchino, Moscow region 142290, Russia
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15
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Goh GKM, Dunker AK, Foster JA, Uversky VN. Shell Disorder Analysis Suggests That Pangolins Offered a Window for a Silent Spread of an Attenuated SARS-CoV-2 Precursor among Humans. J Proteome Res 2020; 19:4543-4552. [PMID: 32790362 PMCID: PMC7640969 DOI: 10.1021/acs.jproteome.0c00460] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Indexed: 02/06/2023]
Abstract
A model to predict the relative levels of respiratory and fecal-oral transmission potentials of coronaviruses (CoVs) by measuring the percentage of protein intrinsic disorder (PID) of the M (Membrane) and N (Nucleoprotein) proteins in their outer and inner shells, respectively, was built before the MERS-CoV outbreak. With MPID = 8.6% and NPID = 50.2%, the 2003 SARS-CoV falls into group B, which consists of CoVs with intermediate levels of both fecal-oral and respiratory transmission potentials. Further validation of the model came with MERS-CoV (MPID = 9%, NPID = 44%) and SARS-CoV-2 (MPID = 5.5%, NPID = 48%) falling into the groups C and B, respectively. Group C contains CoVs with higher fecal-oral but lower respiratory transmission potentials. Unlike SARS-CoV, SARS-CoV-2 with MPID = 5.5% has one of the hardest outer shells among CoVs. Because the hard shell is able to resist the antimicrobial enzymes in body fluids, the infected person is able to shed large quantities of viral particles via saliva and mucus, which could account for the higher contagiousness of SARS-COV-2. Further searches have found that high rigidity of the outer shell is characteristic for the CoVs of burrowing animals, such as rabbits (MPID = 5.6%) and pangolins (MPID = 5-6%), which are in contact with the buried feces. A closer inspection of pangolin-CoVs from 2017 to 2019 reveals that pangolins provided a unique window of opportunity for the entry of an attenuated SARS-CoV-2 precursor into the human population in 2017 or earlier, with the subsequent slow and silent spread as a mild cold that followed by its mutations into the current more virulent form. Evidence of this lies in both the genetic proximity of the pangolin-CoVs to SARS-CoV-2 (∼90%) and differences in N disorder. A 2017 pangolin-CoV strain shows evidence of higher levels of attenuation and higher fecal-oral transmission associated with lower human infectivity via having lower NPID (44.8%). Our shell disorder model predicts this to be a SARS-CoV-2 vaccine strain, as lower inner shell disorder is associated with the lesser virulence in a variety of viruses.
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Affiliation(s)
| | - A. Keith Dunker
- Center
for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - James A. Foster
- Department
of Biological Sciences, University of Idaho, Moscow, Idaho 83844, United States
- Institute
for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, Idaho 83844, United States
| | - Vladimir N. Uversky
- Department
of Molecular Medicine, USF Health Byrd Alzheimer’s Research
Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida 33620, United States
- Laboratory
of New Methods in Biology, Institute for Biological Instrumentation
of the Russian Academy of Sciences, Federal
Research Center “Pushchino Scientific Center for Biological
Research of the Russian Academy of Sciences”, Pushchino, Moscow 119991, Russia
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16
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Pagliari F, Marafioti MG, Genard G, Candeloro P, Viglietto G, Seco J, Tirinato L. ssRNA Virus and Host Lipid Rearrangements: Is There a Role for Lipid Droplets in SARS-CoV-2 Infection? Front Mol Biosci 2020; 7:578964. [PMID: 33134318 PMCID: PMC7579428 DOI: 10.3389/fmolb.2020.578964] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/03/2020] [Indexed: 12/12/2022] Open
Abstract
Since its appearance, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has immediately alarmed the World Health Organization for its very high contagiousness and the complexity of patient clinical profiles. The worldwide scientific community is today gathered in a massive effort in order to develop safe vaccines and effective therapies in the shortest possible time. Every day, new pieces of SARS-CoV-2 infective puzzle are disclosed. Based on knowledge gained with other related coronaviruses and, more in general, on single-strand RNA viruses, we highlight underexplored molecular routes in which lipids and lipid droplets (LDs) might serve essential functions in viral infections. In fact, both lipid homeostasis and the pathways connected to lipids seem to be fundamental in all phases of the coronavirus infection. This review aims at describing potential roles for lipid and LDs in host-virus interactions and suggesting LDs as new and central cellular organelles to be investigated as potential targets against SARS-CoV-2 infection.
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Affiliation(s)
- Francesca Pagliari
- Biomedical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany
| | - Maria Grazia Marafioti
- Biomedical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany
| | - Geraldine Genard
- Biomedical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany
| | - Patrizio Candeloro
- BioNEM Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Giuseppe Viglietto
- Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Joao Seco
- Biomedical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany.,Department of Physics and Astronomy, Heidelberg University, Heidelberg, Germany
| | - Luca Tirinato
- Biomedical Physics in Radiation Oncology, German Cancer Research Center, Heidelberg, Germany.,BioNEM Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
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van Doorn AS, Meijer B, Frampton CMA, Barclay ML, de Boer NKH. Systematic review with meta-analysis: SARS-CoV-2 stool testing and the potential for faecal-oral transmission. Aliment Pharmacol Ther 2020; 52:1276-1288. [PMID: 32852082 PMCID: PMC7461227 DOI: 10.1111/apt.16036] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/04/2020] [Accepted: 07/22/2020] [Indexed: 01/08/2023]
Abstract
BACKGROUND Since the start of the COVID-19 pandemic, there have been many scientific reports regarding gastrointestinal manifestations. Several reports indicate the possibility of viral shedding via faeces and the possibility of faecal-oral transmission. AIMS To critically assess the clinical relevance of testing stool samples and anal swabs and provide an overview of the potential faecal-oral transmission of SARS-CoV-2. METHODS A systematic literature search with MeSH terms was performed, scrutinising the Embase database, Google scholar, MEDLINE database through PubMed and The Cochrane Library, including articles from December 2019 until July 7 2020. Data were subsequently analysed with descriptive statistics. RESULTS Ninety-five studies were included in the qualitative analysis. 934/2149 (43%) patients tested positive for SARS-CoV-2 in stool samples or anal swabs, with positive test results up to 70 days after symptom onset. A meta-analysis executed with studies of at least 10 patients revealed a pooled positive proportion of 51.8% (95% CI 43.8 - 59.7%). Positive faecal samples of 282/443 patients (64%) remained positive for SARS-CoV-2 for a mean of 12.5 days, up to 33 days maximum, after respiratory samples became negative for SARS-CoV-2. Viable SARS-CoV-2 was found in 6/17 (35%) patients in whom this was specifically investigated. CONCLUSIONS Viral shedding of SARS-CoV-2 in stool samples occurs in a substantial proportion of patients, making faecal-oral transmission plausible. Furthermore, detection in stool samples or anal swabs can persist long after negative respiratory testing. Therefore, stool sample or anal swab testing should be (re)considered in relation to decisions for isolating or discharging a patient.
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Affiliation(s)
- Amarylle S. van Doorn
- Departments of Gastroenterology & Clinical PharmacologyChristchurch HospitalCanterbury District Health Board and University of OtagoChristchurchNew Zealand
- Department of Gastroenterology and HepatologyAG&M Research InstituteAmsterdam University Medical CentreVrije Universiteit AmsterdamAmsterdamthe Netherlands
| | - Berrie Meijer
- Department of Gastroenterology and HepatologyAG&M Research InstituteAmsterdam University Medical CentreVrije Universiteit AmsterdamAmsterdamthe Netherlands
- Department of Gastroenterology and HepatologyNoordwest Ziekenhuisgroep Alkmaarthe Netherlands
| | - Chris M. A. Frampton
- Department of Biostatistics & MedicineChristchurch HospitalCanterbury District Health Board and University of OtagoChristchurchNew Zealand
| | - Murray L. Barclay
- Departments of Gastroenterology & Clinical PharmacologyChristchurch HospitalCanterbury District Health Board and University of OtagoChristchurchNew Zealand
| | - Nanne K. H. de Boer
- Department of Gastroenterology and HepatologyAG&M Research InstituteAmsterdam University Medical CentreVrije Universiteit AmsterdamAmsterdamthe Netherlands
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18
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Gupta MN, Roy I. Drugs, host proteins and viral proteins: how their promiscuities shape antiviral design. Biol Rev Camb Philos Soc 2020; 96:205-222. [PMID: 32918378 DOI: 10.1111/brv.12652] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 08/24/2020] [Accepted: 08/27/2020] [Indexed: 12/12/2022]
Abstract
The reciprocal nature of drug specificity and target specificity implies that the same is true for their respective promiscuities. Protein promiscuity has two broadly different types of footprint in drug design. The first is relaxed specificity of binding sites for substrates, inhibitors, effectors or cofactors. The second involves protein-protein interactions of regulatory processes such as signal transduction and transcription, and here protein intrinsic disorder plays an important role. Both viruses and host cells exploit intrinsic disorder for their survival, as do the design and discovery programs for antivirals. Drug action, strictly speaking, always relies upon promiscuous activity, with drug promiscuity enlarging its scope. Drug repurposing searches for additional promiscuity on the part of both the drug and the target in the host. Understanding the subtle nuances of these promiscuities is critical in the design of novel and more effective antivirals.
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Affiliation(s)
- Munishwar Nath Gupta
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Hauz Khas, New Delhi, 110016, India
| | - Ipsita Roy
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab, 160062, India
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19
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Intrinsically disordered proteins of viruses: Involvement in the mechanism of cell regulation and pathogenesis. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2020; 174:1-78. [PMID: 32828463 PMCID: PMC7129803 DOI: 10.1016/bs.pmbts.2020.03.001] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Intrinsically disordered proteins (IDPs) possess the property of inherent flexibility and can be distinguished from other proteins in terms of lack of any fixed structure. Such dynamic behavior of IDPs earned the name "Dancing Proteins." The exploration of these dancing proteins in viruses has just started and crucial details such as correlation of rapid evolution, high rate of mutation and accumulation of disordered contents in viral proteome at least understood partially. In order to gain a complete understanding of this correlation, there is a need to decipher the complexity of viral mediated cell hijacking and pathogenesis in the host organism. Further there is necessity to identify the specific patterns within viral and host IDPs such as aggregation; Molecular recognition features (MoRFs) and their association to virulence, host range and rate of evolution of viruses in order to tackle the viral-mediated diseases. The current book chapter summarizes the aforementioned details and suggests the novel opportunities for further research of IDPs senses in viruses.
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20
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Goh GKM, Dunker AK, Foster JA, Uversky VN. Nipah shell disorder, modes of infection, and virulence. Microb Pathog 2020; 141:103976. [PMID: 31940461 PMCID: PMC7126952 DOI: 10.1016/j.micpath.2020.103976] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 01/10/2020] [Indexed: 12/18/2022]
Abstract
The Nipah Virus (NiV) was first isolated during a 1998-9 outbreak in Malaysia. The outbreak initially infected farm pigs and then moved to humans from pigs with a case-fatality rate (CFR) of about 40%. After 2001, regular outbreaks occurred with higher CFRs (~71%, 2001-5, ~93%, 2008-12). The spread arose from drinking virus-laden palm date sap and human-to-human transmission. Intrinsic disorder analysis revealed strong correlation between the percentage of disorder in the N protein and CFR (Regression: r2 = 0.93, p < 0.01, ANOVA: p < 0.01). Distinct disorder and, therefore, genetic differences can be found in all three group of strains. The fact that the transmission modes of the Malaysia strain are different from those of the Bangladesh strains suggests that the correlations may also be linked to the modes of viral transmission. Analysis of the NiV and related viruses suggests links between modes of transmission and disorder of not just the N protein but, also, of M shell protein. The links among shell disorder, transmission modes, and virulence suggest mechanisms by which viruses are attenuated as they passed through different cell hosts from different animal species. These have implications for development of vaccines and epidemiological molecular analytical tools to contain outbreaks.
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Affiliation(s)
| | - A Keith Dunker
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
| | - James A Foster
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA; Institute for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, ID, USA.
| | - Vladimir N Uversky
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA; Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Moscow region, Russia.
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21
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Goh GKM, Dunker AK, Foster JA, Uversky VN. Shell disorder analysis predicts greater resilience of the SARS-CoV-2 (COVID-19) outside the body and in body fluids. Microb Pathog 2020; 144:104177. [PMID: 32244041 PMCID: PMC7118597 DOI: 10.1016/j.micpath.2020.104177] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/18/2020] [Accepted: 03/27/2020] [Indexed: 12/13/2022]
Abstract
The coronavirus (CoV) family consists of viruses that infects a variety of animals including humans with various levels of respiratory and fecal-oral transmission levels depending on the behavior of the viruses' natural hosts and optimal viral fitness. A model to classify and predict the levels of respective respiratory and fecal-oral transmission potentials of the various viruses was built before the outbreak of MERS-CoV using AI and empirically-based molecular tools to predict the disorder level of proteins. Using the percentages of intrinsic disorder (PID) of the nucleocapsid (N) and membrane (M) proteins of CoV, the model easily clustered the viruses into three groups with the SARS-CoV (M PID = 8%, N PID = 50%) falling into Category B, in which viruses have intermediate levels of both respiratory and fecal-oral transmission potentials. Later, MERS-CoV (M PID = 9%, N PID = 44%) was found to be in Category C, which consists of viruses with lower respiratory transmission potential but with higher fecal-oral transmission capabilities. Based on the peculiarities of disorder distribution, the SARS-CoV-2 (M PID = 6%, N PID = 48%) has to be placed in Category B. Our data show however, that the SARS-CoV-2 is very strange with one of the hardest protective outer shell, (M PID = 6%) among coronaviruses. This means that it might be expected to be highly resilient in saliva or other body fluids and outside the body. An infected body is likelier to shed greater numbers of viral particles since the latter is more resistant to antimicrobial enzymes in body fluids. These particles are also likelier to remain active longer. These factors could account for the greater contagiousness of the SARS-CoV-2 and have implications for efforts to prevent its spread.
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Affiliation(s)
| | - A Keith Dunker
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - James A Foster
- Department of Biological Sciences, University of Idaho, Moscow, ID, USA; Institute for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, ID, USA
| | - Vladimir N Uversky
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA; Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Moscow region, Russia
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Goh GKM, Dunker AK, Foster JA, Uversky VN. Rigidity of the Outer Shell Predicted by a Protein Intrinsic Disorder Model Sheds Light on the COVID-19 (Wuhan-2019-nCoV) Infectivity. Biomolecules 2020; 10:E331. [PMID: 32092911 PMCID: PMC7072294 DOI: 10.3390/biom10020331] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 02/17/2020] [Indexed: 02/07/2023] Open
Abstract
The world is currently witnessing an outbreak of a new coronavirus spreading quickly across China and affecting at least 24 other countries. With almost 65,000 infected, a worldwide death toll of at least 1370 (as of 14 February 2020), and with the potential to affect up to two-thirds of the world population, COVID-19 is considered by the World Health Organization (WHO) to be a global health emergency. The speed of spread and infectivity of COVID-19 (also known as Wuhan-2019-nCoV) are dramatically exceeding those of the Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). In fact, since September 2012, the WHO has been notified of 2494 laboratory-confirmed cases of infection with MERS-CoV, whereas the 2002-2003 epidemic of SARS affected 26 countries and resulted in more than 8000 cases. Therefore, although SARS, MERS, and COVID-19 are all the result of coronaviral infections, the causes of the coronaviruses differ dramatically in their transmissibility. It is likely that these differences in infectivity of coronaviruses can be attributed to the differences in the rigidity of their shells which can be evaluated using computational tools for predicting intrinsic disorder predisposition of the corresponding viral proteins.
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Affiliation(s)
| | - A. Keith Dunker
- Center for Computational Biology, Indiana and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - James A. Foster
- Department of Biological Sciences, University of Idaho, Moscow, ID 83844, USA;
- Institute for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, ID 83844, USA
| | - Vladimir N. Uversky
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
- Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center ‘Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences’, Moscow region, 142290 Pushchino, Russia
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Goh GKM, Dunker AK, Foster JA, Uversky VN. Zika and Flavivirus Shell Disorder: Virulence and Fetal Morbidity. Biomolecules 2019; 9:biom9110710. [PMID: 31698857 PMCID: PMC6920988 DOI: 10.3390/biom9110710] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 10/29/2019] [Accepted: 11/04/2019] [Indexed: 12/12/2022] Open
Abstract
Zika virus (ZIKV) was first discovered in 1947 in Africa. Since then, sporadic ZIKV infections of humans have been reported in Africa and Asia. For a long time, this virus was mostly unnoticed due to its mild symptoms and low fatality rates. However, during the 2015-2016 epidemic in Central and South America, when millions of people were infected, it was discovered that ZIKV causes microcephaly in the babies of mothers infected during pregnancy. An examination of the M and C proteins of the ZIKV shell using the disorder predictor PONDR VLXT revealed that the M protein contains relatively high disorder levels comparable only to those of the yellow fever virus (YFV). On the other hand, the disorder levels in the C protein are relatively low, which can account for the low case fatality rate (CFR) of this virus in contrast to the more virulent YFV, which is characterized by high disorder in its C protein. A larger variation was found in the percentage of intrinsic disorder (PID) in the C protein of various ZIKV strains. Strains of African lineage are characterized by higher PIDs. Using both in vivo and in vitro experiments, laboratories have also previously shown that strains of African origin have a greater potential to inflict higher fetal morbidity than do strains of Asian lineage, with dengue-2 virus (DENV-2) having the least potential. Strong correlations were found between the potential to inflict fetal morbidity and shell disorder in ZIKV (r2 = 0.9) and DENV-2 (DENV-2 + ZIKV, r2 = 0.8). A strong correlation between CFR and PID was also observed when ZIKV was included in an analysis of sets of shell proteins from a variety of flaviviruses (r2 = 0.8). These observations have potential implications for antiviral vaccine development and for the design of cancer therapeutics in terms of developing therapeutic viruses that penetrate hard-to-reach organs.
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Affiliation(s)
- Gerard Kian-Meng Goh
- Goh’s BioComputing, Singapore 548957, Singapore
- Correspondence: ; Tel.: +65-8648-5440
| | - A. Keith Dunker
- Center for Computational Biology, Indiana and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - James A. Foster
- Department of Biological Sciences, University of Idaho, Moscow, ID 83844, USA;
- Institute for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, ID 83844, USA
| | - Vladimir N. Uversky
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA;
- Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Moscow Region 142290, Russia
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24
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Goh GKM, Dunker AK, Foster JA, Uversky VN. HIV Vaccine Mystery and Viral Shell Disorder. Biomolecules 2019; 9:biom9050178. [PMID: 31072073 PMCID: PMC6572542 DOI: 10.3390/biom9050178] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 04/25/2019] [Accepted: 04/30/2019] [Indexed: 12/14/2022] Open
Abstract
Hundreds of billions of dollars have been spent for over three decades in the search for an effective human immunodeficiency virus (HIV) vaccine with no success. There are also at least two other sexually transmitted viruses, for which no vaccine is available, the herpes simplex virus (HSV) and the hepatitis C virus (HCV). Traditional textbook explanatory paradigm of rapid mutation of retroviruses cannot adequately address the unavailability of vaccine for many sexually transmissible viruses, since HSV and HCV are DNA and non-retroviral RNA viruses, respectively, whereas effective vaccine for the horsefly-transmitted retroviral cousin of HIV, equine infectious anemia virus (EIAV), was found in 1973. We reported earlier the highly disordered nature of proteins in outer shells of the HIV, HCV, and HSV. Such levels of disorder are completely absent among the classical viruses, such as smallpox, rabies, yellow fever, and polio viruses, for which efficient vaccines were discovered. This review analyzes the physiology and shell disorder of the various related and non-related viruses to argue that EIAV and the classical viruses need harder shells to survive during harsher conditions of non-sexual transmissions, thus making them vulnerable to antibody detection and neutralization. In contrast, the outer shell of the HIV-1 (with its preferential sexual transmission) is highly disordered, thereby allowing large scale motions of its surface glycoproteins and making it difficult for antibodies to bind to them. The theoretical underpinning of this concept is retrospectively traced to a classical 1920s experiment by the legendary scientist, Oswald Avery. This concept of viral shapeshifting has implications for improved treatment of cancer and infections via immune evasion.
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Affiliation(s)
| | - A Keith Dunker
- Center for Computational Biology, Indiana and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - James A Foster
- Department of Biological Sciences, University of Idaho, Moscow, ID 83844, USA.
- Institute for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, ID 83844, USA.
| | - Vladimir N Uversky
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
- Institute for Biological Instrumentation, Russian Academy of Sciences, Moscow Region, Pushchino 142290, Russia.
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Yang Z, Ran L, Yuan P, Yang Y, Wang K, Xie L, Huang S, Liu J, Song Z. EGFR as a Negative Regulatory Protein Adjusts the Activity and Mobility of NHE3 in the Cell Membrane of IPEC-J2 Cells With TGEV Infection. Front Microbiol 2018; 9:2734. [PMID: 30483239 PMCID: PMC6243134 DOI: 10.3389/fmicb.2018.02734] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 10/25/2018] [Indexed: 11/13/2022] Open
Abstract
Transmissible gastroenteritis (TGE) has caused devastating economic losses to the swine industry worldwide, despite extensive research focusing on the pathogenesis of virus infection. The molecular pathogenic mechanism of TGEV-induced diarrhea in piglets is unknown. Intestinal diarrhea is closely related to the function of the Na+/H+ exchanger protein NHE3 in the brush border membrane of small intestine epithelial cells. The epidermal growth factor receptor (EGFR) may act to regulate NHE3 expression. In addition, EGFR may promote viral invasion of host cells. The present study aimed to determine whether NHE3 activity is regulated by altering EGFR expression to affect Na+ absorption in TGEV-infected intestinal epithelial cells. Porcine intestinal epithelial cells were used as models for TGEV infection. The results showed that Na+ absorption and NHE3 expression levels decreased in TGEV-infected cells. Proliferation of TGEV within IPEC-J2 cells could be inhibited by treatment with the EGFR inhibitor AG1478 and knockdown; resulting in recovery of Na+ absorption in TGEV infected cells and increasing the activity and expression of NHE3. Moreover, we demonstrated that NHE3 activity was regulated through the EGFR/ERK pathway. Importantly, NHE3 mobility on the plasma membrane of TGEV infected cells was significantly weaker than that in normal cells, and EGFR inhibition and knockdown recovered this mobility. Our research indicated that NHE3 activity was negatively regulated by EGFR in TGEV-infected intestinal epithelial cells.
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Affiliation(s)
- Zhou Yang
- Department of Veterinary Medicine, Southwest University, Chongqing, China
| | - Ling Ran
- Department of Veterinary Medicine, Southwest University, Chongqing, China
| | - Peng Yuan
- Department of Veterinary Medicine, Southwest University, Chongqing, China
| | - Yang Yang
- Department of Veterinary Medicine, Southwest University, Chongqing, China
| | - Kai Wang
- Department of Veterinary Medicine, Southwest University, Chongqing, China
| | - Luyi Xie
- Department of Veterinary Medicine, Southwest University, Chongqing, China
| | - Shilei Huang
- Department of Veterinary Medicine, Southwest University, Chongqing, China
| | - Jia Liu
- Department of Veterinary Medicine, Southwest University, Chongqing, China
| | - Zhenhui Song
- Department of Veterinary Medicine, Southwest University, Chongqing, China
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26
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Tarakhovsky A, Prinjha RK. Drawing on disorder: How viruses use histone mimicry to their advantage. J Exp Med 2018; 215:1777-1787. [PMID: 29934321 PMCID: PMC6028506 DOI: 10.1084/jem.20180099] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 04/24/2018] [Accepted: 06/07/2018] [Indexed: 12/16/2022] Open
Abstract
Humans carry trillions of viruses that thrive because of their ability to exploit the host. In this exploitation, viruses promote their own replication by suppressing the host antiviral response and by inducing changes in host biosynthetic processes, often with extremely small genomes of their own. In the review, we discuss the phenomenon of histone mimicry by viral proteins and how this mimicry allows the virus to dial in to the cell's transcriptional processes and establish a cell state that promotes infection. We suggest that histone mimicry is part of a broader viral strategy to use intrinsic protein disorder as a means to overcome the size limitations of its own genome and to maximize its impact on host protein networks. In particular, we discuss how intrinsic protein disorder may enable viral proteins to interfere with phase-separated host protein condensates, including those that contribute to chromatin-mediated control of gene expression.
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Affiliation(s)
- Alexander Tarakhovsky
- Laboratory of the Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY
| | - Rab K Prinjha
- Epigenetics DPU, Oncology and Immuno-inflammation TA Units, GlaxoSmithKline Medicines Research Centre, Stevenage, England, UK
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27
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Zhou J, Li C, Zhao G, Chu H, Wang D, Yan HHN, Poon VKM, Wen L, Wong BHY, Zhao X, Chiu MC, Yang D, Wang Y, Au-Yeung RKH, Chan IHY, Sun S, Chan JFW, To KKW, Memish ZA, Corman VM, Drosten C, Hung IFN, Zhou Y, Leung SY, Yuen KY. Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus. SCIENCE ADVANCES 2017; 3:eaao4966. [PMID: 29152574 PMCID: PMC5687858 DOI: 10.1126/sciadv.aao4966] [Citation(s) in RCA: 286] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 10/20/2017] [Indexed: 05/08/2023]
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) has caused human respiratory infections with a high case fatality rate since 2012. However, the mode of virus transmission is not well understood. The findings of epidemiological and virological studies prompted us to hypothesize that the human gastrointestinal tract could serve as an alternative route to acquire MERS-CoV infection. We demonstrated that human primary intestinal epithelial cells, small intestine explants, and intestinal organoids were highly susceptible to MERS-CoV and can sustain robust viral replication. We also identified the evidence of enteric MERS-CoV infection in the stool specimen of a clinical patient. MERS-CoV was considerably resistant to fed-state gastrointestinal fluids but less tolerant to highly acidic fasted-state gastric fluid. In polarized Caco-2 cells cultured in Transwell inserts, apical MERS-CoV inoculation was more effective in establishing infection than basolateral inoculation. Notably, direct intragastric inoculation of MERS-CoV caused a lethal infection in human DPP4 transgenic mice. Histological examination revealed MERS-CoV enteric infection in all inoculated mice, as shown by the presence of virus-positive cells, progressive inflammation, and epithelial degeneration in small intestines, which were exaggerated in the mice pretreated with the proton pump inhibitor pantoprazole. With the progression of the enteric infection, inflammation, virus-positive cells, and live viruses emerged in the lung tissues, indicating the development of sequential respiratory infection. Taken together, these data suggest that the human intestinal tract may serve as an alternative infection route for MERS-CoV.
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Affiliation(s)
- Jie Zhou
- State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong, China
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
- Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong, China
| | - Cun Li
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Guangyu Zhao
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Hin Chu
- State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong, China
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
- Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong, China
| | - Dong Wang
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Helen Hoi-Ning Yan
- Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Vincent Kwok-Man Poon
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Lei Wen
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Bosco Ho-Yin Wong
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Xiaoyu Zhao
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Man Chun Chiu
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Dong Yang
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Yixin Wang
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Rex K. H. Au-Yeung
- Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | | | - Shihui Sun
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Jasper Fuk-Woo Chan
- State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong, China
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
- Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong, China
- Carol Yu Centre for Infection, University of Hong Kong, Hong Kong, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, University of Hong Kong, Hong Kong, China
| | - Kelvin Kai-Wang To
- State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong, China
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
- Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong, China
- Carol Yu Centre for Infection, University of Hong Kong, Hong Kong, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, University of Hong Kong, Hong Kong, China
| | - Ziad A. Memish
- Ministry of Health and College of Medicine, Alfaisal University, Riyadh, Kingdom of Saudi Arabia
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA
| | - Victor M. Corman
- Institute of Virology, Charité–Universitätsmedizin Berlin, Berlin, Germany
- German Centre for Infection Research (DZIF), Berlin, Germany
| | - Christian Drosten
- Institute of Virology, Charité–Universitätsmedizin Berlin, Berlin, Germany
- German Centre for Infection Research (DZIF), Berlin, Germany
| | - Ivan Fan-Ngai Hung
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Yusen Zhou
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Suet Yi Leung
- Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Kwok-Yung Yuen
- State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong, China
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
- Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong, China
- Carol Yu Centre for Infection, University of Hong Kong, Hong Kong, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, University of Hong Kong, Hong Kong, China
- Corresponding author.
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28
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Zhou J, Li C, Zhao G, Chu H, Wang D, Yan HHN, Poon VKM, Wen L, Wong BHY, Zhao X, Chiu MC, Yang D, Wang Y, Au-Yeung RKH, Chan IHY, Sun S, Chan JFW, To KKW, Memish ZA, Corman VM, Drosten C, Hung IFN, Zhou Y, Leung SY, Yuen KY. Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus. SCIENCE ADVANCES 2017; 3:eaao4966. [PMID: 29152574 DOI: 10.1126/sciadv.aao49660] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 10/20/2017] [Indexed: 05/26/2023]
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) has caused human respiratory infections with a high case fatality rate since 2012. However, the mode of virus transmission is not well understood. The findings of epidemiological and virological studies prompted us to hypothesize that the human gastrointestinal tract could serve as an alternative route to acquire MERS-CoV infection. We demonstrated that human primary intestinal epithelial cells, small intestine explants, and intestinal organoids were highly susceptible to MERS-CoV and can sustain robust viral replication. We also identified the evidence of enteric MERS-CoV infection in the stool specimen of a clinical patient. MERS-CoV was considerably resistant to fed-state gastrointestinal fluids but less tolerant to highly acidic fasted-state gastric fluid. In polarized Caco-2 cells cultured in Transwell inserts, apical MERS-CoV inoculation was more effective in establishing infection than basolateral inoculation. Notably, direct intragastric inoculation of MERS-CoV caused a lethal infection in human DPP4 transgenic mice. Histological examination revealed MERS-CoV enteric infection in all inoculated mice, as shown by the presence of virus-positive cells, progressive inflammation, and epithelial degeneration in small intestines, which were exaggerated in the mice pretreated with the proton pump inhibitor pantoprazole. With the progression of the enteric infection, inflammation, virus-positive cells, and live viruses emerged in the lung tissues, indicating the development of sequential respiratory infection. Taken together, these data suggest that the human intestinal tract may serve as an alternative infection route for MERS-CoV.
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Affiliation(s)
- Jie Zhou
- State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong, China
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
- Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong, China
| | - Cun Li
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Guangyu Zhao
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Hin Chu
- State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong, China
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
- Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong, China
| | - Dong Wang
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Helen Hoi-Ning Yan
- Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Vincent Kwok-Man Poon
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Lei Wen
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Bosco Ho-Yin Wong
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Xiaoyu Zhao
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Man Chun Chiu
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Dong Yang
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Yixin Wang
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Rex K H Au-Yeung
- Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | | | - Shihui Sun
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Jasper Fuk-Woo Chan
- State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong, China
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
- Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong, China
- Carol Yu Centre for Infection, University of Hong Kong, Hong Kong, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, University of Hong Kong, Hong Kong, China
| | - Kelvin Kai-Wang To
- State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong, China
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
- Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong, China
- Carol Yu Centre for Infection, University of Hong Kong, Hong Kong, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, University of Hong Kong, Hong Kong, China
| | - Ziad A Memish
- Ministry of Health and College of Medicine, Alfaisal University, Riyadh, Kingdom of Saudi Arabia
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA
| | - Victor M Corman
- Institute of Virology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- German Centre for Infection Research (DZIF), Berlin, Germany
| | - Christian Drosten
- Institute of Virology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- German Centre for Infection Research (DZIF), Berlin, Germany
| | - Ivan Fan-Ngai Hung
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Yusen Zhou
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
| | - Suet Yi Leung
- Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Kwok-Yung Yuen
- State Key Laboratory of Emerging Infectious Diseases, University of Hong Kong, Hong Kong, China
- Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
- Research Centre of Infection and Immunology, University of Hong Kong, Hong Kong, China
- Carol Yu Centre for Infection, University of Hong Kong, Hong Kong, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, University of Hong Kong, Hong Kong, China
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29
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Goh GKM, Dunker AK, Uversky VN. Correlating Flavivirus virulence and levels of intrinsic disorder in shell proteins: protective roles vs. immune evasion. MOLECULAR BIOSYSTEMS 2017; 12:1881-91. [PMID: 27102744 DOI: 10.1039/c6mb00228e] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Computational analyses revealed correlations between the intrinsic disorder propensity of shell proteins and case fatality rates (CFRs) among Flaviviruses and within at least two Flavivirus species, such as tick-borne encephalitis virus (TBEV) and dengue virus (DENV). The shell proteins analyzed in this study are capsid (C) and membrane (PrM, Pr, and M) proteins. The highest correlations can be found when regression analyses were conducted using Pr (Flavivirus: r(2) = 0.78, p < 0.01) or M (Flavivirus: r(2) = 0.91, p < 0.01) as an independent variable with C and CFR as co-explanatory and dependent variables, respectively. Interestingly, while predicted intrinsic disorder levels (PIDs) of both C and M are positively correlated with the virulence, the PIDs of Pr and CFR are negatively correlated. This is likely due to the fact that the Pr portion of PrM plays various roles in protecting the virion from damage, whereas M and C are assisted by greater potential in binding promiscuity as a result of greater disorder. The C protein of yellow fever virus (YFV), which is the most virulent virus in the sample, has the highest PID levels, whereas the second most virulent TBEV FE subtype has the second highest PID score due to its C protein, and the least virulent West Nile virus (WNV) has the least disordered C protein. This knowledge can be used while working on the development and identification of attenuated strains for vaccine. Curiously, unlike Flaviviruses, a disordered outer shell was described for hepatitis C virus (HCV), human immunodeficiency virus (HIV), and human simplex virus 2 (HSV-2), which currently have no effective vaccine.
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Affiliation(s)
| | - A Keith Dunker
- Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Vladimir N Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA and Department of Biological Science, Faculty of Science, King Abdulaziz University, Jeddah, PO Box 80203, Jeddah 21589, Saudi Arabia and Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russian Federation
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30
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Charon J, Theil S, Nicaise V, Michon T. Protein intrinsic disorder within the Potyvirus genus: from proteome-wide analysis to functional annotation. MOLECULAR BIOSYSTEMS 2016; 12:634-52. [PMID: 26699268 DOI: 10.1039/c5mb00677e] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Within proteins, intrinsically disordered regions (IDRs) are devoid of stable secondary and tertiary structures under physiological conditions and rather exist as dynamic ensembles of inter-converting conformers. Although ubiquitous in all domains of life, the intrinsic disorder content is highly variable in viral genomes. Over the years, functional annotations of disordered regions at the scale of the whole proteome have been conducted for several animal viruses. But to date, similar studies applied to plant viruses are still missing. Based on disorder prediction tools combined with annotation programs and evolutionary studies, we analyzed the intrinsic disorder content in Potyvirus, using a 10-species dataset representative of this genus diversity. In this paper, we revealed that: (i) the Potyvirus proteome displays high disorder content, (ii) disorder is conserved during Potyvirus evolution, suggesting a functional advantage of IDRs, (iii) IDRs evolve faster than ordered regions, and (iv) IDRs may be associated with major biological functions required for the Potyvirus cycle. Notably, the proteins P1, Coat protein (CP) and Viral genome-linked protein (VPg) display a high content of conserved disorder, enriched in specific motifs mimicking eukaryotic functional modules and suggesting strategies of host machinery hijacking. In these three proteins, IDRs are particularly conserved despite their high amino acid polymorphism, indicating a link to adaptive processes. Through this comprehensive study, we further investigate the biological relevance of intrinsic disorder in Potyvirus biology and we propose a functional annotation of potyviral proteome IDRs.
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Affiliation(s)
- Justine Charon
- UMR Biologie du Fruit et Pathologie, INRA, Villenave d'Ornon cedex, France. and UMR Biologie du Fruit et Pathologie, Université de Bordeaux, Villenave d'Ornon cedex, France
| | - Sébastien Theil
- UMR Biologie du Fruit et Pathologie, INRA, Villenave d'Ornon cedex, France. and UMR Biologie du Fruit et Pathologie, Université de Bordeaux, Villenave d'Ornon cedex, France
| | - Valérie Nicaise
- UMR Biologie du Fruit et Pathologie, INRA, Villenave d'Ornon cedex, France. and UMR Biologie du Fruit et Pathologie, Université de Bordeaux, Villenave d'Ornon cedex, France
| | - Thierry Michon
- UMR Biologie du Fruit et Pathologie, INRA, Villenave d'Ornon cedex, France. and UMR Biologie du Fruit et Pathologie, Université de Bordeaux, Villenave d'Ornon cedex, France
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31
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Goh GKM, Dunker AK, Uversky VN. Detection of links between Ebola nucleocapsid and virulence using disorder analysis. MOLECULAR BIOSYSTEMS 2016; 11:2337-44. [PMID: 26086270 DOI: 10.1039/c5mb00240k] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The underlying reasons for the differences in the virulence of various types of Ebola virus (EBOV) remain unknown. Comparison of the percentage of disorder (PID) in nucleocapsid proteins VP30 and NP reveals high correlation between nucleocapsid PIDs and the case-fatality rates of EBOV. The higher disorder of these proteins is likely to be needed for more efficient multiplication of virus copies via more efficient viral RNA transcription and more promiscuous protein binding potential. This is important for the more efficient assistance of nucleocapsid in viral particle budding and of the assembly and mobility of viral proteins across the host membrane and within the cytoplasm. A more comprehensive knowledge of the molecular mechanisms of EBOV virulence would also lead to new and more effective strategies in vaccine development.
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32
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Goh GKM, Dunker AK, Uversky VN. Shell disorder, immune evasion and transmission behaviors among human and animal retroviruses. MOLECULAR BIOSYSTEMS 2016; 11:2312-23. [PMID: 26080321 DOI: 10.1039/c5mb00277j] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
This study involves measurements of percentages of intrinsic disorder (PIDs) in the GAG protein shells of various retroviruses. Unique patterns of shell protein disorder can be seen especially when GAG proteins (matrix M, capsid C, and nucleocapsid N) of primate and non-primate retroviruses are compared. HIV-1 presents the most unique pattern of disorder distribution with generally high levels of disorder in all three proteins, while EIAV (PIDs:: 26, 29, 13) is diametrically different from HIV-1 (N C M PIDs: 39.5 ± 3.0, 44.5 ± 2.6, 56.5 ± 10.8). The HTLV viruses (CPID: 32.8 ± 3.4) resemble HIV-2 (C PID: 26.6 ± 2.9) with a moderately disordered capsid. Totally distinct patterns, however, are seen for the non-primate retroviruses. They generally have highly disordered nucleocapsids (PID > 65%) and more ordered outer shells especially the matrix. These characteristics might be attributed to the differences in the way the retroviruses are transmitted, with non-primate viruses having greater non-sexual transmission components such as oral-fecal transmission. These differences are also evolutionarily related to the ways the viruses evade the host immune systems, and thus, have implications for oncolytic virotherapy and animal models in vaccine research. The importance of protein shell disorder in immune evasion, as related to the case of HIV-1, and the difficult search for its vaccines are highlighted.
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33
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Kanner-Acerbo E, Lowe J. Review of immunological responses to porcine coronaviruses and implications on population based control strategies in epidemic and endemic infections. World J Immunol 2016; 6:60-66. [DOI: 10.5411/wji.v6.i1.60] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Revised: 10/06/2015] [Accepted: 03/16/2016] [Indexed: 02/05/2023] Open
Abstract
Five major porcine coronaviruses (COVs) have been identified which cause severe gastrointestinal (GI) and respiratory disease in pigs. They include transmissible gastroenteritis (TGEV), porcine epidemic diarrhea virus (PEDV), porcine deltacoronavirus, porcine respiratory coronavirus, and porcine hemagglutinating encephalomyelitis. These diseases, especially TGEV and PEDV, have caused epidemics in Europe, Asia, and the Americas over the past 50 years, causing significant economic losses to swine producers. As pigs are a major protein source worldwide there is great interest in understanding, controlling, and preventing these diseases. These diseases have no cure, and current vaccines are not fully protective. On-farm prevention and biosecurity are difficult to enforce and have not stopped the spread of these diseases between herds. Recent advances in the immunology of porcine COVs has revealed that the immune response to porcine COVs shares many similarities with the response to human COVs, leading to increased interest in pigs as models for human disease. Highlights of these advances include the key role of local antigen presenting cells in the gastrointestinal tract in stimulating a protective immune response. This understanding has lead to new proposed vaccines. Advances in the understanding of the ways the viruses evade and degrade the host immune system have also lead to novel proposed therapies. Many of these therapies are in the early development stages, as researchers attempt to create efficacious, cost-effective, and practical therapies for these diseases.
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34
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Borucki MK, Lao V, Hwang M, Gardner S, Adney D, Munster V, Bowen R, Allen JE. Middle East Respiratory Syndrome Coronavirus Intra-Host Populations Are Characterized by Numerous High Frequency Variants. PLoS One 2016; 11:e0146251. [PMID: 26790002 PMCID: PMC4720378 DOI: 10.1371/journal.pone.0146251] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 12/15/2015] [Indexed: 12/23/2022] Open
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging human pathogen related to SARS virus. In vitro studies indicate this virus may have a broad host range suggesting an increased pandemic potential. Genetic and epidemiological evidence indicate camels serve as a reservoir for MERS virus but the mechanism of cross species transmission is unclear and many questions remain regarding the susceptibility of humans to infection. Deep sequencing data was obtained from the nasal samples of three camels that had been experimentally infected with a human MERS-CoV isolate. A majority of the genome was covered and average coverage was greater than 12,000x depth. Although only 5 mutations were detected in the consensus sequences, 473 intrahost single nucleotide variants were identified. Many of these variants were present at high frequencies and could potentially influence viral phenotype and the sensitivity of detection assays that target these regions for primer or probe binding.
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Affiliation(s)
- Monica K. Borucki
- Lawrence Livermore National Laboratory, Livermore, California, United States of America
- * E-mail:
| | - Victoria Lao
- Lawrence Livermore National Laboratory, Livermore, California, United States of America
| | - Mona Hwang
- Lawrence Livermore National Laboratory, Livermore, California, United States of America
| | - Shea Gardner
- Lawrence Livermore National Laboratory, Livermore, California, United States of America
| | - Danielle Adney
- Colorado State University, Fort Collins, Colorado, United States of America
| | - Vincent Munster
- National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, United States of America
| | - Richard Bowen
- Colorado State University, Fort Collins, Colorado, United States of America
| | - Jonathan E. Allen
- Lawrence Livermore National Laboratory, Livermore, California, United States of America
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Meng F, Badierah RA, Almehdar HA, Redwan EM, Kurgan L, Uversky VN. Unstructural biology of the dengue virus proteins. FEBS J 2015; 282:3368-94. [DOI: 10.1111/febs.13349] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2015] [Revised: 06/01/2015] [Accepted: 06/15/2015] [Indexed: 01/02/2023]
Affiliation(s)
- Fanchi Meng
- Department of Electrical and Computer Engineering; University of Alberta; Edmonton Alberta Canada
| | - Reaid A. Badierah
- Biological Department; Faculty of Science; King Abdulaziz University; Jeddah Saudi Arabia
| | - Hussein A. Almehdar
- Biological Department; Faculty of Science; King Abdulaziz University; Jeddah Saudi Arabia
| | - Elrashdy M. Redwan
- Biological Department; Faculty of Science; King Abdulaziz University; Jeddah Saudi Arabia
- Therapeutic and Protective Proteins Laboratory; Protein Research Department; Genetic Engineering and Biotechnology Research Institute; City for Scientific Research and Technology Applications; New Borg El-Arab Alexandria Egypt
| | - Lukasz Kurgan
- Department of Electrical and Computer Engineering; University of Alberta; Edmonton Alberta Canada
| | - Vladimir N. Uversky
- Biological Department; Faculty of Science; King Abdulaziz University; Jeddah Saudi Arabia
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute; Morsani College of Medicine; University of South Florida; Tampa FL USA
- Laboratory of Structural Dynamics, Stability and Folding of Proteins; Institute of Cytology; Russian Academy of Sciences; St Petersburg Russia
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Abstract
A novel coronavirus, MERS-CoV (NCoV, HCoV-EMC/2012), originating from the Middle-East, has been discovered. Incoming data reveal that the virus is highly virulent to humans. A model that categorizes coronaviuses according to the hardness of their shells was developed before the discovery of MERS-CoV. Using protein intrinsic disorder prediction, coronaviruses were categorized into three groups that can be linked to the levels of oral-fecal and respiratory transmission regardless of genetic proximity. Using this model, MERS-CoV is placed into disorder group C, which consists of coronaviruses that have relatively hard inner and outer shells. The members of this group are likely to persist in the environment for a longer period of time and possess the highest oral-fecal components but relatively low respiratory transmission components. Oral-urine and saliva transmission are also highly possible since both require harder protective shells. Results show that disorder prediction can be used as a tool that suggests clues to look for in further epidemiological investigations.
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