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1.
Front Immunol ; 12: 807134, 2021.
Article in English | MEDLINE | ID: covidwho-1604257

ABSTRACT

ORF8 is a viral immunoglobulin-like (Ig-like) domain protein encoded by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA genome. It tends to evolve rapidly and interfere with immune responses. However, the structural characteristics of various coronavirus ORF8 proteins and their subsequent effects on biological functions remain unclear. Herein, we determined the crystal structures of SARS-CoV-2 ORF8 (S84) (one of the epidemic isoforms) and the bat coronavirus RaTG13 ORF8 variant at 1.62 Å and 1.76 Å resolution, respectively. Comparison of these ORF8 proteins demonstrates that the 62-77 residues in Ig-like domain of coronavirus ORF8 adopt different conformations. Combined with mutagenesis assays, the residue Cys20 of ORF8 is responsible for forming the covalent disulfide-linked dimer in crystal packing and in vitro biochemical conditions. Furthermore, immune cell-binding assays indicate that various ORF8 (SARS-CoV-2 ORF8 (L84), ORF8 (S84), and RaTG13 ORF8) proteins have different interaction capabilities with human CD14+ monocytes in human peripheral blood. These results provide new insights into the specific characteristics of various coronavirus ORF8 and suggest that ORF8 variants may influence disease-related immune responses.


Subject(s)
COVID-19/immunology , Chiroptera/immunology , Immunity/immunology , Immunoglobulin Domains/immunology , Viral Proteins/immunology , Animals , Binding Sites/genetics , COVID-19/virology , Cells, Cultured , Chiroptera/genetics , Chiroptera/metabolism , Crystallography, X-Ray , Humans , Immunity/genetics , Immunoglobulin Domains/genetics , Lipopolysaccharide Receptors/immunology , Lipopolysaccharide Receptors/metabolism , Models, Molecular , Monocytes/immunology , Monocytes/metabolism , Mutation , Protein Binding , Species Specificity , Viral Proteins/classification , Viral Proteins/genetics
2.
Proc Natl Acad Sci U S A ; 119(1)2022 01 04.
Article in English | MEDLINE | ID: covidwho-1595265

ABSTRACT

Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) provokes a potentially fatal pneumonia with multiorgan failure, and high systemic inflammation. To gain mechanistic insight and ferret out the root of this immune dysregulation, we modeled, by in vitro coculture, the interactions between infected epithelial cells and immunocytes. A strong response was induced in monocytes and B cells, with a SARS-CoV-2-specific inflammatory gene cluster distinct from that seen in influenza A or Ebola virus-infected cocultures, and which reproduced deviations reported in blood or lung myeloid cells from COVID-19 patients. A substantial fraction of the effect could be reproduced after individual transfection of several SARS-CoV-2 proteins (Spike and some nonstructural proteins), mediated by soluble factors, but not via transcriptional induction. This response was greatly muted in monocytes from healthy children, perhaps a clue to the age dependency of COVID-19. These results suggest that the inflammatory malfunction in COVID-19 is rooted in the earliest perturbations that SARS-CoV-2 induces in epithelia.


Subject(s)
COVID-19/immunology , Epithelial Cells/immunology , Monocytes/immunology , SARS-CoV-2/pathogenicity , Adult , B-Lymphocytes/immunology , COVID-19/pathology , Child , Coculture Techniques , Ebolavirus/pathogenicity , Epithelial Cells/virology , Gene Expression Profiling , Humans , Inflammation , Influenza A virus/pathogenicity , Lung/immunology , Myeloid Cells/immunology , Species Specificity , Viral Proteins/immunology
3.
Sci Rep ; 11(1): 24145, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1585802

ABSTRACT

Recent studies suggest that coronaviruses circulate widely in Southeast Asian bat species and that the progenitors of the SARS-Cov-2 virus could have originated in rhinolophid bats in the region. Our objective was to assess the diversity and circulation patterns of coronavirus in several bat species in Southeast Asia. We undertook monthly live-capture sessions and sampling in Cambodia over 17 months to cover all phases of the annual reproduction cycle of bats and test specifically the association between their age and CoV infection status. We additionally examined current information on the reproductive phenology of Rhinolophus and other bat species presently known to occur in mainland southeast China, Vietnam, Laos and Cambodia. Results from our longitudinal monitoring (573 bats belonging to 8 species) showed an overall proportion of positive PCR tests for CoV of 4.2% (24/573) in cave-dwelling bats from Kampot and 4.75% (22/463) in flying-foxes from Kandal. Phylogenetic analysis showed that the PCR amplicon sequences of CoVs (n = 46) obtained clustered in Alphacoronavirus and Betacoronavirus. Interestingly, Hipposideros larvatus sensu lato harbored viruses from both genera. Our results suggest an association between positive detections of coronaviruses and juvenile and immature bats in Cambodia (OR = 3.24 [1.46-7.76], p = 0.005). Since the limited data presently available from literature review indicates that reproduction is largely synchronized among rhinolophid and hipposiderid bats in our study region, particularly in its more seasonal portions (above 16° N), this may lead to seasonal patterns in CoV circulation. Overall, our study suggests that surveillance of CoV in insectivorous bat species in Southeast Asia, including SARS-CoV-related coronaviruses in rhinolophid bats, could be targeted from June to October for species exhibiting high proportions of juveniles and immatures during these months. It also highlights the need to develop long-term longitudinal surveys of bats and improve our understanding of their ecology in the region, for both biodiversity conservation and public health reasons.


Subject(s)
Alphacoronavirus/genetics , Betacoronavirus/genetics , COVID-19/transmission , Chiroptera/growth & development , SARS-CoV-2/genetics , Alphacoronavirus/classification , Animals , Asia, Southeastern/epidemiology , Betacoronavirus/classification , COVID-19/epidemiology , COVID-19/virology , Cambodia/epidemiology , Chiroptera/classification , Chiroptera/virology , Epidemics/prevention & control , Evolution, Molecular , Genome, Viral/genetics , Geography , Humans , Longitudinal Studies , Male , Phylogeny , SARS-CoV-2/classification , SARS-CoV-2/physiology , Species Specificity
4.
Biochem J ; 478(19): 3671-3684, 2021 10 15.
Article in English | MEDLINE | ID: covidwho-1557441

ABSTRACT

COVID-19, the clinical syndrome caused by the SARS-CoV-2 virus, has rapidly spread globally causing hundreds of millions of infections and over two million deaths. The potential animal reservoirs for SARS-CoV-2 are currently unknown, however sequence analysis has provided plausible potential candidate species. SARS-CoV-2 binds to the angiotensin I converting enzyme 2 (ACE2) to enable its entry into host cells and establish infection. We analyzed the binding surface of ACE2 from several important animal species to begin to understand the parameters for the ACE2 recognition by the SARS-CoV-2 spike protein receptor binding domain (RBD). We employed Shannon entropy analysis to determine the variability of ACE2 across its sequence and particularly in its RBD interacting region, and assessed differences between various species' ACE2 and human ACE2. Recombinant ACE2 from human, hamster, horseshoe bat, cat, ferret, and cow were evaluated for RBD binding. A gradient of binding affinities were seen where human and hamster ACE2 were similarly in the low nanomolar range, followed by cat and cow. Surprisingly, horseshoe bat (Rhinolophus sinicus) and ferret (Mustela putorius) ACE2s had poor binding activity compared with the other species' ACE2. The residue differences and binding properties between the species' variants provide a framework for understanding ACE2-RBD binding and virus tropism.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/epidemiology , COVID-19/metabolism , Cats , Dogs , Humans , Mice , Protein Binding , Protein Domains , SARS-CoV-2/metabolism , Species Specificity , Spike Glycoprotein, Coronavirus/metabolism , Viral Tropism
5.
Emerg Microbes Infect ; 10(1): 2199-2201, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1505680

ABSTRACT

We report pilot studies to evaluate the susceptibility of common domestic livestock (cattle, sheep, goat, alpaca, rabbit, and horse) to intranasal infection with SARS-CoV-2. None of the infected animals shed infectious virus via nasal, oral, or faecal routes, although viral RNA was detected in several animals. Further, neutralizing antibody titres were low or non-existent one month following infection. These results suggest that domestic livestock are unlikely to contribute to SARS-CoV-2 epidemiology.


Subject(s)
COVID-19/veterinary , Host Specificity , Livestock/virology , SARS-CoV-2/pathogenicity , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , Camelids, New World/virology , Cattle/virology , Chlorocebus aethiops , Disease Reservoirs/virology , Goats/virology , Horses/virology , Host Specificity/immunology , Humans , Nasal Cavity/virology , RNA, Viral/analysis , Rabbits/virology , Rectum/virology , Respiratory System/virology , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Sheep/virology , Species Specificity , Vero Cells , Virus Shedding , Viscera/virology
6.
J Am Soc Nephrol ; 32(1): 86-97, 2021 01.
Article in English | MEDLINE | ID: covidwho-1496654

ABSTRACT

BACKGROUND: Cultured cell lines are widely used for research in the physiology, pathophysiology, toxicology, and pharmacology of the renal proximal tubule. The lines that are most appropriate for a given use depend upon the genes expressed. New tools for transcriptomic profiling using RNA sequencing (RNA-Seq) make it possible to catalog expressed genes in each cell line. METHODS: Fourteen different proximal tubule cell lines, representing six species, were grown on permeable supports under conditions specific for the respective lines. RNA-Seq followed standard procedures. RESULTS: Transcripts expressed in cell lines variably matched transcripts selectively expressed in native proximal tubule. Opossum kidney (OK) cells displayed the highest percentage match (45% of proximal marker genes [TPM threshold =15]), with pig kidney cells (LLC-PK1) close behind (39%). Lower-percentage matches were seen for various human lines, including HK-2 (26%), and lines from rodent kidneys, such as NRK-52E (23%). Nominally, identical OK cells from different sources differed substantially in expression of proximal tubule markers. Mapping cell line transcriptomes to gene sets for various proximal tubule functions (sodium and water transport, protein transport, metabolic functions, endocrine functions) showed that different lines may be optimal for experimentally modeling each function. An online resource (https://esbl.nhlbi.nih.gov/JBrowse/KCT/) has been created to interrogate cell line transcriptome data. Proteomic analysis of NRK-52E cells confirmed low expression of many proximal tubule marker proteins. CONCLUSIONS: No cell line fully matched the transcriptome of native proximal tubule cells. However, some of the lines tested are suitable for the study of particular metabolic and transport processes seen in the proximal tubule.


Subject(s)
Cell Culture Techniques/methods , Kidney Tubules, Proximal/metabolism , Transcriptome , Animals , Biological Transport , Cell Line , Chromatography, Liquid , Gene Expression Profiling , Humans , Internet , Mice , Opossums , Proteomics , RNA-Seq , Rats , Sequence Analysis, RNA , Species Specificity , Swine , Tandem Mass Spectrometry
7.
Front Immunol ; 12: 754642, 2021.
Article in English | MEDLINE | ID: covidwho-1485059

ABSTRACT

Understanding SARS-CoV-2 immune pathology is critical for the development of effective vaccines and treatments. Here, we employed unbiased serial whole-blood transcriptome profiling by weighted gene network correlation analysis (WGCNA) at pre-specified timepoints of infection to understand SARS-CoV-2-related immune alterations in a cohort of rhesus macaques (RMs) and African green monkeys (AGMs) presenting with varying degrees of pulmonary pathology. We found that the bulk of transcriptional changes occurred at day 3 post-infection and normalized to pre-infection levels by 3 weeks. There was evidence of coordination of transcriptional networks in blood (defined by WGCNA) and the nasopharyngeal SARS-CoV-2 burden as well as the absolute monocyte count. Pathway analysis of gene modules revealed prominent regulation of type I and type II interferon stimulated genes (ISGs) in both RMs and AGMs, with the latter species exhibiting a greater breadth of ISG upregulation. Notably, pathways relating to neutrophil degranulation were enriched in blood of SARS-CoV-2 infected AGMs, but not RMs. Our results elude to hallmark similarities as well as differences in the RM and AGM acute response to SARS-CoV-2 infection, and may help guide the selection of particular NHP species in modeling aspects of COVID-19 disease outcome.


Subject(s)
COVID-19/immunology , Cell Degranulation , Neutrophils/immunology , SARS-CoV-2/immunology , Animals , COVID-19/blood , Chlorocebus aethiops , Disease Models, Animal , Macaca mulatta , Neutrophils/metabolism , SARS-CoV-2/metabolism , Species Specificity
8.
Viruses ; 13(10)2021 10 04.
Article in English | MEDLINE | ID: covidwho-1457477

ABSTRACT

Sialodacryoadenitis virus (SDAV) is known to be an etiological agent, causing infections in laboratory rats. Until now, its role has only been considered in studies on respiratory and salivary gland infections. The scant literature data, consisting mainly of papers from the last century, do not sufficiently address the topic of SDAV infections. The ongoing pandemic has demonstrated, once again, the role of the Coronaviridae family as extremely dangerous etiological agents of human zoonoses. The ability of coronaviruses to cross the species barrier and change to hosts commonly found in close proximity to humans highlights the need to characterize SDAV infections. The main host of the infection is the rat, as mentioned above. Rats inhabit large urban agglomerations, carrying a vast epidemic threat. Of the 2277 existing rodent species, 217 are reservoirs for 66 zoonotic diseases caused by viruses, bacteria, fungi, and protozoa. This review provides insight into the current state of knowledge of SDAV characteristics and its likely zoonotic potential.


Subject(s)
Coronavirus Infections/veterinary , Coronavirus, Rat/genetics , Coronavirus, Rat/pathogenicity , Viral Zoonoses/epidemiology , Animals , Coronavirus Infections/transmission , Coronavirus, Rat/classification , Rats , Species Specificity , Virus Replication/physiology
9.
Nat Commun ; 12(1): 5839, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1454764

ABSTRACT

There is an urgent need to understand the nature of immune responses against SARS-CoV-2, to inform risk-mitigation strategies for people living with HIV (PLWH). Here we show that the majority of PLWH with ART suppressed HIV viral load, mount a detectable adaptive immune response to SARS-CoV-2. Humoral and SARS-CoV-2-specific T cell responses are comparable between HIV-positive and negative subjects and persist 5-7 months following predominately mild COVID-19 disease. T cell responses against Spike, Membrane and Nucleoprotein are the most prominent, with SARS-CoV-2-specific CD4 T cells outnumbering CD8 T cells. We further show that the overall magnitude of SARS-CoV-2-specific T cell responses relates to the size of the naive CD4 T cell pool and the CD4:CD8 ratio in PLWH. These findings suggest that inadequate immune reconstitution on ART, could hinder immune responses to SARS-CoV-2 with implications for the individual management and vaccine effectiveness in PLWH.


Subject(s)
HIV Infections/immunology , HIV Infections/virology , Immunity, Humoral , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Adult , Aged , Antibodies, Viral/blood , Antibodies, Viral/immunology , Antibody Formation/immunology , Antigens, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Cohort Studies , Female , Genome, Human , HIV Infections/blood , Humans , Interferon-gamma/metabolism , Male , Middle Aged , Phenotype , Species Specificity , Tissue Donors
10.
Biochem J ; 478(19): 3671-3684, 2021 10 15.
Article in English | MEDLINE | ID: covidwho-1437701

ABSTRACT

COVID-19, the clinical syndrome caused by the SARS-CoV-2 virus, has rapidly spread globally causing hundreds of millions of infections and over two million deaths. The potential animal reservoirs for SARS-CoV-2 are currently unknown, however sequence analysis has provided plausible potential candidate species. SARS-CoV-2 binds to the angiotensin I converting enzyme 2 (ACE2) to enable its entry into host cells and establish infection. We analyzed the binding surface of ACE2 from several important animal species to begin to understand the parameters for the ACE2 recognition by the SARS-CoV-2 spike protein receptor binding domain (RBD). We employed Shannon entropy analysis to determine the variability of ACE2 across its sequence and particularly in its RBD interacting region, and assessed differences between various species' ACE2 and human ACE2. Recombinant ACE2 from human, hamster, horseshoe bat, cat, ferret, and cow were evaluated for RBD binding. A gradient of binding affinities were seen where human and hamster ACE2 were similarly in the low nanomolar range, followed by cat and cow. Surprisingly, horseshoe bat (Rhinolophus sinicus) and ferret (Mustela putorius) ACE2s had poor binding activity compared with the other species' ACE2. The residue differences and binding properties between the species' variants provide a framework for understanding ACE2-RBD binding and virus tropism.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/epidemiology , COVID-19/metabolism , Cats , Dogs , Humans , Mice , Protein Binding , Protein Domains , SARS-CoV-2/metabolism , Species Specificity , Spike Glycoprotein, Coronavirus/metabolism , Viral Tropism
11.
Placenta ; 115: 70-77, 2021 11.
Article in English | MEDLINE | ID: covidwho-1433733

ABSTRACT

Species differences are among the main reasons for the high failure rate of preclinical studies. A better awareness and understanding of these differences might help to improve the outcome of preclinical research. In reproduction, the placenta is the central organ regulating fetal exposure to a substance circulating in the maternal organism. Exact information about placental transfer can help to better estimate the toxic potential of a substance. From an evolutionary point of view, the chorioallantoic placenta is the organ with the highest anatomical diversity among species. Moreover, frequently used animal models in reproduction belong to rodents and lagomorphs, two groups that are characterized by the generation of an additional type of placenta, which is crucial for fetal development, but absent from humans: the inverted yolk sac placenta. Taken together, the translatability of placental transfer studies from laboratory animals to humans is challenging, which is supported by the fact that numerous species-dependent toxic effects are described in literature. Thus, reliable human-relevant data are frequently lacking and the toxic potential of chemicals and pharmaceuticals for humans can hardly be estimated, often resulting in recommendations that medical treatments or exposure to chemicals should be avoided for safety reasons. Although species differences of placental anatomy have been described frequently and the need for human-relevant research models has been emphasized, analyses of substances with species-dependent placental transfer have been performed only sporadically. Here, we present examples for species-specific placental transfer, including that of nanoparticles and pharmaceuticals, and discuss potential underlying mechanisms. With respect to the COVID 19-pandemic it might be of interest that some antiviral drugs are reported to feature species-specific placental transfer. Further, differences in placental structure and antibody transfer may affect placental transfer of ZIKA virus.


Subject(s)
Maternal-Fetal Exchange/physiology , Placenta/metabolism , Animals , Antiviral Agents/pharmacokinetics , Biological Transport/physiology , COVID-19/drug therapy , COVID-19/transmission , COVID-19/virology , Female , Humans , Infectious Disease Transmission, Vertical , Maternal-Fetal Exchange/drug effects , Placenta/drug effects , Pregnancy , Pregnancy Complications, Infectious/drug therapy , Pregnancy Complications, Infectious/metabolism , Pregnancy Complications, Infectious/virology , SARS-CoV-2/metabolism , Species Specificity , Yolk Sac/metabolism , Yolk Sac/physiology , Zika Virus/metabolism , Zika Virus Infection/drug therapy , Zika Virus Infection/transmission
12.
Nat Commun ; 12(1): 3358, 2021 06 07.
Article in English | MEDLINE | ID: covidwho-1397869

ABSTRACT

Early stages of embryogenesis depend on subcellular localization and transport of maternal mRNA. However, systematic analysis of these processes is hindered by a lack of spatio-temporal information in single-cell RNA sequencing. Here, we combine spatially-resolved transcriptomics and single-cell RNA labeling to perform a spatio-temporal analysis of the transcriptome during early zebrafish development. We measure spatial localization of mRNA molecules within the one-cell stage embryo, which allows us to identify a class of mRNAs that are specifically localized at an extraembryonic position, the vegetal pole. Furthermore, we establish a method for high-throughput single-cell RNA labeling in early zebrafish embryos, which enables us to follow the fate of individual maternal transcripts until gastrulation. This approach reveals that many localized transcripts are specifically transported to the primordial germ cells. Finally, we acquire spatial transcriptomes of two xenopus species and compare evolutionary conservation of localized genes as well as enriched sequence motifs.


Subject(s)
Cell Tracking/methods , Embryo, Nonmammalian/metabolism , RNA, Messenger/genetics , Transcriptome/genetics , Zebrafish/genetics , Animals , Embryo, Nonmammalian/cytology , Embryo, Nonmammalian/embryology , Female , Gene Expression Regulation, Developmental , Oocytes/cytology , Oocytes/metabolism , RNA, Messenger/metabolism , Single-Cell Analysis/methods , Spatio-Temporal Analysis , Species Specificity , Xenopus/embryology , Xenopus/genetics , Xenopus laevis/embryology , Xenopus laevis/genetics , Zebrafish/embryology
13.
PLoS Pathog ; 17(9): e1009814, 2021 09.
Article in English | MEDLINE | ID: covidwho-1394561

ABSTRACT

Many of us had refresher courses in virology, immunology, and epidemiology in 2020, and we were reminded of the fact that Homo sapiens, the wiliest predator on the planet, has been hunting everything that moves for millennia. These repeated interspecies contacts inherently lead to recurrent zoonosis (nonhuman to human) and anthroponosis (human to nonhuman). Given the accelerating changes in our ecosystems since the neolithic revolution, it was not surprising to see a virus that spreads via aerosolization and liquid droplets cause a pandemic in a few months. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic begs the question-which viruses could cause a global threat? In this Opinion, the characteristics that make adenoviruses a risk, which include efficient intra- and interspecies transmission, thermostable particles, persistent/latent infections in diverse hosts, and the ability to readily recombine and escape herd immunity, are discussed.


Subject(s)
Adenovirus Infections, Human/mortality , Pandemics/statistics & numerical data , Adenovirus Infections, Human/epidemiology , Animals , Human-Animal Interaction , Humans , Recombination, Genetic , Risk Factors , Species Specificity , Transcription, Genetic
14.
Mol Biol Evol ; 38(2): 702-715, 2021 01 23.
Article in English | MEDLINE | ID: covidwho-1387955

ABSTRACT

Despite SARS-CoV and SARS-CoV-2 being equipped with highly similar protein arsenals, the corresponding zoonoses have spread among humans at extremely different rates. The specific characteristics of these viruses that led to such distinct outcomes remain unclear. Here, we apply proteome-wide comparative structural analysis aiming to identify the unique molecular elements in the SARS-CoV-2 proteome that may explain the differing consequences. By combining protein modeling and molecular dynamics simulations, we suggest nonconservative substitutions in functional regions of the spike glycoprotein (S), nsp1, and nsp3 that are contributing to differences in virulence. Particularly, we explain why the substitutions at the receptor-binding domain of S affect the structure-dynamics behavior in complexes with putative host receptors. Conservation of functional protein regions within the two taxa is also noteworthy. We suggest that the highly conserved main protease, nsp5, of SARS-CoV and SARS-CoV-2 is part of their mechanism of circumventing the host interferon antiviral response. Overall, most substitutions occur on the protein surfaces and may be modulating their antigenic properties and interactions with other macromolecules. Our results imply that the striking difference in the pervasiveness of SARS-CoV-2 and SARS-CoV among humans seems to significantly derive from molecular features that modulate the efficiency of viral particles in entering the host cells and blocking the host immune response.


Subject(s)
Molecular Dynamics Simulation , Proteomics , SARS Virus/chemistry , SARS Virus/pathogenicity , SARS-CoV-2/chemistry , SARS-CoV-2/pathogenicity , Viral Proteins/chemistry , Animals , Humans , Protein Domains , SARS Virus/metabolism , SARS-CoV-2/metabolism , Species Specificity , Viral Proteins/metabolism
16.
Mol Inform ; 40(9): e2100031, 2021 09.
Article in English | MEDLINE | ID: covidwho-1351262

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to be a global threat, causing millions of deaths worldwide. SARS-CoV-2 is an enveloped virus with spike (S) glycoproteins conferring binding to the host cell's angiotensin-converting enzyme 2 (ACE2), which is critical for cellular entry. The host range of the virus extends well beyond humans and non-human primates. Natural and experimental infections have confirmed the high susceptibility of cats, ferrets, and Syrian hamsters, whereas dogs, mice, rats, pigs, and chickens are refractory to SARS-CoV-2 infection. To investigate the underlying reason for the variable susceptibility observed in different species, we have developed molecular descriptors to efficiently analyse dynamic simulation models of complexes between SARS-CoV-2 S and ACE2. Our extensive analyses represent the first systematic structure-based approach that allows predictions of species susceptibility to SARS-CoV-2 infection.


Subject(s)
SARS-CoV-2/chemistry , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , Cats , Dogs , Ferrets , Haplorhini , Humans , Mesocricetus , Mice , Molecular Dynamics Simulation , Rats , SARS-CoV-2/metabolism , Species Specificity , Swine
17.
Sci Rep ; 11(1): 16145, 2021 08 09.
Article in English | MEDLINE | ID: covidwho-1349686

ABSTRACT

The genetic element s2m has been acquired through horizontal transfer by many distantly related viruses, including the SARS-related coronaviruses. Here we show that s2m is evolutionarily conserved in these viruses. Though several lineages of severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) devoid of the element can be found, these variants seem to have been short lived, indicating that they were less evolutionary fit than their s2m-containing counterparts. On a species-level, however, there do not appear to be any losses and this pattern strongly suggests that the s2m element is essential to virus replication in SARS-CoV-2 and related viruses. Further experiments are needed to elucidate the function of s2m.


Subject(s)
Coronaviridae/genetics , Interspersed Repetitive Sequences/genetics , RNA, Viral/genetics , SARS-CoV-2/genetics , Virus Replication/genetics , Animals , Base Sequence , COVID-19/virology , Coronaviridae/classification , Evolution, Molecular , Gene Transfer, Horizontal , Humans , Phylogeny , SARS-CoV-2/physiology , Sequence Homology, Nucleic Acid , Species Specificity
18.
Brief Bioinform ; 22(2): 963-975, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1343638

ABSTRACT

The Novel Coronavirus Disease 2019 (COVID-19) has become an international public health emergency, which poses the most serious threat to the human health around the world. Accumulating evidences have shown that the new coronavirus could not only infect human beings, but also can infect other species which might result in the cross-species infections. In this research, 1056 ACE2 protein sequences are collected from the NCBI database, and 173 species with >60% sequence identity compared with that of human beings are selected for further analysis. We find 14 polar residues forming the binding interface of ACE2/2019-nCoV-Spike complex play an important role in maintaining protein-protein stability. Among them, 8 polar residues at the same positions with that of human ACE2 are highly conserved, which ensure its basic binding affinity with the novel coronavirus. 5 of other 6 unconserved polar residues (positions at human ACE2: Q24, D30, K31, H34 and E35) are proved to have an effect on the binding patterns among species. We select 21 species keeping close contacts with human beings, construct their ACE2 three-dimensional structures by Homology Modeling method and calculate the binding free energies of their ACE2/2019-nCoV-Spike complexes. We find the ACE2 from all the 21 species possess the capabilities to bind with the novel coronavirus. Compared with the human beings, 8 species (cow, deer, cynomys, chimpanzee, monkey, sheep, dolphin and whale) present almost the same binding abilities, and 3 species (bat, pig and dog) show significant improvements in binding affinities. We hope this research could provide significant help for the future epidemic detection, drug and vaccine development and even the global eco-system protections.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , SARS-CoV-2/metabolism , Animals , Humans , Protein Binding , Species Specificity , Spike Glycoprotein, Coronavirus/metabolism
19.
FASEB J ; 35(9): e21798, 2021 09.
Article in English | MEDLINE | ID: covidwho-1334263

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic threatens human species with mortality rate of roughly 2%. We can hardly predict the time of herd immunity against and end of COVID-19 with or without success of vaccine. One way to overcome the situation is to define what delineates disease severity and serves as a molecular target. The most successful analogy is found in BCR-ABL in chronic myeloid leukemia, which is the golden biomarker, and simultaneously, the most effective molecular target. We hypothesize that S100 calcium-binding protein A8 (S100A8) is one such molecule. The underlying evidence includes accumulating clinical information that S100A8 is upregulated in severe forms of COVID-19, pathological similarities of the affected lungs between COVID-19 and S100A8-induced acute respiratory distress syndrome (ARDS) model, homeostatic inflammation theory in which S100A8 is an endogenous ligand for endotoxin sensor Toll-like receptor 4/Myeloid differentiation protein-2 (TLR4/MD-2) and mediates hyper-inflammation even after elimination of endotoxin-producing extrinsic pathogens, analogous findings between COVID-19-associated ARDS and pre-metastatic lungs such as S100A8 upregulation, pulmonary recruitment of myeloid cells, increased vascular permeability, and activation coagulation cascade. A successful treatment in an animal COVID-19 model is given with a reagent capable of abrogating interaction between S100A8/S100A9 and TLR4. In this paper, we try to verify our hypothesis that S100A8 governs COVID-19-associated ARDS.


Subject(s)
COVID-19/complications , Calgranulin A/physiology , Cytokine Release Syndrome/etiology , Inflammation/etiology , Pandemics , Respiratory Distress Syndrome/etiology , SARS-CoV-2/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , Animals , Antiviral Agents/pharmacology , COVID-19/genetics , COVID-19/pathology , Calgranulin A/blood , Calgranulin A/genetics , Chemokine CXCL11/blood , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/pathology , Disaccharides/pharmacology , Disaccharides/therapeutic use , Disease Models, Animal , Drug Discovery , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Inflammation/genetics , Inflammation/pathology , Lung/metabolism , Lung/pathology , Lung/virology , Lung Neoplasms/drug therapy , Lung Neoplasms/secondary , Lymphocyte Antigen 96/physiology , Macaca mulatta , Mice , Mice, Transgenic , Models, Biological , Mutation , Respiratory Distress Syndrome/genetics , Respiratory Distress Syndrome/metabolism , Species Specificity , Sugar Phosphates/pharmacology , Sugar Phosphates/therapeutic use , Toll-Like Receptor 4/physiology , Up-Regulation , Virus Internalization
20.
Front Immunol ; 12: 663912, 2021.
Article in English | MEDLINE | ID: covidwho-1325523

ABSTRACT

The Spike (S) protein of the SARS-CoV-2 virus is critical for its ability to attach and fuse into the host cells, leading to infection, and transmission. In this review, we have initially performed a meta-analysis of keywords associated with the S protein to frame the outline of important research findings and directions related to it. Based on this outline, we have reviewed the structure, uniqueness, and origin of the S protein of SARS-CoV-2. Furthermore, the interactions of the Spike protein with host and its implications in COVID-19 pathogenesis, as well as drug and vaccine development, are discussed. We have also summarized the recent advances in detection methods using S protein-based RT-PCR, ELISA, point-of-care lateral flow immunoassay, and graphene-based field-effect transistor (FET) biosensors. Finally, we have also discussed the emerging Spike mutants and the efficacy of the Spike-based vaccines against those strains. Overall, we have covered most of the recent advances on the SARS-CoV-2 Spike protein and its possible implications in countering this virus.


Subject(s)
SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/prevention & control , COVID-19/virology , COVID-19 Testing , COVID-19 Vaccines/immunology , Host-Pathogen Interactions , Humans , Mutation , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Species Specificity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
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