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1.
Sci Rep ; 12(1): 9399, 2022 Jun 07.
Article in English | MEDLINE | ID: covidwho-1882769

ABSTRACT

COVID-19, caused by SARS-CoV-2, is a primarily pulmonary disease that can affect several organs, directly or indirectly. To date, there are many questions about the different pathological mechanisms. Here, we generate an approach to identify the cellular-level tropism of SARS-CoV-2 using human proteomics, virus-host interactions, and enrichment analysis. Through a network-based approach, the molecular context was visualized and analyzed. This procedure was also performed for SARS-CoV-1. We obtained proteomes and interactomes from 145 different cells corresponding to 57 different tissues. We discarded the cells without the proteins known for interacting with the virus, such as ACE2 or TMPRSS2. Of the remaining cells, a gradient of susceptibility to infection was observed. In addition, we identified proteins associated with the coagulation cascade that can be directly or indirectly affected by viral proteins. As a whole we identified 55 cells that could be potentially controlled by the virus, with different susceptibilities, mainly being pneumocytes, heart, kidney, liver, or small intestine cells. These results help to explain the molecular context and provide elements for possible treatments in the current situation. This strategy may be useful for other viruses, especially those with limited reported PPI, such as a new virus.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Host Microbial Interactions , Humans , Tropism
2.
Lancet Microbe ; 1(1): e1, 2020 05.
Article in English | MEDLINE | ID: covidwho-1829749
3.
Viruses ; 14(5)2022 04 21.
Article in English | MEDLINE | ID: covidwho-1822442

ABSTRACT

A canine coronavirus (CCoV) has now been reported from two independent human samples from Malaysia (respiratory, collected in 2017-2018; CCoV-HuPn-2018) and Haiti (urine, collected in 2017); these two viruses were nearly genetically identical. In an effort to identify any novel adaptations associated with this apparent shift in tropism we carried out detailed evolutionary analyses of the spike gene of this virus in the context of related Alphacoronavirus 1 species. The spike 0-domain retains homology to CCoV2b (enteric infections) and Transmissible Gastroenteritis Virus (TGEV; enteric and respiratory). This domain is subject to relaxed selection pressure and an increased rate of molecular evolution. It contains unique amino acid substitutions, including within a region important for sialic acid binding and pathogenesis in TGEV. Overall, the spike gene is extensively recombinant, with a feline coronavirus type II strain serving a prominent role in the recombinant history of the virus. Molecular divergence time for a segment of the gene where temporal signal could be determined, was estimated at around 60 years ago. We hypothesize that the virus had an enteric origin, but that it may be losing that particular tropism, possibly because of mutations in the sialic acid binding region of the spike 0-domain.


Subject(s)
Coronavirus, Canine , Animals , Cats , Dogs , N-Acetylneuraminic Acid , Spike Glycoprotein, Coronavirus/genetics , Tropism , Zoonoses
4.
J Clin Virol ; 152: 105170, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1814679

ABSTRACT

BACKGROUND: The Omicron variant of concern is characterised by more than 50 distinct mutations, most in the spike protein. The implications of these for disease transmission, tissue tropism and diagnostic testing needs study. OBJECTIVES: We evaluated the performance of RT-PCR on saliva (SA) swabs and antigen testing on mid-turbinate MT samples relative to RT-PCR on MT swabs. Patients (n = 453) presenting for outpatient testing at the Groote Schuur Hospital COVID-19 testing centre in Cape Town South Africa were recruited. Participants were recruited during the Delta (n = 304) and Omicron (n = 149) waves. RESULTS: In 30 confirmed Delta infections, positive percent agreement (PPA) of RT-PCR on saliva was only 73% compared to a composite standard of either MT or SA RT-PCR positivity, with rapid decay by day 3 after symptom onset. In contrast, in the 70 Omicron infections, SA performed as well as, or better than, MT samples up to day 5, with an overall PPA of SA swabs of 96% and MT of 93%. A change in antigen test performance was noted, with PPA of 93% in Delta, but only 68% for Omicron. CONCLUSIONS: Altered shedding kinetics appear to be present in Omicron-infected patients with more viral RNA detectable in saliva. Saliva swabs are a promising alternative to nasal samples, especially early in infection when sampling of both sites could improve detection. Lower sensitivity of antigen tests in Omicron is a concern and requires further study.


Subject(s)
COVID-19 Testing , COVID-19 , Humans , SARS-CoV-2 , Sensitivity and Specificity , South Africa , Tropism
5.
Cell Rep ; 38(12): 110558, 2022 03 22.
Article in English | MEDLINE | ID: covidwho-1797096

ABSTRACT

Mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) may alter viral host tropism and affect the activities of neutralizing antibodies. Here, we investigated 153 RBD mutants and 11 globally circulating variants of concern (VOCs) and variants of interest (VOIs) (including Omicron) for their antigenic changes and cross-species tropism in cells expressing 18 ACE2 orthologs. Several RBD mutations strengthened viral infectivity in cells expressing ACE2 orthologs of non-human animals, particularly those less susceptible to the ancestral strain. The mutations surrounding amino acids (aas) 439-448 and aa 484 are more likely to cause neutralization resistance. Strikingly, enhanced cross-species infection potential in the mouse and ferret, instead of the neutralization-escape scores of the mutations, account for the positive correlation with the cumulative prevalence of mutations in humans. These findings present insights for potential drivers of circulating SARS-CoV-2 variants and provide informative parameters for tracking and forecasting spreading mutations.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Ferrets , Humans , Membrane Glycoproteins/metabolism , Mice , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus , Tropism , Viral Envelope Proteins
6.
Nat Metab ; 4(3): 310-319, 2022 03.
Article in English | MEDLINE | ID: covidwho-1764213

ABSTRACT

Extrapulmonary manifestations of COVID-19 have gained attention due to their links to clinical outcomes and their potential long-term sequelae1. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) displays tropism towards several organs, including the heart and kidney. Whether it also directly affects the liver has been debated2,3. Here we provide clinical, histopathological, molecular and bioinformatic evidence for the hepatic tropism of SARS-CoV-2. We find that liver injury, indicated by a high frequency of abnormal liver function tests, is a common clinical feature of COVID-19 in two independent cohorts of patients with COVID-19 requiring hospitalization. Using autopsy samples obtained from a third patient cohort, we provide multiple levels of evidence for SARS-CoV-2 liver tropism, including viral RNA detection in 69% of autopsy liver specimens, and successful isolation of infectious SARS-CoV-2 from liver tissue postmortem. Furthermore, we identify transcription-, proteomic- and transcription factor-based activity profiles in hepatic autopsy samples, revealing similarities to the signatures associated with multiple other viral infections of the human liver. Together, we provide a comprehensive multimodal analysis of SARS-CoV-2 liver tropism, which increases our understanding of the molecular consequences of severe COVID-19 and could be useful for the identification of organ-specific pharmacological targets.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Liver , Proteomics , Tropism
7.
Nat Commun ; 13(1): 1589, 2022 03 24.
Article in English | MEDLINE | ID: covidwho-1764177

ABSTRACT

Progressive respiratory failure and hyperinflammatory response is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. Despite mounting evidence of disruption of the hypothalamus-pituitary-adrenal axis in COVID-19, relatively little is known about the tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to adrenal glands and associated changes. Here we demonstrate adrenal viral tropism and replication in COVID-19 patients. Adrenal glands showed inflammation accompanied by inflammatory cell death. Histopathologic analysis revealed widespread microthrombosis and severe adrenal injury. In addition, activation of the glycerophospholipid metabolism and reduction of cortisone intensities were characteristic for COVID-19 specimens. In conclusion, our autopsy series suggests that SARS-CoV-2 facilitates the induction of adrenalitis. Given the central role of adrenal glands in immunoregulation and taking into account the significant adrenal injury observed, monitoring of developing adrenal insufficiency might be essential in acute SARS-CoV-2 infection and during recovery.


Subject(s)
COVID-19 , Autopsy , Humans , Research , SARS-CoV-2 , Tropism
8.
PLoS Pathog ; 18(3): e1010197, 2022 03.
Article in English | MEDLINE | ID: covidwho-1753207

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) in humans, has a broad host range, and is able to infect domestic and wild animal species. Notably, white-tailed deer (WTD, Odocoileus virginianus), the most widely distributed cervid species in the Americas, were shown to be highly susceptible to SARS-CoV-2 in challenge studies and reported natural infection/exposure rates approaching 30-40% in free-ranging WTD in the U.S. Thus, understanding the infection and transmission dynamics of SARS-CoV-2 in WTD is critical to prevent future zoonotic transmission to humans, at the human-WTD interface during hunting or venison farming, and for implementation of effective disease control measures. Here, we demonstrated that following intranasal inoculation with SARS-CoV-2 B.1 lineage, WTD fawns (~8-month-old) shed infectious virus up to day 5 post-inoculation (pi), with high viral loads shed in nasal and oral secretions. This resulted in efficient deer-to-deer transmission on day 3 pi. Consistent a with lack of infectious SARS-CoV-2 shedding after day 5 pi, no transmission was observed to contact animals added on days 6 and 9 pi. We have also investigated the tropism and sites of SARS-CoV-2 replication in adult WTD (3-4 years of age). Infectious virus was detected up to day 6 pi in nasal secretions, and from various respiratory-, lymphoid-, and central nervous system tissues, indicating broad tissue tropism and multiple sites of virus replication. The study provides important insights on the infection and transmission dynamics of SARS-CoV-2 in WTD, a wild animal species that is highly susceptible to infection and with the potential to become a reservoir for the virus in the field.


Subject(s)
COVID-19 , Deer , Animals , COVID-19/veterinary , SARS-CoV-2 , Tropism
9.
Curr Microbiol ; 79(5): 133, 2022 Mar 16.
Article in English | MEDLINE | ID: covidwho-1739301

ABSTRACT

The recent pandemic which arose from China, is caused by a pathogenic virus named "severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2)". Its rapid global expansion has inflicted an extreme public health concern. The attachment of receptor-binding domains (RBD) of the spike proteins (S) to the host cell's membrane, with or without the help of other cellular components such as proteases and especially co-receptors, is required for the first stage of its pathogenesis. In addition to humans, angiotensin-converting enzyme 2 (ACE2) is found on a wide range of vertebrate host's cellular surface. SARS-CoV-2 has a broad spectrum of tropism; thus, it can infect a vast range of tissues, organs, and hosts; even though the surface amino acids of the spike protein conflict in the receptor-binding region. Due to the heterogeneous ACE2 distribution and the presence of different domains on the SARS-CoV-2 spike protein for binding, the virus entry into diverse host cell types may depend on the host cells' receptor presentation with or without co-receptors. This review investigates multiple current types of receptor and co-receptor tropisms, with other molecular factors alongside their respective mechanisms, which facilitate the binding and entry of SARS-CoV-2 into the cells, extending the severity of the coronavirus disease 2019 (COVID-19). Understanding the pathogenesis of COVID-19 from this perspective can effectively help prevent this disease and provide more potent treatment strategies, particularly in vulnerable people with various cellular-level susceptibilities.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Peptidyl-Dipeptidase A/metabolism , Probability , Receptors, Virus/genetics , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus , Tropism
10.
Viruses ; 14(3)2022 03 03.
Article in English | MEDLINE | ID: covidwho-1732234

ABSTRACT

Although the respiratory tract is the main target of SARS-CoV-2, other tissues and organs are permissive to the infection. In this report, we investigated this wide-spectrum tropism by studying the SARS-CoV-2 genetic intra-host variability in multiple tissues. The virological and histological investigation of multiple specimens from a post-mortem COVID-19 patient was performed. SARS-CoV-2 genome was detected in several tissues, including the lower respiratory system, cardio-vascular biopsies, stomach, pancreas, adrenal gland, mediastinal ganglion and testicles. Subgenomic RNA transcripts were also detected, in favor of an active viral replication, especially in testicles. Ultra-deep sequencing allowed us to highlight several SARS-CoV-2 mutations according to tissue distribution. More specifically, mutations of the spike protein, i.e., V341A (18.3%), E654 (44%) and H655R (30.8%), were detected in the inferior vena cava. SARS-CoV-2 variability can contribute to heterogeneous distributions of viral quasispecies, which may affect the COVID-19 pathogeny.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , Tropism , Virus Replication
11.
Viruses ; 14(1)2021 12 31.
Article in English | MEDLINE | ID: covidwho-1636493

ABSTRACT

Cell surface receptors play a key role in a virus' ability to recognize and invade cells and tissues, which basically defines viral pathogenicity [...].


Subject(s)
Receptors, Virus/metabolism , Viral Tropism/physiology , Antiviral Agents , COVID-19 , Epithelial Cells , Humans , SARS-CoV-2 , Tropism , Vaccines
12.
Commun Biol ; 4(1): 1196, 2021 10 13.
Article in English | MEDLINE | ID: covidwho-1467140

ABSTRACT

Emerging mutations in SARS-CoV-2 cause several waves of COVID-19 pandemic. Here we investigate the infectivity and antigenicity of ten emerging SARS-CoV-2 variants-B.1.1.298, B.1.1.7(Alpha), B.1.351(Beta), P.1(Gamma), P.2(Zeta), B.1.429(Epsilon), B.1.525(Eta), B.1.526-1(Iota), B.1.526-2(Iota), B.1.1.318-and seven corresponding single amino acid mutations in the receptor-binding domain using SARS-CoV-2 pseudovirus. The results indicate that the pseudovirus of most of the SARS-CoV-2 variants (except B.1.1.298) display slightly increased infectivity in human and monkey cell lines, especially B.1.351, B.1.525 and B.1.526 in Calu-3 cells. The K417N/T, N501Y, or E484K-carrying variants exhibit significantly increased abilities to infect mouse ACE2-overexpressing cells. The activities of furin, TMPRSS2, and cathepsin L are increased against most of the variants. RBD amino acid mutations comprising K417T/N, L452R, Y453F, S477N, E484K, and N501Y cause significant immune escape from 11 of 13 monoclonal antibodies. However, the resistance to neutralization by convalescent serum or vaccines elicited serum is mainly caused by the E484K mutation. The convalescent serum from B.1.1.7- and B.1.351-infected patients neutralized the variants themselves better than other SARS-CoV-2 variants. Our study provides insights regarding therapeutic antibodies and vaccines, and highlights the importance of E484K mutation.


Subject(s)
COVID-19/virology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Animals , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19/therapy , Cell Line , HEK293 Cells , Humans , Immunization, Passive/methods , Mammals/immunology , Mice , Mutation , Pandemics , Primates/immunology , Protein Binding , Tropism/genetics
13.
15.
Cells ; 10(8)2021 07 27.
Article in English | MEDLINE | ID: covidwho-1335012

ABSTRACT

Multiorgan tropism of SARS-CoV-2 has previously been shown for several major organs. We have comprehensively analyzed 25 different formalin-fixed paraffin-embedded (FFPE) tissues/organs from autopsies of fatal COVID-19 cases (n = 8), using histopathological assessment, detection of SARS-CoV-2 RNA using polymerase chain reaction and RNA in situ hybridization, viral protein using immunohistochemistry, and virus particles using transmission electron microscopy. SARS-CoV-2 RNA was mainly localized in epithelial cells across all organs. Next to lung, trachea, kidney, heart, or liver, viral RNA was also found in tonsils, salivary glands, oropharynx, thyroid, adrenal gland, testicles, prostate, ovaries, small bowel, lymph nodes, skin and skeletal muscle. Viral RNA was predominantly found in cells expressing ACE2, TMPRSS2, or both. The SARS-CoV-2 replicating RNA was also detected in these organs. Immunohistochemistry and electron microscopy were not suitable for reliable and specific SARS-CoV-2 detection in autopsies. These findings were validated using in situ hybridization on external COVID-19 autopsy samples (n = 9). Apart from the lung, correlation of viral detection and histopathological assessment did not reveal any specific alterations that could be attributed to SARS-CoV-2. In summary, SARS-CoV-2 and its replication could be observed across all organ systems, which co-localizes with ACE2 and TMPRSS2 mainly in epithelial but also in mesenchymal and endothelial cells. Apart from the respiratory tract, no specific (histo-)morphologic alterations could be assigned to the SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/metabolism , Endothelial Cells/metabolism , RNA, Viral/analysis , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Aged , Autopsy , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Endothelial Cells/pathology , Endothelial Cells/virology , Female , Gene Expression Regulation , Humans , Male , Middle Aged , Organ Specificity , Tropism
17.
Microb Biotechnol ; 14(1): 51-58, 2021 01.
Article in English | MEDLINE | ID: covidwho-1307660

ABSTRACT

This Crystal Ball speculates on the potential of molecular decoys for prevention and therapy in infectious diseases. It is dedicated to the memory of Singh Chhatwal, who pioneered research on disguises and decoys produced by Streptococcus, and so much more.


Subject(s)
Microbiota , Streptococcus , Memory , Tropism
18.
Cell Rep ; 34(11): 108872, 2021 03 16.
Article in English | MEDLINE | ID: covidwho-1135279

ABSTRACT

Viruses need to hijack the translational machinery of the host cell for a productive infection to happen. However, given the dynamic landscape of tRNA pools among tissues, it is unclear whether different viruses infecting different tissues have adapted their codon usage toward their tropism. Here, we collect the coding sequences of 502 human-infecting viruses and determine that tropism explains changes in codon usage. Using the tRNA abundances across 23 human tissues from The Cancer Genome Atlas (TCGA), we build an in silico model of translational efficiency that validates the correspondence of the viral codon usage with the translational machinery of their tropism. For instance, we detect that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is specifically adapted to the upper respiratory tract and alveoli. Furthermore, this correspondence is specifically defined in early viral proteins. The observed tissue-specific translational efficiency could be useful for the development of antiviral therapies and vaccines.


Subject(s)
Protein Biosynthesis/genetics , Virus Diseases/genetics , Viruses/genetics , Cell Line , Cell Line, Tumor , Codon Usage/genetics , Genes, Neoplasm/genetics , HCT116 Cells , HEK293 Cells , HeLa Cells , Hep G2 Cells , Humans , Pulmonary Alveoli/virology , RNA, Transfer/genetics , Respiratory Tract Infections/virology , Tropism/genetics , Viral Proteins/genetics , Virus Diseases/virology
19.
Lancet Microbe ; 1(1): e2-e3, 2020 05.
Article in English | MEDLINE | ID: covidwho-1087359
20.
Lancet Microbe ; 1(1): e14-e23, 2020 05.
Article in English | MEDLINE | ID: covidwho-1087358

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported from China in January, 2020. SARS-CoV-2 is efficiently transmitted from person to person and, in 2 months, has caused more than 82 000 laboratory-confirmed cases of coronavirus disease 2019 (COVID-19) and 2800 deaths in 46 countries. The total number of cases and deaths has surpassed that of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV). Although both COVID-19 and severe acute respiratory syndrome (SARS) manifest as pneumonia, COVID-19 is associated with apparently more efficient transmission, fewer cases of diarrhoea, increased mental confusion, and a lower crude fatality rate. However, the underlying virus-host interactive characteristics conferring these observations on transmissibility and clinical manifestations of COVID-19 remain unknown. METHODS: We systematically investigated the cellular susceptibility, species tropism, replication kinetics, and cell damage of SARS-CoV-2 and compared findings with those for SARS-CoV. We compared SARS-CoV-2 and SARS-CoV replication in different cell lines with one-way ANOVA. For the area under the curve comparison between SARS-CoV-2 and SARS-CoV replication in Calu3 (pulmonary) and Caco2 (intestinal) cells, we used Student's t test. We analysed cell damage induced by SARS-CoV-2 and SARS-CoV with one-way ANOVA. FINDINGS: SARS-CoV-2 infected and replicated to comparable levels in human Caco2 cells and Calu3 cells over a period of 120 h (p=0·52). By contrast, SARS-CoV infected and replicated more efficiently in Caco2 cells than in Calu3 cells under the same multiplicity of infection (p=0·0098). SARS-CoV-2, but not SARS-CoV, replicated modestly in U251 (neuronal) cells (p=0·036). For animal species cell tropism, both SARS-CoV and SARS-CoV-2 replicated in non-human primate, cat, rabbit, and pig cells. SARS-CoV, but not SARS-CoV-2, infected and replicated in Rhinolophus sinicus bat kidney cells. SARS-CoV-2 consistently induced significantly delayed and milder levels of cell damage than did SARS-CoV in non-human primate cells (VeroE6, p=0·016; FRhK4, p=0·0004). INTERPRETATION: As far as we know, our study presents the first quantitative data for tropism, replication kinetics, and cell damage of SARS-CoV-2. These data provide novel insights into the lower incidence of diarrhoea, decreased disease severity, and reduced mortality in patients with COVID-19, with respect to the pathogenesis and high transmissibility of SARS-CoV-2 compared with SARS-CoV. FUNDING: May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, The Hong Kong Hainan Commercial Association South China Microbiology Research Fund, The Jessie & George Ho Charitable Foundation, Perfect Shape Medical, The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government, The Theme-Based Research Scheme of the Research Grants Council, Sanming Project of Medicine in Shenzhen, and The High Level-Hospital Program, Health Commission of Guangdong Province, China.


Subject(s)
COVID-19 , SARS Virus , Animals , Caco-2 Cells , Diarrhea , Humans , Kinetics , Rabbits , SARS-CoV-2 , Swine , Tropism
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