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PubMed1999

Acute and persistent infection of human neural cell lines by human coronavirus OC43.

Human coronaviruses (HuCV) are recognized respiratory pathogens. Data accumulated by different laboratories suggest their neurotropic potential. For example, primary cultures of human astrocytes and microglia were shown to be susceptible to an infection by the OC43 strain of HuCV (A. Bonavia, N. Arbour, V. W. Yong, and P. J. Talbot, J. Virol. 71:800-806, 1997). We speculate that the neurotropism of HuCV will lead to persistence within the central nervous system, as was observed for murine coronaviruses. As a first step in the verification of our hypothesis, we have characterized the susceptibility of various human neural cell lines to infection by HuCV-OC43. Viral antigen, infectious virus progeny, and viral RNA were monitored during both acute and persistent infections. The astrocytoma cell lines U-87 MG, U-373 MG, and GL-15, as well as neuroblastoma SK-N-SH, neuroglioma H4, oligodendrocytic MO3.13, and the CHME-5 immortalized fetal microglial cell lines, were all susceptible to an acute infection by HuCV-OC43. Viral antigen and RNA and release of infectious virions were observed during persistent HuCV-OC43 infections ( approximately 130 days of culture) of U-87 MG, U-373 MG, MO3.13, and H4 cell lines. Nucleotide sequences of RNA encoding the putatively hypervariable viral S1 gene fragment obtained after 130 days of culture were compared to that of initial virus input. Point mutations leading to amino acid changes were observed in all persistently infected cell lines. Moreover, an in-frame deletion was also observed in persistently infected H4 cells. Some point mutations were observed in some molecular clones but not all, suggesting evolution of the viral population and the emergence of viral quasispecies during persistent infection of H4, U-87 MG, and MO3.13 cell lines. These results are consistent with the potential persistence of HuCV-OC43 in cells of the human nervous system, accompanied by the production of infectious virions and molecular variation of viral genomic RNA.

Cell Line↗

PubMed1993

HLA class I antigen serves as a receptor for human coronavirus OC43.

Human coronaviruses are associated with acute respiratory and enteric disease in man as such their target cells are probably the epithelial cells lining the respiratory and enteric tract. Attachment of virus to specific receptors on the cell surface is a major determinant of virus tropism in pathogenesis (1). Recently, aminopeptidase-N was identified as a cell receptor for the 229e coronavirus (2). Cell receptor(s) for OC43 coronavirus have not been identified. However, it is of pathologic significance that OC43 virus shares DNA sequence homology with the two coronavirus isolates, SK and SD, from the brain of patients with multiple sclerosis (MS) (3). Probing MS and control brain with probes specific for human, murine, porcine and bovine coronavirus by in situ hybridization resulted in the detection of coronavirus RNA in 12 of 22 MS brain samples; five of which were positive with the OC43 probe (4). A study of virus-ligand interactions of OC43 with human rhabdomyosarcoma (RD) cells, which are highly susceptible to virus infection, was undertaken to identify possible cell receptors. The binding of virus collected from the supernatant of infected cells to cell proteins immobilized on nitrocellulose paper was used to screen for virus-ligand interactions. The next step was the identification or development of antibodies to each of the ligands, and to test their ability to blockade receptor activity by culturing infected cells in medium containing the ligand antibodies and measuring the effect on virus yield. The preliminary experiments reported here reveal an interesting observation of strong affinity of OC43 virus for the HLA class I antigen.

Antibodies↗

PubMed1995

Analysis of cellular receptors for human coronavirus OC43.

Bovine coronavirus (BCV), human coronavirus OC43 (HCV-OC43) and hemagglutinating encephalomyelitis virus (HEV) are serologically related viruses that all have hemagglutinating activity. The receptor determinant for attachment to erythrocytes has been shown to be N-acetyl-9-O-acetylneuraminic acid (Neu5,9Ac2). We compared the ability of the three coronaviruses to recognize 9-O-acetylated sialic acid and found that they all bind to Neu5,9Ac2 attached to galactose in either A2,3 or A2,6-linkage. There are, however, some differences in the minimum amount of sialic acid that is required on the cell surface for agglutination by these viruses. Evidence is presented that HCV-OC43 uses Neu5,9Ac2 as a receptor determinant not only for agglutination of erythrocytes but also for attachment to and infection of a cultured cell line, MDCK I cells.

Animals↗

PubMed1981

Coronavirus isolates SK and SD from multiple sclerosis patients are serologically related to murine coronaviruses A59 and JHM and human coronavirus OC43, but not to human coronavirus 229E.

Two coronaviruses (SK and SD), isolated from fresh autopsy brain tissue from two multiple sclerosis patients, were compared with known human and murine coronaviruses. In plaque neutralization assays, antisera prepared against multiple sclerosis isolates SK and SD demonstrated significant cross-reactivity to each other and to murine coronavirus A59, weak cross-reactivity to murine coronavirus JHM, but no cross-reactivity to the human coronavirus 229E. Antiserum to SK or SD failed to inhibit hemagglutination of chicken erythrocytes by the human coronavirus OC43. However, OC43 antiserum neutralized both SD and SK. Specific coronavirus polypeptides were identified and compared by immunoprecipitation and polyacrylamide gel electrophoresis. Infected and mock-infected 17Cl-1 cells were pretreated with actinomycin D and labeled with [35S]methionine. Polypeptides in Nonidet P-40 cytoplasmic extracts were immunoprecipitated with homologous and heterologous antisera. Identical polypeptides were precipitated from A59-, SD-, or SK-infected cell extracts by SD, SK, OC43, or A59 antisera. The polypeptides of human virus 229E were antigenically distinct, with the exception of weak recognition of a polypeptide of 50,000 molecular weight. We conclude that the two multiple sclerosis virus isolates SK and SD are closely related serologically to the murine coronavirus A59 and the human coronavirus OC43.

Antibodies, Viral↗

PubMed2006

Evolutionary history of the closely related group 2 coronaviruses: porcine hemagglutinating encephalomyelitis virus, bovine coronavirus, and human coronavirus OC43.

The close genetic and antigenic relatedness among the group 2 coronaviruses human coronavirus OC43 (HCoV-OC43), bovine coronavirus (BCoV), and porcine hemagglutinating encephalomyelitis virus (PHEV) suggests that these three viruses with different host specificities diverged fairly recently. In this study, we determined the complete genomic sequence of PHEV (strain PHEV-VW572), revealing the presence of a truncated group 2-specific ns2 gene in PHEV in comparison to other group 2 coronaviruses. Using a relaxed molecular clock approach, we reconstructed the evolutionary relationships between PHEV, BCoV, and HCoV-OC43 in real-time units, which indicated relatively recent common ancestors for these species-specific coronaviruses.

Animals↗

PubMed1995

Genomic relationship of porcine hemagglutinating encephalomyelitis virus to bovine coronavirus and human coronavirus OC43 as studied by the use of bovine coronavirus S gene-specific probes.

The genomic relationship of porcine hemagglutinating encephalomyelitis virus (HEV) to bovine coronavirus (BCV) and human coronavirus (HCV) strain OC43 was examined by dot blot hybridization assays. Two BCV S gene-specific probes were generated by polymerase chain reaction from the avirulent L9-strain of BCV. Probes were located in the S1 and the S2 region of the peplomeric (S) glycoprotein gene. The S1 probe (726 bp) hybridized with BCV and HCV-OC43, but not with HEV under moderate stringency hybridization conditions (50 degrees C). Only slight signals were present with mouse hepatitis virus (MHV) and no signals were observed with feline infectious peritonitis virus (FIPV) or canine coronavirus (CCV). At high stringency conditions (60 degrees C) the S1 probe hybridized with BCV only. Using the S2 probe (680 bp) under moderate stringency conditions, hybridization signals were obtained with BCV, HCV-OC43 and HEV (strains 67N, NT9, VW572). The signals obtained by the three HEV strains were altogether weaker than with BCV and HCV-OC43. The S2 probe did not react with MHV, FIPV and CCV. At high stringency the S2-specific probe hybridized with BCV and HCV-OC43 but did not hybridize with HEV. Nucleotide sequence analysis of the region covering the S2 probe in HEV revealed 92.6% nucleotide sequence homology to BCV and 91.9% to HCV-OC43. In contrast, the region covering the S1 probe in HEV could not be amplified using the BCV S1-specific primers. The hybridization and sequencing results thus indicate a closer genomic relationship between BCV and HCV-OC43 than there is between HEV and BCV or HCV-OC43 respectively.

Animals↗

PubMed2006

Molecular analysis of Brazilian strains of bovine coronavirus (BCoV) reveals a deletion within the hypervariable region of the S1 subunit of the spike glycoprotein also found in human coronavirus OC43.

Bovine coronavirus (BCoV) causes enteric and respiratory dis- orders in calves and dysentery in cows. In this study, 51 stool samples of calves from 10 Brazilian dairy farms were analysed by an RT-PCR that amplifies a 488-bp fragment of the hypervariable region of the spike glycoprotein gene. Maximum parsimony genealogy with a heuristic algorithm using sequences from 15 field strains studied here and 10 sequences from GenBank and bredavirus as an outgroup virus showed the existence of two major clusters (1 and 2) in this viral species, the Brazilian strains segregating in both of them. The mean nucleotide identity between the 15 Brazilian strains was 98.34%, with a mean amino acid similarity of 98%. Strains from cluster 2 showed a deletion of 6 amino acids inside domain II of the spike protein that was also found in human coronavirus strain OC43, supporting the recent proposal of a zoonotic spill- over of BCoV. These results contribute to the molecular characterization of BCoV, to the prediction of the efficiency of immunogens, and to the definition of molecular markers useful for epidemiologic surveys on coronavirus-caused diseases.

Amino Acid Sequence↗

PubMed2006

Inter- and intra-variant genetic heterogeneity of human coronavirus OC43 strains in France.

Human coronavirus OC43 (HCoV-OC43) causes acute, self-limited respiratory infections. A close relationship between bovine coronaviruses (BCoVs) and HCoV-OC43 has recently been demonstrated. This study includes seven clinical, non-cell culture-adapted, contemporary HCoV-OC43 strains detected in France in 2003. By using RT-PCR and clonal sequencing of the S1 gene of HCoV-OC43, the inter-variant heterogeneity of the HCoV-OC43 circulating strains was studied and the intra-variant diversity was assessed by investigation of a quasispecies cloud. This paper brings to the forefront a high genetic diversity of circulating HCoV-OC43 variants. Genetically different groups are defined among the variants described in this study. One of these variants holds characteristics of an outlier and presents a deletion of 12 nt, also found in BCoV strains. Moreover, the presence of HCoV-OC43 as a quasispecies cloud in vivo during an acute respiratory-tract illness was discovered. It has also been revealed that quasispecies-cloud sizes are similar for the two viral populations tested.

Child, Preschool↗

PubMed1990

Comparison of the replication of distinct strains of human coronavirus OC43 in organotypic human colon cells (Caco-2) and mouse intestine.

Three strains of human coronavirus (HCV) OC43 were compared for their ability to cause enteric infections and to induce interferon alpha (IFN alpha) using the Caco-2 human colon carcinoma cell line which exhibits spontaneous epithelial differentiation in vitro. MRC-5 cell culture grown stocks were prepared from: 1. CV Paris, a strain of OC43 recovered from an outbreak of necrotizing enterocolitis in newborns. 2. CV Mb, a neurotropic strain of OC43 which exhibits strict neuronal specificity in murine neuronal cell cultures. 3. CV Rd, a strain of OC43 which grows to a high titer in human rhabdomyosarcoma (RD) cells. Immunofluorescent staining for nucleocapsid antigen and plaque assay in MRC-5 cells was used to detect viral replication. BG-9 (human foreskin) cells challenged with vesicular stomatitis virus were used to detect IFN alpha production by human peripheral blood monocytes (PBMC) stimulated by virus infected Caco-2 cells. Caco-2 cells infected with virus at a multiplicity of infection of 0.5 yielded 10(4.6) and 10(4.4) plaque forming units/ml (pfu/ml) with CV Rd and CV Paris respectively, while CV Mb yielded only 10(3) pfu/ml. Caco-2 cells infected with CV Rd induced 64 IU/ml of IFN alpha in PBMC while these cells infected with CV Paris induced less than 2 IU/ml IFN alpha. In cells infected with CV Mb 4 IU/ml IFN alpha was detected. The results suggest that a lack of IFN alpha induction by CV Paris may be an indicator of its enteropathogenic potential.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2005

Development of one-step, real-time, quantitative reverse transcriptase PCR assays for absolute quantitation of human coronaviruses OC43 and 229E.

The clinical significance of human coronaviruses in more severe respiratory illnesses has recently been shown to be higher than was previously assumed. Rapid and reliable diagnosis of human coronavirus infections therefore becomes indispensable in a routine clinical setting. In this study, we present a very sensitive and specific TaqMan-based, real-time quantitative reverse transcriptase PCR (qRT-PCR) for the rapid detection and quantitation of human coronaviruses (HCoVs) OC43 and 229E. Absolute viral load measurement in clinical samples was achieved through the construction of in-house HCoV OC43 and 229E cRNA standards for the generation of a standard curve. The HCoV OC43 assay allows quantitation over a range from 20 to 2 x 10(8) RNA copies per reaction mixture (5 microl RNA extract). When this is extrapolated to clinical samples, this corresponds to a detection range of 10(3) to 10(10) viral genome equivalents per ml. By using the HCoV 229E qRT-PCR assay, viral RNA copies ranging from 200 to 2 x 10(9) per reaction mixture can be detected, which corresponds to 10(4) to 10(11) viral genome equivalents per ml sample. A total of 100 respiratory samples screened for the presence of HCoVs OC43 and 229E by using conventional RT-PCR were assessed in parallel by the qRT-PCR assays. By use of the real-time qRT-PCR techniques, the detection rate of HCoVs OC43 and 229E increased from 2.0% to 3.1% and from 0.3% to 2.5%, respectively. The real-time qRT-PCR assays described here allow the rapid, specific, and sensitive laboratory detection and quantitation of human coronaviruses OC43 and 229E.

Child↗

PubMed1978

Seroepidemiologic study of human coronavirus OC43 infections in Italy.

Human Coronavirus OC43 from suckling mouse brain (SMB) suspension has been adapted to grow in human embryonic lung fibroblast cell cultures. Complement-fixing and hemagglutinating antigens were prepared from infected cell cultures and used in parallel with the same antigens from SMB for a study of the prevalence of OC43 antibody in Northern Italy as well as for the serodiagnosis of recent OC43 infections and reinfections. Results show (i) a higher sensitivity of the hemagglutination-inhibition as compared to the complement fixation test both for antibody detection in seroepidemiological studies and serodiagnosis of acute infections, (ii) a high prevalence of OC43 antibody in Northern Italy, so that only exceptionally are people older than 12 years seronegative, (iii) a high rate of OC43 reinfections during the winter-spring season 1976/77 in a population sample with preexisting antibody (iv) a good quality of reagents prepared from cell cultures, and hence free of contaminating mouse viruses, such as mouse hepatitis virus.

Adolescent↗

PubMed2005

Complete genomic sequence of human coronavirus OC43: molecular clock analysis suggests a relatively recent zoonotic coronavirus transmission event.

Coronaviruses are enveloped, positive-stranded RNA viruses with a genome of approximately 30 kb. Based on genetic similarities, coronaviruses are classified into three groups. Two group 2 coronaviruses, human coronavirus OC43 (HCoV-OC43) and bovine coronavirus (BCoV), show remarkable antigenic and genetic similarities. In this study, we report the first complete genome sequence (30,738 nucleotides) of the prototype HCoV-OC43 strain (ATCC VR759). Complete genome and open reading frame (ORF) analyses were performed in comparison to the BCoV genome. In the region between the spike and membrane protein genes, a 290-nucleotide deletion is present, corresponding to the absence of BCoV ORFs ns4.9 and ns4.8. Nucleotide and amino acid similarity percentages were determined for the major HCoV-OC43 ORFs and for those of other group 2 coronaviruses. The highest degree of similarity is demonstrated between HCoV-OC43 and BCoV in all ORFs with the exception of the E gene. Molecular clock analysis of the spike gene sequences of BCoV and HCoV-OC43 suggests a relatively recent zoonotic transmission event and dates their most recent common ancestor to around 1890. An evolutionary rate in the order of 4 x 10(-4) nucleotide changes per site per year was estimated. This is the first animal-human zoonotic pair of coronaviruses that can be analyzed in order to gain insights into the processes of adaptation of a nonhuman coronavirus to a human host, which is important for understanding the interspecies transmission events that led to the origin of the severe acute respiratory syndrome outbreak.

Animals↗

PubMed2000

Activation of glial cells by human coronavirus OC43 infection.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease that could be triggered by a viral infection. Coronaviruses induce an MS-like disease in rodents, are neuroinvasive in humans and can infect primary cultures of human astrocytes and microglia. Infection of the human astrocytic cell line U-373MG by the OC43 strain of human coronavirus caused an upregulation of IL-6, TNF-alpha, and MCP-1 mRNA expression. This virus also modulated the activity of matrix metalloproteinases-2 and -9 and augmented nitric oxide production in both U-373MG cells and the human microglial cell line CHME-5. Thus, a coronaviral infection of glial cells could lead to the production of inflammatory molecules that have been associated with central nervous system pathologies such as MS.

Astrocytes↗

PubMed1995

Sequence and expression of the ns2 protein gene of human coronavirus OC43.

The complete nucleotide sequence of the ns2 gene of human coronavirus OC43 (HCV-OC43) was determined. Sequence analysis revealed an open reading frame that could encode a protein of 278 amino acids, with an estimated molecular mass of 32.2 kDa. Six potential phosphorylation sites are present but no sites of N-glycosylation were found. The amino acid sequence of the HCV-OC43 ns2 protein shows 92% identity with that of the Mebus strain of bovine coronavirus (BCV). However, a stretch of nine consecutive amino acids near the C terminus is completely different, causing it to be very hydrophilic, which contrasts with the hydrophobic nature of this region in BCV. As shown by immunofluorescence with a monospecific antiserum, the ns2 protein was expressed in the cytoplasm of HCV-OC43-infected HRT-18 cells.

Amino Acid Sequence↗

PubMed1996

DNA probe for the human coronavirus OC43 also detects neonatal calf diarrhea coronavirus (NCDCV).

Human coronaviruses (HCV) OC43 and 229E are the second most frequently isolated agents of common colds, and have also been associated with severe upper respiratory infections in children and with gastroenteritis of unknown etiology, such as infantile necrotizing enterocolitis. While HCV-OC43 and neonatal calf diarrhea coronavirus NCDCV cannot be held responsible for enteric infection in man, serological data suggest the possible existence of a human coronavirus, antigenically related to HCV-OC43 and NCDCV, and responsible for enteric infections. We developed a rapid and sensitive method for the diagnosis of the human respiratory coronavirus infections, and for detecting these viruses in suspect coronavirus infections. This assay entails a reverse transcriptase polymerase chain reaction, followed by Southern blot analysis with a probe specific for the amplification products.

Blotting, Southern↗

PubMed1996

The region between the M and S genes of porcine haemagglutinating encephalomyelitis virus is highly similar to human coronavirus OC43.

The nucleotide sequences of the regions between the membrane and spike protein genes of three strains of porcine haemagglutinating encephalomyelitis virus (HEV) were determined. A total of 739 (HEV strain 67N) and 751 (strains NT9 and VW572) nucleotides were sequenced. Two ORFs, potentially encoding proteins of 12.8 and 9.6 kDa, were identified. Pairwise comparisons with the corresponding ORFs in bovine coronavirus (BCV) and human coronavirus (HCV) OC43 revealed sequence similarities of greater than 88.5 percent at the nucleotide and 85.3 percent at the amino acid level for the 12.8 kDa ORF product. For the 9.6 kDa ORF product similarities were greater than 96.9 percent and 95.2 percent, respectively. An additional 12 nucleotide deletion upstream of the 12.8 kDa ORF start codon was found in HEV 67N compared to NT9 and VW572. These results reveal a genomic organization of HEV in the region analysed that is homologous to HCV OC43 but different from BCV.

Amino Acid Sequence↗

PubMed1996

Structural and functional analysis of the S proteins of two human coronavirus OC43 strains adapted to growth in different cells.

The receptor-binding activity of strain CU (grown in MDCK I cells) and of strain VA (adapted to Vero cells) of human coronavirus OC43 was analyzed and compared with the binding activity of bovine coronavirus (BCV) and of the OC43 strain provided by the American Type Culture Collection (AT). Results obtained with resialylated erythrocytes indicated that the ability of the viruses to recognize 9-O-acetylated sialic acid in an alpha 2,6-linkage decreased in the following order: AT > CU > BCV > VA. Only minor differences were observed with respect to the alpha 2,3-linkage. The amino acid sequence of the S protein of strain CU and VA was derived from the nucleotide sequence of the cloned gene. Strain VA differed from strain CU in 34 positions, 18 in the S1 and 16 in the S2 subunit.

Adaptation, Physiological↗

PubMed1993

Structural and functional analysis of the surface protein of human coronavirus OC43.

The two surface glycoproteins S and HE of human coronavirus OC43 (HCV-OC43) were isolated from the viral membrane and purified. Only the S protein was able to agglutinate chicken erythrocytes, indicating that this viral protein is the major hemagglutinin of HCV-OC43. The receptor determinant recognized by this virus on the surface of erythrocytes is N-acetyl-9-O-acetylneuraminic acid (Neu5,9Ac2) which is also used by bovine coronavirus for attachment to cells. By analyzing erythrocytes containing different amounts of Neu5,9Ac2 in either of two linkage types, it was found that there are subtle differences in the affinity of both viruses for 9-O-acetylated sialic acid. Bovine coronavirus was more efficient in recognizing low amounts of Neu5,9Ac2 alpha 2,3 linked to galactose, whereas HCV-OC43 was superior with respect to the alpha 2,6 linkage. The gene coding for the S protein of HCV-OC43 was cloned and sequenced. A large open reading frame predicts a polypeptide of 150 kDa in the unglycosylated form. A protein of about 190 kDa is expected if the 20 potential glycosylation sites are used for attachment of N-linked oligosaccharide side chains. These predictions were confirmed by in vitro transcription and translation of the gene in the presence or absence of canine pancreatic microsomal membranes. A high degree of sequence homology was found between the S proteins of HCV-OC43 and bovine coronavirus. Structural and functional analyses of more strains should help to identify the location of the sialic acid-binding site.

Agglutination Tests↗