Properties of Coronaviridae

The coronaviruses were so named because the unusually large dub-shaped peplomers projecting from the envelope give the particle the appearance of a solar corona (Fig. 27-1). The virion is pleomorphic, being roughly spherical in the case of the genus Coronavirus but often disk-, kidney-, or rod-shaped in the case of the genus Torovirus, and can range in size from 60 to 220 nm. The tubular nucleocapsid, difficult to discern in electron micrographs, is composed of a phosphorylated nucleoprotein (N) and seems to be connected directly to an unusual transmembrane protein, M, which spans the viral envelope three times and performs the role normally filled by matrix protein in other enveloped viruses. A very large (200K), heavily glycosylated envelope glycoprotein S (for spike) forms the bulky peplomers and carries cell

Receptor Destroying Enzyme
Fig. 27-1 Coronaviridae Negatively stained preparation of virions Bar, 100 nm. (Courtesy Dr. F A Murphy.)

binding, membrane fusion, and hemagglutinating activities. The human Coronavirus OC43 also possesses a third glycoprotein, HE (for hemagglutinin-esterase) which closely resembles a similar cell-bindmg/receptor-destroying enzyme found in influenza C virus.

The genome consists of a single linear molecule of ssRNA of positive polarity, about 30 kb in size, which is 5' capped and 3' polyadenylated, and is infectious (Table 27-1).

Classification

Two genera, Coronavirus and Torovirus, contain viruses infecting humans. The genus Coronavirus includes two human serotypes causing respiratory disease, the prototype strains being HCV-229E and HCV-OC43, which are clearly distinguishable from one another by neutralization or hemagglutination inhibition. The status of the "human enteric coronaviruses" and human toroviruses has yet to be determined.

Table 27-1

Properties of Coronaviridae

Pleomorphic spherical virion, Caronavtrus 60-220 nm (average 100 nm), Tonwiws 120-140 nm Envelope with large widely spaced, club-shaped peplorners Tubular nuclcocapsid with helical symmetry

Linear plus sense ssRNA genome, 30 kb (range 27-33 kb), capped, polyadenylated, infectious Three or four structural proteins: nucleoprolem (N), peplomer glycoprotein (S), transmembrane glycoprotein (M), sometimes hemagglutinin-esterase (HE) Replicates in cytoplasm, genome transcribed to lull-length minus sense RNA, from which is transcribed a 3'-cotcrrninal nested set of mRNAs, only the unique 5' sequences of which are translated; budding into endoplasmic reticulum and Golgi cisternae, virions released by exo-cytosis

Viral Replication

The strategy of expression of the coronavirus genome is unique (Fig. 27-2). The infectious, plus sense viral RNA is translated directly, the product of the 5' two-thirds of the genome being two polyproteins, the larger of which is produced by ribosomal frame-shifting; each is posttranslationally self-cleaved and the resulting polypeptides assembled to form an RNA polymerase. This enzyme is then employed to transcribe a full-length complementary (minus sense) RNA, from which in turn are transcribed not only full-length new plus strands, but also a 3'-coterminal nested set of subgenomic mRNAs. The nested set comprises 5-7 overlapping species of plus sense mRNAs which extend for different lengths from their common 3' ends and share a common 70 nucleotide 5' leader sequence. They are generated by a leader-primed mechanism of discontinuous transcription, whereby the polymerase first transcribes the noncoding leader sequence from the 3' end of the minus sense antigenome, then the capped leader RNA dissociates from the template and reassociates with a complementary sequence at the start of any one of the genes to continue copying the template right through to its 5' end. Only the unique sequence toward the 5' end which is not shared with the next smallest mRNA in the nested set is translated, the product therefore being a unique protein in most cases. A puzzling finding is that subgenomic minus sense RNA species complementary to the nested set of plus sense mRNAs are also present in infected cells, giving nse to the intriguing possibility that coronavirus mRNAs may be self-replicating.

The synthesis, processing, oligomer!zation, and transport of the several envelope glycoproteins have been studied in depth and display some unusual features. For example, the envelope protein M, which in some coronavirus

Genomic RNA (+} Negative Strand (- ) Template mRNAs( + ) <

Genomic RNA (+} Negative Strand (- ) Template mRNAs( + ) <

Fig. 27-2 Coronavirus transcription and translation After release of the plus strand genomic RNA in the cytoplasm, an RNA-dependent RNA polymerase is synthesized which transcribes a full-length minus strand RNA, from which are synthesized (a) new genomic RNA, (b) an overlapping series of subgenomic mRNAs, and (c) leader RNA, The genomic RNA and mRNAs are capped and polyadenylated (zigzag line) and form a "nested set" with common 3' ends and a common leader sequence on the 5' end Only the unique sequence of the mRNAs toward the end is translated, to produce several nonstructural proteins (NS) and four structural proteins M (El), transmembrane glycoprotein, S (E2), peplomer glycoprotein; N, nucleoprotein, and in some coronaviruses HE (E3), hemagglutinin-esterase glycoprotein. [Modified from K V Holmes, in "Fields Virology" (B N. Fields, D. M Knipe, R. M Chanock, M. S Hirsch, ] L. Melnick, T P. Monafh, and B Roizman, eds.), 2nd Ed., p 847 Raven, New York, 1990 |

Proteins 30K NS

None

Fig. 27-2 Coronavirus transcription and translation After release of the plus strand genomic RNA in the cytoplasm, an RNA-dependent RNA polymerase is synthesized which transcribes a full-length minus strand RNA, from which are synthesized (a) new genomic RNA, (b) an overlapping series of subgenomic mRNAs, and (c) leader RNA, The genomic RNA and mRNAs are capped and polyadenylated (zigzag line) and form a "nested set" with common 3' ends and a common leader sequence on the 5' end Only the unique sequence of the mRNAs toward the end is translated, to produce several nonstructural proteins (NS) and four structural proteins M (El), transmembrane glycoprotein, S (E2), peplomer glycoprotein; N, nucleoprotein, and in some coronaviruses HE (E3), hemagglutinin-esterase glycoprotein. [Modified from K V Holmes, in "Fields Virology" (B N. Fields, D. M Knipe, R. M Chanock, M. S Hirsch, ] L. Melnick, T P. Monafh, and B Roizman, eds.), 2nd Ed., p 847 Raven, New York, 1990 |

species contains O-Iinked rather than N-linked glycans, is directed exclusively to certain internal membranes, namely, cisternae of the endoplasmic reticulum and the Golgi complex, as a result of which virions bud only from these regions and not from the plasma membrane. The virions are then transported in vesicles to the plasma membrane for exit from the cell by exocytosis (see Fig. 3-9B). Following their release many of the mature enveloped virions remain adherent to the outside of the cell. The whole oi the replication cycle is confined to the cytoplasm, and indeed can occur in enucleate cells.

Genetic recombination occurs at high frequency between the genomes of different but related coronaviruses. This may be an important mechanism for generation of genetic diversity in nature.

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