S Functions During Dissemination of Coronavirus Infections

In considering the entire infection cycle, we advance now to describing intracellular events as they pertain to S protein and virion morphogenesis. As stated above, the action of S proteins during entry delivers viral genomes into cells. These genomes are monopartite 27-32 kb single-stranded, positive-sense RNAs (Lai and Stohlman, 1978). The organization of genes on this large RNA has been well characterized, and the mechanisms of gene expression are understood in some detail and are not described here (for reviews, see Lai and Cavanagh, 1997; Sawicki and Sawicki, 1998). As is typical of RNA virus genomes, the vast majority is translated, with the 5' ~two thirds encoding so-called "nonstructural" proteins that are not found in virions and the remaining ~one third encoding primarily "structural," that is, virion proteins (Figure 4.5). On eclipse, the nonstructural proteins are synthesized without delay, thereby generating RNA-dependent RNA replicase activities that subsequently transcribe antigenomic (negative-sense) RNAs, as well as several subgenomic viral mRNAs. The essential virion proteins S, E (envelope), M (matrix), and N (nucleocapsid) are translated from the newly created set of 3' proximal subgenomic mRNAs, whose abundance in infected cells is far greater than genomic (virion) RNA, thereby permitting accumulation of virion proteins to the levels required for particle assembly.

A defining characteristic of coronavirion morphogenesis is its intracellular assembly (Figure 4.6), known for some time to take place in the ER-Golgi intermediate compartment

Figure 4.5. Coronavirus genome organization. Depictions of the murine coronavirus MHV (31.2 kb: GenBank accession number NC 001846) and human SARS coronavirus (29.7 kb: # AY278741) positive strand RNA genome. The 5' end is capped, followed by a leader (L) sequence and ┬źniranslated region (UTR). The polymerase and protease polyprotein complex is encoded along two open reading frames (1a and 1b) by a ribosomal frame-shifting mechanism and subsequently proteolytically processed into smaller fragments. Vertical lines with globular heads indicate intergenic (IG) sequences. Shaded boxes are structural proteins (sequentially: HE, S, E, M, N) that incorporate into virion particles. Genomes are polyadenylated. Drawn approximately to scale.

Figure 4.5. Coronavirus genome organization. Depictions of the murine coronavirus MHV (31.2 kb: GenBank accession number NC 001846) and human SARS coronavirus (29.7 kb: # AY278741) positive strand RNA genome. The 5' end is capped, followed by a leader (L) sequence and ┬źniranslated region (UTR). The polymerase and protease polyprotein complex is encoded along two open reading frames (1a and 1b) by a ribosomal frame-shifting mechanism and subsequently proteolytically processed into smaller fragments. Vertical lines with globular heads indicate intergenic (IG) sequences. Shaded boxes are structural proteins (sequentially: HE, S, E, M, N) that incorporate into virion particles. Genomes are polyadenylated. Drawn approximately to scale.

(Krijnske-Locker et al., 1994). Infectious virus production requires newly synthesized genome RNA and its associated N proteins, as well as the three integral-membrane proteins S, E, and M. The assembly process, described in greater detail in the legend to Figure 4.6, involves a series of noncovalent interactions; S associating with M (de Haan et al., 1999), M with N (Kuo and Masters, 2002), and N or M with virion RNA (Nelson and Stohlman, 1993; Narayanan et al., 2003). Interestingly, assembly and secretion of intracellular vesicles requires only M and E (Vennema et al., 1996); S and the ribonucleocapsids are dispensable and must be considered to be passive participants in particle morphogenesis. Thus, the S proteins, depending on their affinity for M and their abundance relative to M, may or may not engage in the virion assembly process. In model coronavirus infections, S-M affinities and molar ratios are such that only a portion of S proteins assemble into virions and significant proportions of the population advance as free proteins through the exocytic pathway and on to infected-cell surfaces (Figure 4.6). As there is no evidence that any coronavirus budding takes place at plasma membrane locations, these cell-surface S proteins likely function solely to mediate the cell-cell fusions that facilitate rapid spread of infection. Little is presently known about the relative efficiencies of S-M interactions among the coronaviruses, although the interacting portions of these proteins do indeed differ among virus strains. One might speculate that relatively low S-M affinities reflect adaptations to growth under conditions where syncytial spread of infection provides selective advantages that are greater than those afforded by high S-M affinities favoring efficient infective virion morphogenesis.

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