Applications to the SARS Coronavirus

As of September 2003, over 30 Ssars sequences were posted in gene banks. To appreciate the sequence variations, one must view the data in the context of known and presumed SARS-CoV epidemiology. This virus is generally considered to be of zoonotic origin. While the natural wild or domestic animal reservoir is probably unknown, isolates strikingly similar to human SARS-CoV has been isolated from exotic animals in Guangdong, China (Guan et al., 2003). These animals included asymptomatic palm civits and raccoon dogs, all housed in a single live animal market. The collection of animal CoV sequences shows some limited diversity (18 nt differences in the 29,709 nt genomes). Speculation is that around November 2002, one or more of these zoonotic "SZ" viruses infected humans and generated SARS fever, dry cough, and pneumonia. Virus from the initially infected human (the true "index" patient) may never be available, but viruses that have been isolated from Guangdong patients have interesting variation relative to "SZ" isolates. In comparing animal SZ viruses with the available collection of human SARS-CoV isolates, 11 clear S polymorphisms were detected (Guan et al., 2003; see Figure 4.8). These appear to be relatively scattered changes throughout the 1,200-residue S ectodomain, and in this regard show some similarity to a collection of

Figure 4.8. Human vs animal spike sequences. Shown are amino acid differences between spikes of human SARS and animal isolates. Numbers indicate location of spike residue. Dashed line demarcates boundary between S1 and S2 regions. Residue 894 resides within a candidate fusion peptide upstream of heptad repeat 1. Residue 1163 is within heptad repeat 2. TM indicates transmembrane region.

Figure 4.8. Human vs animal spike sequences. Shown are amino acid differences between spikes of human SARS and animal isolates. Numbers indicate location of spike residue. Dashed line demarcates boundary between S1 and S2 regions. Residue 894 resides within a candidate fusion peptide upstream of heptad repeat 1. Residue 1163 is within heptad repeat 2. TM indicates transmembrane region.

16 scattered differences between murine-specific and laboratory-generated zoonotic forms of murine hepatitis coronavirus (Baric et al., 1997, 1999).

Assigning xenotropic potential to a particular combination of these 11 mutations is a challenging but important undertaking. This might be accomplished by employing the approaches used successfully to identify correlates of murine hepatitis virus virulence. S cDNAs encoding SZ or SARS isoforms, as well as SZ/SARS chimeras, can be easily constructed and then used to create recombinant coronaviruses. Tropism of the recombinants for human or animal cells can then be assessed using traditional virological methods. The next challenge will be to correlate S variations to alterations in receptor-binding or membrane fusion potentials. In all likelihood, the successful approaches will again be relatively traditional ones in which soluble S fragments—SZ, SARS, and SZ/SARS chimeras—are developed as mimics of authentic coronaviruses and then used as ligands for binding to human or animal cells, or once identified, SARS cellular receptors and their homologs in animal cells. By titrating soluble S ligands, relative affinities might be obtained. Questions concerning whether SARS polymorphisms specifically affect the membrane fusion reaction can then be addressed by relatively straightforward assays in which S-induced syncytia are measured (Nussbaum et al., 1994). Among the murine coronaviruses, there are S polymorphisms that have no effect on S binding to CEACAM receptors, but yet dramatically impact membrane fusion (Krueger et al., 2001). It will be important to determine whether there are similar variabilities in the SARS S proteins, and whether the membrane fusion process is central to SARS-CoV species transfer and human pathogenicity.

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