Ron, Here's more detail on the upcoming Lancet paper:
The SARS paper by Yi Guan et al, soon to be published in this week's Lancet, provides molecular epidemiological evidence indicating that the vast majority of SARS cases in Hong Kong (and by extension, the rest of the world outside of Mainland China), link back to the Metropole Hotel. Although there were at least four other cases (represented by HKU-33867, HKU-36871, CUHK-W1, CUHK-L2) from mainland China (Guangzhou and Shenzhen) that antedated the Metropole Hotel transmission, PCR analysis of the a 2149 bp fragment of the S1 gene from 137 patients indicates that they all link back to the sequences found in the Metropole Hotel isolates, including two isolates HK-33a and HK-33b from the Metropole Hotel index case. In the region surveyed, the two Metropole Hotel isolates differ in one position, C22559T. However, the mutation is a silent and found in 10 clinical samples, but the mutation is not present in any of the SARS CoV isolates at GenBank.
Interestingly, two of these samples also have the Tor2 mutation, T23220G, which is the only specific mutation in the S gene found in isolates linked to the super spreader events that seeded the epidemics in Toronto, Singapore, Hanoi, and Hong Kong. Even more interesting however, is the fact that 18 additional samples have the Tor2 mutation. This result provides strong clues for the fate of the missing Metropole mutations. The Tor2 mutation is relatively rare, and up until this week, it was not reported in any of the SARS CoV sequences at GenBank. However, the complete sequence of Shanghai QXC was deposited and it has the Tor2 mutation (the previously deposited partial sequence did not cover this region).
The QXC sequence was from a Shanghai tourist who had visited Beijing prior to developing SARS last May, and the sequence does have several Beijing specific mutations, as well as polymorphisms seen only in earlier mainland isolates. However, the Beijing and mainland markers are missing from the 3/ end of the genome, which has a Metropole Hotel-like sequences, including the Tor2 mutation.
Thus, the recombination in QXC is of interest, but the Tor2 mutation in 20 Hong Kong samples raises an additional issue since the mutation was not present in either isolate from the Metropole Hotel index case. Moreover, the Toronto index case checked out of the Metropole Hotel the day the Metropole Hotel index case arrived, so there was no time for her to be infected and pass the infection to others in Hong Kong. Creative scenarios can be used to get the mutation to Hong King such as transmission through some common object carried by the Toronto index case that was contaminated by the Metropole Index case, or transmission in Toronto followed by retransmission by a third party back to Hong Kong. However, the simplest explanation invokes multiple variants within the Metropole Hotel index case. Base on the two isolates, the index case had a least two distinct SARS CoVs, but data from other isolates outside of Hong Kong suggest that there were many variations which subsequently appeared in patients linked to the index cases for Hanoi and Singapore.
These other examples have been previewed previously, but the presence of 20 samples with the Tor2 mutation in Hong Kong provides the strongest evidence for multiple variants in super spreaders, including the Metropole hotel index case. |
