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Paradigm Shift Intervention Monitoring
MERS Jeddah As SARS Guangzhou - Emergence
The above comments from a letter submitted by Christian Drosten to ProMED on April 26 suggest that the 25 cases linked to the partial spike sequences were infected by the same novel sub-clade represented by the 6 nearly full sequences (C7149 and C7770 from hospital A collected on April 3 and 7, respectively, as well as C7569 from hospital B collected on April 5, followed by Jeddah sequences C8826 and C9055 collected on April 12 and April 14 from hospital A and C, respectively, as well as Mecca (C9355) collected on April 15) uploaded to the Drosten website.
All six of these sequences were nearly identical, even though they originated from 4 different hospitals in two different cites (Jeddah and Mecca).
This novel sub-clade is defined by 9 polymorphisms that have never been reported in any human MERS sequence (listed below with 4 camel sequence isolated from Taif in late 2003). Two of the polymorphisms are in the Spike gene (C23804T and A23953G), and the later encodes Q833R, which has not been reported in any MERS sequence other than the six recently uploaded from Jeddah and Mecca. Both of these polymorphisms are located between the Spike receptor binding domain and the first heptad repeat (see figure 5 here) and therefore are almost certainly within the partial spike sequence that exactly matched the released sequences (which were all identical to each other in this region).
In addition to spike polymorphism Q833R, the novel sub-clade has a change in ORF8b, T28778A, which encodes L6Q, which also has never been reported in a MERS sequences. Moreover, ORF8b has another non-synonymous change, L40P, which has never been reported in a human MERS sequence.
In addition to the 9 polymorphisms not cited in any prior human MERS sequence, the novel sub-clade has two additional changes that are rarely seen in human MERS sequences. One is a synonymous change, C16174T, which has only been reported in one MERS sequence, Taif-2, while the other is non-synonymous and creates changes in two proteins, K60N in ORF8b and D126H in the overlapping N gene. Human MERS sequences with this change are limited to a sub-clade that emerged late in the Al Hasa outbreak and was detected in 4 patients who were almost certainly contacts of each other (AH19, AH26, AH27, AH28) based on matching collection dates for the latter three case (who would have been infected by the same index case, AH19).
Thus, as seen in the table below, the protein of ORF8b, which is 112 amino acids in length, has three changes in the first 60 positions (L6Q, L40P, and K60N), which may limit the function of the protein product which may be involved in regulating RNA levels. ORF8 was disrupted by the 29 nt deletion in SARS-CoV, which was associated with the dramatic spread of the virus after the incident at the Metropole Hotel on Feb 20-21, 2003 which led to major nosocomial outbreaks in Hong Kong, Singapore, Hanoi, and Toronto linked to patients who were guests or visitors on the ninth floor of the hotel (the index case was in room 911).
The presence of three changes on ORF 8b, and ORF8 disruption in SARS-CoV by the 29 nt deletion, raises serious pandemic concerns.
11 Defining Polymorphisms For Jeddah Sub-Clade
Nucleotide Protein Taif Camels + Limited Human
C5658T P1794S 378 505 503 363
C9659T 378 505 503 363
T12257C 378 505
T16174C 505 503 Taif 2
C17836T 503 363
C23804T 378 505 503
T28880C L40P 378 505
G28941C K60N 378 505 AH19 AH26 AH27 AH28
G28941C D126H 378 505 AH19 AH26 AH27 AH28