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Neurotropic E627K PB2 Mutations in All Qinghai H5N1 Isolates

Recombinomics Commentary

July 7, 2005

The paper in tomorrow's Science describes sequences in 4 more isolates from Qinghai lake.  There are two isolates from bar headed geese (A/BH Goose/QH/1/05(H5N1) and A/BH Goose/2/05) as well as greater black headed gull, Gbh Gull/QH/1/05 (H5N1) and a brown headed gull, Bh Gull/QH/1/05 (H5N1).  Like today's Nature report, the isolates are reassortants with three genes (HA, NA, PA) closest to an isolate from a 2003 chicken in Shantou, A/chicken/ST/4231/03(H5N1) or the cluster of isolates from South Korea and Japan in 2003 and 2004 respectively, while the other 5 genes (PB2, PB1, PA, MA, NS) are closest to a 2004 peregrine falcon from Hong Kong, A/Pf/HK/D0028L/04(H5N1).

The data further support the notion that the relationship between the Qinghai isolates and the Shantou isolate are due to the fact that the Shantou isolate is from migratory birds which infected birds in South Korea, Japan, and Shantou.  Similarly, the peregrine falcon isolate in Hong Kong would also represent additional migratory bird sequences.

The Science paper has phylogenetic trees for all 8 genes and most of the genes related to the peregrine falcon are also closer to the isolates from Vietnam and Thailand.  However, the most striking association with the Vietnam and Thailand isolates is the E627K change in the PB2 gene.  Several of the human isolates in Vietnam and Thailand have the E627K mutation, which is associated with increased virulence.

All H5N1 isolates with E627K are from humans, including some from the 1997 H5N1 outbreak in Hong Kong, with two notable exceptions.  The isolates from the Sri Lanka Tiger zoo outbreak in August and earlier tiger and leopard deaths at a nearby zoo in early 2004 all have E627K, as does the brain isolate from an infected pheasant, A/Pheasant/Hong Kong/FY155/01-MB(H5N1) in Hong Kong in 2001  This result is similar to that obtained for WS/33, the first human influenza isolate.  WS/33 was passage in mice in 1940 and WSN/33 was obtained from mouse brain and it too had E627K (the PB2 sequence of WS/33 is not available).

As indicated in the Science and Nature papers, the bar headed geese displayed neurological symptoms and all had the E627K mutation.  Similarly, the tigers at the Sri Racha zoo had neurological problems as did wild birds in Thailand, although Thailand has not deposited any of its 2005 isolates, including those from birds with nerve problems or those from wild birds.

The bar headed geese winter in northern India and when they began to migrate to Qinhai Lake there was a meningitis outbreak in northern India.  Although serum collected in 2002 from three poultry workers in India was H5N1 positive, India has never reported H5N1 in people or poultry, although there were mysterious deaths of people, peacocks, and pigs in Uttar Pradesh in northern India in February.

The finding of  E627K in all eight reported Qinghai isolates is cause for concern, and the lack of testing throughout Asia in general and China and India in particular, remains scandalously poor.  Questions also remain regading the die-off of shearwaters along the east coast of the United States.  They have been washing ashore from Florida to Maryland and show neurological symptoms before dying.

In any event, movement of E627K via migratory birds could cause significant problems for birds and humans, and boxun reports indicate the damage to humans has already begun.

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