Key found to why and how of pandemic flu

[Guest guest]

Scientists Find Key to What Could Make Bird Flu a Human Pandemic

By Keim Email 01.06.08 | 1:00 PM

In a lab in Valencia, Spain, veterinarians take a blood sample from a

duck to test it for bird flu.

Image: AP / Bustamante

Scientists have identified a key mechanism necessary for bird flu to

morph from a rare but deadly infection into a pandemic that could kill

millions of people.

MIT scientists reported in Sunday's issue of Nature Biotechnology that

the shape of certain cells in the virus could be key to allowing it to

easily pass from human to human. In birds, the shape of cells in the

virus match the shape of sugars in the animals' respiratory tracts,

allowing the infection to easily latch onto the animals. In humans,

those shapes don't match up -- but if the virus morphed so they did,

it could lead to a pandemic.

" We're like a sitting duck, waiting for an H5N1 virus that can attach

to us, " said Cummings, an Emory University biochemist and

influenza cell specialist who did not participate in the study. " This

research moves us to the point where we can start anticipating what

might happen. "

Since its 1997 outbreak in Hong Kong, H5N1 avian influenza has spread

rapidly around the world -- first in poultry, then in wild birds. It's

killed millions of fowl in 66 countries, most since 2003. But it has

yet to become a common human killer. What H5N1 lacks in human

infectiousness, however, it makes up for in lethality: of 348 people

in 14 countries infected by H5N1 since 2003, 216 died.

The virus is constantly evolving. Each infected bird population is a

giant petri dish of potential mutations. If H5N1 learns to spread

among people as well as it spreads in birds, the consequences could be

catastrophic. A 1918 influenza pandemic killed 50 million people, and

outbreaks in 1957 and 1968 killed another three million.

With H5N1, humans have so far benefited from the differences between

cells in our noses and throats and those of birds -- but that could

change. With the MIT scientists' discovery, doctors can monitor H5N1

strains for early evidence of human virulence. They may also make

precisely targeted vaccines and drugs in advance of outbreaks.

Massachusetts Institute of Technology cell biologist and study

co-author Ram Sasisekharan and his colleagues studied two strains of

avian influenza, H3N2 and H1N1 -- the latter closely related to the

killer 1918 virus -- that spread from birds to people. They found that

the viruses connected to particular types of sugar found on the

surface of upper respiratory tract cells.

These sugars act like doorknobs. When a single viral particle meets a

cell, it grapples with the sugar molecule, using it as entry point for

invasion. Once inside the cell, the virus produces copies of itself

that soon explode outwards, infecting new cells and becoming airborne

with each breath.

Both H3N2 and H1N1 latched onto sugar configurations known as a2-6

sialylated glycans, found exclusively in our upper respiratory tracts.

Birds possess slightly different sugars, known as a2-3 sialylated

glycans, to which H5N1 connects easily. In order to spread efficiently

between people, said Sasisekharan, H5N1 would have to configure itself

to our own sugars.

Sasisekharan's team then identified the unique shapes taken by our

a2-6 sialylated glycans, which vary between regions of the respiratory

tract. They identified two shapes, roughly resembling an umbrella and

a cone, that would be the likely connecting points for a pandemic H5N1

strain.

" People hadn't really thought about the shape of the structures as

being so relevant in this regard, " Cummings said.

Scientists can now search for evidence of necessary configurations in

new strains of H5N1, perhaps stifling them before the transformation

is complete. They can also predict the genetic mutations necessary for

H5N1 to bind to our sugars, and use the knowledge to develop

specifically targeted vaccines and drugs.

" Rather than looking for a needle in a haystack, this lets us focus, "

Sasisekharan said.

http://www.wired.com/medtech/health/news/2008/01/bird_flu_receptor

[Guest guest]

Scientists discover new key to flu transmission

By Steenhuysen Sun Jan 6, 1:14 PM ET

CHICAGO (Reuters) - Flu viruses must be able to pick a very specific

type of lock before entering human respiratory cells, U.S. researchers

said on Sunday, offering a new understanding of how flu viruses work.

The discovery may help scientists better monitor changes in the H5N1

bird flu virus that could trigger a deadly pandemic in humans. And it

may lead to better ways to fight it, they said.

The scientists found that a flu virus must be able to attach itself to

an umbrella-shaped receptor coating human respiratory cells before it

can infect cells in the upper airways.

" What the lock needs is the right key. It opens the door, " said Ram

Sasisekharan, a professor of biological engineering and health

sciences at Massachusetts Institute of Technology in Cambridge.

The H5N1 avian flu virus now almost exclusively infects birds. But it

can occasionally pass to a person.

Experts have feared that the bird flu virus would evolve slightly into

a form that people can easily catch and pass to one another,

triggering an epidemic.

" We now know what to look for, " said Sasisekharan, whose study appears

in the journal Nature Biotechnology.

Before a flu virus can enter a human respiratory cell, a protein on

the surface of the virus must bind with chains of sugars called

glycans that sit on the outside of the cells.

Scientists have classified these chains according to how they are

linked together chemically. In birds, the virus binds with alpha 2-3

receptors; in humans, it binds with alpha 2-6 receptors.

To infect humans, scientists thought the H5N1 bird flu virus would

need to simply mutate so it could bind with alpha 2-6 receptors. But

it turns out not all alpha 2-6 receptors are the same. Some are short

and cone-shaped and some are long and umbrella-shaped.

" Defining human and bird receptors just by linkage forgets to take

shape into account, " Sasisekharan said in a telephone interview.

VIRUS SURVEILLANCE

Shape difference may explain why humans can get bird flu from a bird

and not pass it along easily to other humans, he said.

So far, the bird flu virus has found a way to bind only to the

cone-shaped structures in human upper airways. The virus has already

killed 216 people and infected 348 people in 14 countries, according

to the World Health Organization.

But the study found that the most infectious human flu viruses bind

with the umbrella-shaped receptors in the upper respiratory tract. The

researchers believe the H5N1 bird flu virus would need to adapt so it

could latch on to these umbrella-shaped receptors before it could be

spread readily from human to human.

Understanding this mechanism could lead to better surveillance of

changes in the virus and may lead to the development of new and better

drugs to treat flu viruses.

" It opens up ways for people to bring in different kinds of small

molecule approaches for new drug development, " Sasisekharan said,

adding the work could help seasonal flu sufferers as well.

http://news./s/nm/20080106/hl_nm/birdflu_shape_dc;_ylt=AgYKJRNdUieo105g\

87IQ7_9a24cA

[Guest guest]

The lock and key nature of viral infections isn't a new thing by a long shot. What's significant here is that a specific key has been identified for a specific lock. It's a research breakthrough.Don <DCFrench@...> wrote: Scientists Find Key to What Could Make Bird Flu a Human PandemicBy Keim Email 01.06.08 | 1:00 PMIn a lab in Valencia, Spain, veterinarians take a blood sample from aduck to test it for bird flu.Image: AP / BustamanteScientists have identified a key mechanism necessary for bird

flu tomorph from a rare but deadly infection into a pandemic that could killmillions of people.MIT scientists reported in Sunday's issue of Nature Biotechnology thatthe shape of certain cells in the virus could be key to allowing it toeasily pass from human to human. In birds, the shape of cells in thevirus match the shape of sugars in the animals' respiratory tracts,allowing the infection to easily latch onto the animals. In humans,those shapes don't match up -- but if the virus morphed so they did,it could lead to a pandemic."We're like a sitting duck, waiting for an H5N1 virus that can attachto us," said Cummings, an Emory University biochemist andinfluenza cell specialist who did not participate in the study. "Thisresearch moves us to the point where we can start anticipating whatmight happen."Since its 1997 outbreak in Hong Kong, H5N1 avian influenza has spreadrapidly around the world

-- first in poultry, then in wild birds. It'skilled millions of fowl in 66 countries, most since 2003. But it hasyet to become a common human killer. What H5N1 lacks in humaninfectiousness, however, it makes up for in lethality: of 348 peoplein 14 countries infected by H5N1 since 2003, 216 died.The virus is constantly evolving. Each infected bird population is agiant petri dish of potential mutations. If H5N1 learns to spreadamong people as well as it spreads in birds, the consequences could becatastrophic. A 1918 influenza pandemic killed 50 million people, andoutbreaks in 1957 and 1968 killed another three million.With H5N1, humans have so far benefited from the differences betweencells in our noses and throats and those of birds -- but that couldchange. With the MIT scientists' discovery, doctors can monitor H5N1strains for early evidence of human virulence. They may also makeprecisely targeted vaccines and

drugs in advance of outbreaks.Massachusetts Institute of Technology cell biologist and studyco-author Ram Sasisekharan and his colleagues studied two strains ofavian influenza, H3N2 and H1N1 -- the latter closely related to thekiller 1918 virus -- that spread from birds to people. They found thatthe viruses connected to particular types of sugar found on thesurface of upper respiratory tract cells.These sugars act like doorknobs. When a single viral particle meets acell, it grapples with the sugar molecule, using it as entry point forinvasion. Once inside the cell, the virus produces copies of itselfthat soon explode outwards, infecting new cells and becoming airbornewith each breath.Both H3N2 and H1N1 latched onto sugar configurations known as a2-6sialylated glycans, found exclusively in our upper respiratory tracts.Birds possess slightly different sugars, known as a2-3 sialylatedglycans, to which

H5N1 connects easily. In order to spread efficientlybetween people, said Sasisekharan, H5N1 would have to configure itselfto our own sugars.Sasisekharan's team then identified the unique shapes taken by oura2-6 sialylated glycans, which vary between regions of the respiratorytract. They identified two shapes, roughly resembling an umbrella anda cone, that would be the likely connecting points for a pandemic H5N1strain."People hadn't really thought about the shape of the structures asbeing so relevant in this regard," Cummings said.Scientists can now search for evidence of necessary configurations innew strains of H5N1, perhaps stifling them before the transformationis complete. They can also predict the genetic mutations necessary forH5N1 to bind to our sugars, and use the knowledge to developspecifically targeted vaccines and drugs."Rather than looking for a needle in a haystack, this lets us

focus,"Sasisekharan said. http://www.wired.com/medtech/health/news/2008/01/bird_flu_receptor . Do one thing every day that scares you. Eleanor Roosevelt