H. pylori punches holes in cell junctions

[Guest guest]

ASCB 2002 - Day 1 - Sunday 15 December 2002

Report:

H. pylori punches holes in cell junctions

Investigator: Amieva

15 December 2002

by Damaris Christensen

Proteins made by particularly aggressive strains of

the bacterium Heliobacter pylori disrupt cell junctions, the mechanical

connections between neighboring cells, researchers said today. " This is

a clue as to where to focus our attention " as scientists try to

understand why the bacteria sometimes cause disease, said researcher

R. Amieva, a postdoctoral fellow at Stanford University.

More than half of the people on this planet are

infected with H. pylori. In some, but not all, the infection triggers

ulcers and stomach cancers. Researchers have known that the bacterium

attaches to cells near cell junctions (called tight junctions) it's not

entirely clear why H. pylori tends to attach near these cell junctions.

Some researchers have speculated that nutrients or

minerals might leak through and benefit the bacteria. That would fit

with Amieva's findings that cell junctions become disrupted and leaky

after the H. pylori protein, called cagA, binds to compounds associated

with the junction.

Only relatively aggressive forms of H. pylori - those

associated with disease - make cagA. After a bacterium binds to a cell,

it forms tiny microneedles and injects the cagA protein into the target

cell.

Most researchers study H. pylori in cancer cells

derived from stomach tissue. However, Amieva said, these cells differ

from the normal tissue in important ways.

Most epithelial cells are organized so that the cell

membranes facing the outer world (apical membranes) have different

receptors and proteins than membranes linked to other cells within the

same tissue (basolateral membranes). Cancer cells lack this normal

polarity, and also don't form normal cell junctions. Amieva and his

colleagues decided to look at the effects of H. pylori infection in MDCK

cells. These epithelial cells, derived from dog kidneys, are polarized

and form well-studied cell junctions.

After the bacterium injects cagA into a cell, some of

the protein stays near the bacteria inside the cell and some migrates to

the so-called tight cell junctions, Amieva reported. " We think it leads

the bug to the junctions. " He reported that cagA attracts and attaches

to scaffolding proteins called ZO-1 proteins, which attach to membrane

receptors in cell junctions and bring together many proteins in the

area. Thus, disrupting ZO-1 probably alters the normal activity of cell

junctions.

" After cagA moves in to the cell junction, cells start

to change shape and look very strange, as if they are losing their sense

of up and down, " Amieva told BioMedNet News. " That may be a step along

the road to cancer. "

After the protein starts to perturb these fine control

mechanisms, he added, " eventually cells can't go back and fix

themselves. " Strains of H. pylori lacking only the cagA gene can bind to

cells, and the bacteria can survive, he said. However, these strains of

H. pylori do not disrupt ZO-1, make gap junctions leaky, or trigger

alterations in cell shape.

A variety of signaling molecules are found near cell

junctions, and other research has linked phosphorylation of signaling

molecules to cagA's virulence, said Raphail Valdivia of Duke University

in Durham, North Carolina.

" This is very interesting work, " Valdivia said. " It

suggests that by disrupting tight junctions and the signaling complexes,

cagA might cause morphology changes that may transform cells and lead to

cancer. "

Another hope is that studying cagA will provide

insight, not just into disease pathogenesis, but also into the normal

biology of cell junctions. " Bacteria are the best cell biologists,

because they have to learn how the cell functions in order to survive, "

Amieva said. He hopes that H. pylori can be manipulated as a tool to

help elucidate the activity and function of cell junctions and

associated proteins.