Islamabad, Jan 26 : Ever since the water supply in
Walkerton, Ont., was contaminated by E. coli in 2000, Dr. Philip Marsden has
been trying to figure out just how a toxin released by that particular strain of
the bacteria causes kidney damage in children.
Now Dr. Marsden and his
team based at St. Michael's Hospital and the University of Toronto have made new
discoveries about the basic workings of endothelial cells that could lead to a
diagnostic test for the serious kidney disease known as hemolytic uremic
syndrome (HUS) and a possible treatment.
Endothelial cells line the
inside of blood vessels and are the cells most severely affected in HUS, one of
the most common causes of sudden onset kidney failure in children.
His
work took a sudden twist in May 2011, when an E. coli outbreak swept northern
Germany and researchers discovered that a different strain of the bacteria was
producing the identical toxin. This time the HUS mainly affected adults,
especially women, and was associated with severe kidney failure and
strokes.
Dr. Marsden's team extracted endothelial cells from healthy
people and exposed them to the toxin in a culture dish. They discovered a
biological pathway never before known to have played a role in the development
of HUS.
Specifically, they found that the toxin can increase the level of
a chemokine, namely SDF-1, and its receptor, CXCR4. Chemokines are small
secreted proteins that stimulate cells to move or migrate. CXCR4 was already
known to stimulate the release and migration of the precursors of white blood
cells from bone marrow, to change how blood vessels grow and to help the AIDS
virus enter cells.
Dr. Marsden has found that too much communication
between SDF-1 and CXCR4 molecules can also impact the development of HUS in
animals and humans. His team made two important discoveries, published in The
Journal of Clinical Investigation:
Injecting the drug plerixafor/AMD3100
(sold under the brand name Mozobil) into mice exposed to the E. coli toxin
changed their survival rate and helped improve the HUS, suggesting future
therapy options for humans. The drug blocks SDF-1 action on cells that express
CXCR4. The drug is used to mobilize precursor stem cells from the bone marrow in
some bone marrow transplant recipients during the treatment of non-Hodgkin
lymphoma and multiple myeloma.
Blood tests taken from children with
E. coli showed that those who went on to develop HUS had higher levels of the
protein SDF-1 -- as much as four times higher than other children with E. coli
who did not go on to develop HUS. This suggests that a blood test could be used
to predict who is most likely to develop the potentially fatal HUS, meaning they
could be monitored more closely.
Dr. Marsden, who is a nephrologist, said
a safe water supply and clean food supply chain is the most important step in
preventing HUS caused by E. coli.
"If we can measure SDF-1 levels in real
time during an E.coli outbreak and confirm these findings, then we have a strong
case for a trial of plerixafor/AMD3100 in patients with toxin-producing E. coli
to see if it prevents or improves cases of HUS," he
said.
Ends
SA/EN
