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HOW MONTEZUMA GETS HIS REVENGE

Johns Hopkins Medicine
Media Relations and Public Affairs
Media Contact: Audrey Huang
410-614-5105; audrey@jhmi.edu
June 14, 2008

HOW MONTEZUMA GETS HIS REVENGE
--Johns Hopkins Researchers Discover Clue to How Dysentery Parasite Might Evade Immune System

Every year, about 500 million people worldwide are infected with the
parasite that causes dysentery, a global medical burden that among
infectious diseases is second only to malaria. In a new study
appearing in the June 15 issue of Genes and Development, Johns
Hopkins researchers may have found a way to ease this burden by
discovering a new enzyme that may help the dysentery-causing amoeba
evade the immune system.

"This is the first enzyme to be identified that looks like it could
mediate immune system evasion," says Sin Urban, Ph.D., an assistant
professor of molecular biology and genetics at Hopkins.

The EhROM1 enzyme, it turns out, is part of an ancient group of
enzymes-they are found in every branch of life from bacteria to
man-known as rhomboid enzymes. In most animals, rhomboid enzymes seem
to play a role in cell-to-cell communication, but a couple of years
ago Urban found that malaria parasites use rhomboid enzymes for a
more sinister purpose: to enter host cells uninvited.

That led his team to scour the DNA of other parasites to see if any
of them also had genes that encode rhomboid enzymes. They found that
the dysentery-causing amoeba Entamoeba histolytica contains one
rhomboid enzyme and named it EhROM1.

"Plasmodia, the parasites that cause malaria, grab onto a host cell
and push their way in," explains Urban. "Once inside they use
rhomboid enzymes to cut themselves loose." But amoebas don't enter
cells to cause dysentery, so Urban's team set out to figure out how
these parasites use EhROM1.

They first identified protein targets cut by EhROM1 by looking for
amoeba proteins that had structural signatures similar to those cut
by malaria rhomboids. They found these signatures in a family of
proteins-lectins-that are found on cell surfaces. The researchers put
both proteins into cells and verified that EhROM1 does cut one
particular lectin, and the more EhROM1 they added, the more lectin
pieces resulted.

Every cell has on its surface proteins recognizable by sentries of
the immune system that constantly survey the body for intruders, and
amoebas are no different. To evade the immune system, amoebas shift
all their surface proteins to the rear end of the cell then, like a
dump truck, shed these proteins into the fluid around them.

Lectin, it turns out, is one of the proteins that during immune
evasion moves to the rear and is shed by the amoeba. So collaborating
researchers at Stanford University then looked to see if EhROM1
follows lectin and sure enough found that EhROM1 clusters at the
cap-the cluster of surface proteins waiting to be shed.

"We're excited to see if EhROM1 plays a specific role in the cap
shedding during immune evasion," says Urban.

What's more, the EhROM1 enzyme is remarkably similar to those found
in malaria parasites, suggesting that any potential drugs targeting
EhROM1 might be able to treat two of the world's most prevalent diseases.

The research was funded by the National Institutes of Health and
the Burroughs-Wellcome Fund.

Authors on the paper are Leigh Baxt and Upinder Singh of Stanford
University, and Rosanna Baker and Urban of Hopkins.

On the Web:

http://www.genesdev.org/

 

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