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 study
appearing in the June 15 issue of Genes &
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," said Sin Urban, an assistant professor of
molecular biology and
genetics in the School of
Medicine.
The EhROM1 enzyme, it turns out, is part of an ancient
group of enzymes — 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 discovery 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," Urban
said. "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 and 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," Urban said.
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.