UCLA. US: Deficiency of the hormone hepcidin
makes people vulnerable to Vibrio vulnificus, but a medical form of the
hormone can cure the infection.
Every summer, the news reports on a bacterium called Vibrio vulnificus
found in warm saltwater that causes people to get sick, or die, after
they eat raw tainted shellfish or when an open wound comes in contact
with seawater.
People with a weakened immune system, chronic liver disease or iron
overload disease are most at risk for severe illness. Vibrio vulnificus
infections in high-risk individuals are fatal 50 percent of the time.
Now, researchers at UCLA have figured out why those with iron
overload disease are so vulnerable. People with the common genetic iron
overload disease called hereditary hemochromatosis have a deficiency of
the iron-regulating hormone hepcidin and thus develop excess iron in
their blood and tissue, providing prime growth conditions for Vibrio
vulnificus.
The study also found that minihepcidin, a medicinal form of the
hormone hepcidin that lowers iron levels in blood, could cure the
infection by restricting bacterial growth.
The early findings were reported online Jan. 14 in the journal Cell Host and Microbe.
“This is the first time that the association of hepcidin deficiency
and susceptibility to Vibrio vulnificus infection was tested,” said
senior author Dr. Yonca Bulut, a clinical professor of pediatrics at
Mattel Children’s Hospital at UCLA and a researcher with the UCLA
Children’s Discovery and Innovation Institute. “The dramatic
effectiveness of the new treatment, even after the infection was
established, was impressive.”
To conduct the study, researchers compared the fatality of Vibrio
vulnificus infection in healthy mice with mice that lacked hepcidin,
modeling human hereditary hemochromatosis. The results showed that the
infection was much more lethal in hepcidin-deficient mice because they
could not decrease iron levels in the blood in response to infection, a
process mediated by hepcidin in healthy mice.
Giving minihepcidin to susceptible hepcidin-deficient mice to lower
the amount of iron in the blood prevented infection if the hormone was
given before the Vibrio vulnificus was introduced. Additionally, mice
given minihepcidin three hours after the bacterium was introduced were
cured of any infection.
Hereditary hemochromatosis is a genetic disease that causes the body
to absorb and store too much iron. It affects as many as 1 in every 200
people in the United States. Since it can take decades for the body to
store damaging levels of iron, many people may not be aware that they
have the disease until signs of the condition begin to appear later in
life.
The co-directors of the UCLA Center for Iron Disorders, Dr. Tomas
Ganz, a professor of medicine and pathology at the David Geffen School
of Medicine at UCLA, and Elizabeta Nemeth, a professor of medicine at
UCLA, led the invention of minihepcidins at UCLA. Minihepcidins are
being developed for treatment of iron-overload disorders, such as
hereditary hemochromatosis and Cooley’s anemia. The use of minihepcidin
to treat potentially lethal infections is a possible new application.
“We found that hepcidin is required for resistance to a Vibrio
vulnificus infection,” said the study’s lead author Joao Arezes, a
visiting graduate student from the University of Porto in Portugal. “The
development of the treatment tested in mouse models could reduce the
high mortality rate of this disease.”
The next stage of research is to understand why Vibrio
vulnificus bacteria become so lethal when iron levels are high, and to
learn which other microbes respond similarly to excess iron.
The research was conducted at the UCLA Center for Iron Disorders.
Other study authors were Grace Jung, Victoria Gabayan, Erika Valore,
Piotr Ruchala, Ganz and Nemeth, all of UCLA, and Paul Gulig of the
University of Florida.
The study was funded by the UCLA Today’s and Tomorrow’s Children
Fund, the UCLA Stein/Oppenheimer Endowment Award, the UCLA Children’s
Discovery and Innovation Institute and the National Institutes of Health
(grant R01 DK090554).