A UCSD
research team has discovered that drugs that help white blood cells
up the ante against bacteria have potential as treatments for difficult
infections, including those caused by invasive (“flesh-eating”)
Streptococcus bacteria.
Randall Johnson, UCSD professor
of biology, and Victor Nizet, associate
professor of pediatrics at the UCSD School of Medicine, led the
study, which was
published in The Journal of Clinical Investigation. The research
team discovered that white blood cells increase their levels of
a protein known as hypoxia
inducible transcription factor-1, or
HIF-1, in direct response to Streptococcus, Staphylococcus, Salmonella,
and other
disease-causing bacteria. HIF-1 protein,
in turn, stimulates white blood cells to
release compounds that kill bacteria.
The researchers compared how well white blood cells in which
HIF-1 levels were elevated, normal or zero, could kill bacteria,
including
Streptococcus,which has been isolated from a patient with flesh-
eating disease. They found that the greater the HIF-1 levels
in white blood cells, the greater their bacterial killing power. “
The placement of essential microbial killing functions of white blood
cells under regulation of HIF-1 represents an elegant controlled
response system,” explains Johnson. “Under HIF-1 regulation,
antimicrobial genes are expressed only
in infected tissues and not in healthy
tissues where they could produce unwanted inflammatory damage.” Their findings led the researchers to explore potential medical
implications. With the assistance of Emmanuel Theodorakis,
UCSD professor of chemistry
and biochemistry, they selected a group of chemicals that act to
increase
cellular HIF-1 levels. These molecules
significantly enhanced the capacity of white blood cells to kill
bacteria. “
Our findings offer proof of concept that small molecules can have
a beneficial effect by modulating the production of HIF-1 protein
in white blood cells,” says Theodorakis. “
Rather than designing drugs to target the bacteria,” Nizet
concludes, “medications that promote HIF-1 activity could be
used to boost the bacterial killing ability of white blood cells
and promote the resolution of infection through the actions of our
natural immune defenses.”  — Sherry Seethaler
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