Research in mice on Klebsiella pneumoniae could
pave the way for better broad-spectrum antibiotics for humans
Newswise, September 14, 2016— If you get pneumonia, or even an
infected cut, your body is now a war zone.
And as your immune system battles the invading bacteria, the
outcome of that war may hinge on a microscopic arms race based not on missiles
or bombs, but on an essential element: iron.
Now, scientists from the University of Michigan Medical School
say they have figured out how that race for iron actually increases the risk we
face from one of our most dangerous microscopic foes, Klebsiella pneumoniae. They
made the discovery in mice with pneumonia.
K. pneumoniae has already figured out how to overcome our best
defenses – including, in some cases, all our most powerful antibiotics.
It’s the third-most-common cause of infections that arise in
hospitalized patients, and causes pneumonia, urinary tract infections, wound
infections and bloodstream infections.
In its most drug-resistant form, it’s considered one of the
carbapenem resistant Enterobacteriaceae, or CRE – so called "nightmare
bacteria".
The new findings could aid the search for drugs to fight it,
and other “superbugs”.
Iron scavenging – and more
In a new paper in the journal mBio, the team led by Michael
Bachman, M.D., Ph.D. report what happens after the bacteria send out tiny
iron-scavenging molecules.
Called siderophores, those molecules have long been thought of
as a way for bacteria to gather a precious element needed to grow and
reproduce, by attaching to iron and stealing it from us.
Siderophores from K. pneumoniae are hundreds of times more powerful
at grabbing iron than the proteins that our own bodies produce. What’s more,
the bacteria produce a kind of siderophore that our defense systems can’t
neutralize.
But Bachman and his colleagues show that bacterial
siderophores do much more than just grab iron. Their experiments show that K.
pneumoniae actually use the molecules to help them invade the rest of the body
beyond their initial point of entry, and to bring on inflammation caused by our
own immune system.
“This is a bacterium that has evolved new ways to get iron,
and it turns out that the mechanism it uses also causes cellular stress during
infections,” says Bachman, an assistant professor of pathology at U-M.
“That response triggers an immune response that tells our
bodies to fight the infection, but it also activates a mechanism that allows
bacteria to escape and travel to the rest of the body.”
That mechanism, a protein called Hif-1alpha, normally helps
our bodies respond to low oxygen or low iron. But when K. pneumoniae
siderophores activate it, it worsens the infection. Exactly how is still a
mystery.
Bachman sees the effects of K. pneumoniae on patients in his work as a clinical microbiologist at the U-M Health System, where he’s associate director of clinical microbiology.
That motivates him to study it in the lab, though he notes
that it’s too early to say exactly how the discovery could be used to help
patients.
One promising route could be to develop strategies to prevent
the bacteria from sending out siderophores in the first place -- or to use the
siderophores to bring antibiotics back into bacterial cells.
Or, it may even be possible to create a vaccine based on
siderophores to teach the immune system to attack them as invaders.
Meanwhile, he and others at U-M including Microbiology &
Immunology chair Harry Mobley, Ph.D., are pursuing a broader goal through U-M’s
Host Microbiome Initiative.
Using an advanced genetic technique called transposon
sequencing, they’re working to figure out which genes K. pneumoniae and other
superbugs absolutely need in order to cause infections.
How they did it
To figure out the double role that siderophores play in a K.
pneumoniae infection, Bachman and his colleagues had to figure out how to
create bacteria that would not reproduce, while still producing siderophores.
They were able to mutate bacteria in a way that kept iron-laden siderophores
from getting back into the bacterial cells and promoting growth.
That way, the number of bacteria in a mouse’s body stayed the
same, but the researchers could study what the siderophores did.
They expected that if the siderophores grabbed enough iron
from the mouse’s lung tissue and robbed the mouse an essential element, the
mouse’s cells would respond.
Indeed, they found that the mouse immune system was triggered
directly by the siderophores, causing the release of molecules called cytokines
that attract infection-fighting cells and cause inflammation as a result. The
activation of Hif-1alpha was part of this – because the mouse cells sensed that
iron supply was low.
So, the team figured out how to eliminate Hif-1alpha in the
cells lining the mouse lungs – and showed that in these mice, most of the
bacteria couldn’t escape from the lungs to the spleen.
But in mice that made Hif-1alpha, more K. pneumoniae bacteria spread
to the rest of the body, making the infection worse.
“This work provides us with motivation to target the
production of siderophores, rather than just the uptake of them,” says Bachman.
“Now that we know that the bacteria cause cellular stress just
by secreting them, we may be able to prevent these effects if we neutralize
them.”
The research was funded by the Natural Sciences and
Engineering Research Council of Canada, through a grant to co-author Martin
Dozois. Dozois and co-author Sebastien Houle are at the Institut national de la
recherche scientifique, Institut Armand-Frappier, in Laval, Quebec.
Recent U-M
Ph.D. recipient Victoria Holden is the study’s first author, and the authors
also include former research technician Paul Breen. Reference: mBio,
7(6):e01397-16, doi:10.1128/mBio.01397-16.
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