EMD Millipore eBook - 18

Analyzing Cell Death * Plague Protein Stalls Cell Death, Speeds Host Death

first author Adam Caulfield, Ph.D., a research
associate in Dr. Lathem's lab.
"As we reviewed possible hits, the 'aha
moment' came when we saw Fas ligand on the
list of affected proteins, because we know Fas is
an integral receptor for controlling cell death,"
recalled Dr. Lathem. "The process of Pla degrading
Fas ligand effectively prevents the lungs from
being able to clear the infection."
After verifying their findings using cell
cultures, Dr. Lathem conducted preclinical tests
using mice, arriving at the same conclusion. In
the article, the authors wrote that "wild-type
Y. pestis, but not a Pla mutant (Δpla), degrades
FasL, which results in decreased downstream
caspase-3/7 activation and reduced apoptosis.
Similarly, lungs of mice challenged with wild-type
Y. pestis show reduced levels of FasL and activated
caspase-3/7 compared to Δpla infection."

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| GENengnews.com

"The loss of FasL or inhibition of caspase
activity alters host inflammatory responses and
enables enhanced Y. pestis outgrowth in the
lungs," they added. "Thus, by degrading FasL,
Y. pestis manipulates host cell death pathways
to facilitate infection."
"Now that we have identified this as a method
by which plague bacteria can manipulate the
immune system, we have something to look for
when studying other respiratory infections," Dr.
Lathem concluded. "This could be a common
feature, where we see other bacteria manipulating
cell death pathways by altering Fas signaling."
Dr. Lathem believes that a restoration of Fas
signaling may give antibiotics more time to work,
and scientists in his lab are exploring that possibility.
They will also be looking at different bacterial
infections to see if any manipulate cell death by
altering Fas signaling in a similar manner." n
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