Vanderbilt University researchers have found a way to block the signaling pathways that lead to lethal shock, a deadly complication of infections caused by Gram-negative bacteria that produce the endotoxin lipopolysaccharide (LPS), a potent virulence factor.
In the journal PLOS ONE, Antonio DiGiandomenico, Ph.D., Jacek Hawiger, M.D., Ph.D., and colleagues report that a cell-penetrating peptide they developed, cSN50.1, dramatically increased survival in mice exposed to high doses of LPS.
When LPS binds to its sensors on immune and vascular cells, it triggers mobilization of stress-responsive transcription factors (SRTFs) to the nucleus. In this signaling cascade, specialized proteins called importins/karyopherins ferry SRTFs into the cell nucleus where they reprogram gene expression. The ensuing “genomic storm” ramps up production of inflammatory molecules that induce fever and blood vessel injury. When left unchecked, this ultimately leads to multiple organ failure and death.
The cSN50.1 peptide targets importins, thereby reducing nuclear transport of SRTFs. The researchers concluded that controlling nuclear import may aid antibiotics in treating Gram-negative bacterial infections.
This work was supported by National Institutes of Health grants HL087531, HL069452, HL069765, DK090146 and HL087531, the Vanderbilt Immunotherapy Program, and was dedicated to the late Dr. Robert D. Collins, a longtime mentor, colleague, and friend to the authors.
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