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May 17, 2016
Drug might help treat sepsis
At a Glance
- A DNA enzyme called Top1 plays a key role in turning on genes that cause inflammation in mouse and human cells in response to pathogens.
- A drug blocking this enzyme rescued mice from lethal inflammatory responses, suggesting a potential treatment for sepsis.
Sepsis is a life-threatening condition in which the body launches a massive immune response to an infection. It can be triggered by different types of microbes (such as viruses and bacteria). To combat infections, the body turns on antimicrobial genes that cause the production and release of inflammatory chemicals into the affected site and bloodstream. This response is essential for the body’s protection, but its over-activation can cause widespread and exaggerated inflammation that can result in tissue damage, organ failure, and sometimes death.
A team of scientists led by Dr. Ivan Marazzi at the Icahn School of Medicine at Mount Sinai investigated antimicrobial gene activation during infection to better understand the body’s immune response to microbes. The research was funded in part by NIH’s National Institute of Allergy and Infectious Diseases (NIAID). Results appeared online on April 28, 2016, in Science.
The researchers exposed mouse and human cells infected with flu viruses to various chemicals that block gene activation. By looking at the expression of genes known to be turned on during viral infection, they observed that one chemical, camptothecin (CPT), reduced virus-induced gene activation. CPT blocks a DNA enzyme called topoisomerase 1 (Top1). Genetic depletion of Top1 in flu virus-infected cells reduced the expression of 84 genes—predominantly genes that are specifically induced in response to infection.
Another drug that's similar to CPT and also blocks Top1, topotecan (TPT), prevented the activation of antimicrobial genes in human cells infected with either bacteria or Ebola virus. The researchers mapped the genomic distribution of TPT and found that TPT sits near regions of DNA that turn on antimicrobial genes, called promoters. Top1 is reduced at such sites when TPT is present.
The scientists administered CPT to mice with severe inflammatory responses. They found that 70% to 94% of mice treated with the drug were rescued from a lethal reaction caused by either infection with the bacteria Staphylococcus aureus, co-infection with both a flu virus and Staphylococcus aureus, or acute liver failure. Together, the results suggest that drugs that inhibit Top1 may help control dangerous inflammatory responses.
“Our findings suggest a therapeutic usage of Top 1 inhibition for the treatment of severe-and sometimes lethal inflammatory conditions in people affected by sepsis, pandemics, and many congenital deficiencies associated with acute inflammatory episodes—what is known as a cytokine, or inflammatory, storm,” says Marazzi.
Drugs that are similar to CPT, such as TPT, are already FDA-approved as anticancer agents. More studies are needed to test whether they would be useful for treating sepsis.
—by Tianna Hicklin, Ph.D.
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Reference: Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. Rialdi A, Campisi L, Zhao N, Lagda AC, Pietzsch C, Ho JS, Martinez-Gil L, Fenouil R, Chen X, Edwards M, Metreveli G, Jordan S, Peralta Z, Munoz-Fontela C, Bouvier N, Merad M, Jin J, Weirauch M, Heinz S, Benner C, van Bakel H, Basler C, García-Sastre A, Bukreyev A, Marazzi I. Science. 2016 Apr 28. pii: aad7993. [Epub ahead of print]. PMID: 27127234
Funding: NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and the U.S. Department of Defense.