Drug might help treat sepsis

NIH | MAY 30, 2016

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 biofilm of thermophilic bacteria. Photo: Wikimwdia Commons (CC BY-SA 3.0)

A team of scientists investigated antimicrobial gene activation during infection to better understand the body’s immune response to microbes.

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.

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