Sepsis is a deadly infection triggered by an uncontrolled immune response. Now researchers at the Mount Sinai School of Medicine have shown that a cancer drug, at a low dose, might be sufficient to stop the immune response from becoming overblown. And the findings may also have strong implications for other inflammatory conditions.
The new work, headed up by senior investigator Ivan Marazzi at Mount Sinai’s Icahn School of Medicine, was published last week in the journal Science.
The human body defends itself against invading pathogens by activating its innate immune system, and in doing so, a pattern of gene expression that orchestrates a fine-tuned immune response. When this goes wrong, however, excessive inflammation ensues and the infection may trigger an inflammatory progression into diseases like sepsis.
The researchers found that a protein called topoisomerase 1 (Top1) positively regulates RNA polymerase II (RNAPII) transcriptional activity at genes activated by pathogens. Using a Top1 inhibitor they were able to suppress the host response toward infection with influenza virus, ebolavirus and bacterial products.
They also demonstrated that they could rescue mice that were subsequently exposed to a lethal inflammatory stimuli using the Top1 inhibitor.
In the animal experiments, Top1 inhibition could be used at 1/50 of the normal chemotherapy dosing and still rescue 70% to 90% of the mice challenged with an experimental infection.
"Our results suggest that a therapy based on Top 1 inhibition could save millions of people affected by sepsis, pandemics, and many congenital deficiencies associated with acute inflammatory episodes--what is known as a cytokine, or inflammatory, storm," said Marazzi in a news release. "These storms occur because the body does not know how to adjust the appropriate level of inflammation that is good enough to suppress an infection but doesn't harm the body itself. This drug appears to offer that life-saving correction."