Infection causes inflammation, which contributes to pathogen clearance and organismal survival. The balance between the intensity and resolution of an inflammatory response is key for the fitness of the organism. Sepsis, for example, is a life-threatening condition caused by an excessive host response to infection, which in turn leads to multi-organ failure and death. Worldwide, millions of people each year succumb to sepsis. With an overall mortality rate of 20 to 50%, sepsis is the 10th leading cause of death (more than HIV and breast cancer) in the United States, according to the Centers for Disease Control and Prevention. Estimates indicate that 250,000 to 500,000 people die from sepsis annually in the United States. Children and the elderly are especially vulnerable to sepsis; it is the most common cause of death in infants and children. Childhood pneumonia, often caused by virus-bacteria co-infection, leads to septic shock and lung destruction. This occurs after bacterial invasion even in the presence of an appropriate antibiotic therapy. Finding remedies to treat sepsis and diseases associated with detrimental acute inflammatory reactions is thus pivotal for humankind.

We reasoned that if excessive inflammation in response to infection leads to lethal consequences, dampening inflammation could be advantageous for the host. At least two strategies could be used to suppress inflammatory responses associated with infection. One is indirect and targets the pathogen (antibiotics). The second one, which we used, directly acts on the host response itself. In such a strategy, the suppression of acute inflammation would bypass the fatal outcome associated with overt inflammation and would “buy time” to allow the host immune response to eliminate the pathogen. After microbial invasion, many steps could be targeted between the early phases of the cellular response (sensing of the pathogen and signal transduction) and the information flow from DNA to RNA to proteins that act as inflammatory mediators (i.e., cytokines). We decided to identify and chemically inhibit cellular factors that act at the DNA (chromatin) level and play a primary role in activating the expression of inflammatory genes.

We found that chemical inhibition of topoisomerase 1 (Top1), an enzyme that unwinds DNA, suppresses the expression of infection-induced genes with little to no effect on housekeeping gene expression and without cellular damage. In vitro, depletion or chemical inhibition of Top1 in epithelial cells and macrophages suppresses the host response against influenza and Ebola viruses as well as bacterial products. At the mechanistic level, as shown by chemical genetics and epigenetic approaches, Top1 inhibition primarily suppresses RNA polymerase II (RNAPII) activity at pathogen-associated molecular pattern (PAMP)–induced genes. These genes require SWI/SNF chromatin remodeling for activation and display unique genetic and epigenetic features, such as the presence of IRF3 binding sites, low basal levels of RNAPII, histone H3 Lys²⁷ acetylation marks, DNA hypersensitivity, and CpG islands. This gene “signature” of specificity was also validated using public data sets. In vivo, Top1 inhibition therapy rescued 70 to 90% mortality caused by exacerbated inflammation in three mouse models: acute bacteria infection, liver failure, and virus-bacteria co-infection. Strikingly, one to three doses of inhibitors were sufficient for the protective effect in all models, without overt side effects.

The inflammatory immune response against microbes is essential in protecting us against infections. In some cases, such as highly …