Activation of Thousands of Genes in the Lungs and Kidneys by Sepsis is Countered by the Selective Nuclear Blockade

The steady rise of sepsis globally has reached almost 49 million cases in 2017, and 11 million sepsis-related deaths. The genomic response to sepsis comprising multi-system stage of raging microbial inflammation has been reported in the whole blood, while effective treatment is lacking besides anti-microbial therapy and supportive measures. Here we show that, astoundingly, 6,237 significantly expressed genes in sepsis are increased or decreased in the lungs, the site of acute respiratory distress syndrome (ARDS). Moreover, 5,483 significantly expressed genes in sepsis are increased or decreased in the kidneys, the site of acute injury (AKI). This massive genomic response to polymicrobial sepsis is countered by the selective nuclear blockade with the cell-penetrating Nuclear Transport Checkpoint Inhibitor (NTCI). It controlled 3,735 sepsis-induced genes in the lungs and 1,951 sepsis-induced genes in the kidneys. The NTCI also reduced without antimicrobial therapy the bacterial dissemination: 18-fold in the blood, 11-fold in the lungs, and 9-fold in the spleen. This enhancement of bacterial clearance was not significant in the kidneys. Cumulatively, identification of the sepsis-responsive host's genes and their control by the selective nuclear blockade advances a better understanding of the multi-system mechanism of sepsis. Moreover, it spurs much-needed new diagnostic, therapeutic, and preventive approaches. Overall design: We investigated the lungs' and kidneys' genome response to polymicrobial sepsis. We also established an impact of nuclear import blockade on gene expression in sepsis. Polymicrobial sepsis was induced in 8-10-week-old female C57BL/6 mice (Jackson Laboratories, Bar Harbor, ME) by a single intraperitoneal injection of cecal microbiome (CM) stock solution. Mice were treated with saline or with cell-penetrating nuclear transport checkpoint inhibitor (NTCI), cSN50.1 peptide. A control group of mice were challenged with sham (5% dextrose) and treated with saline. A gene expression profiling (RNA-seq) was performed using NGS of lungs and kidneys total RNA samples from mice euthanized at 6 hours post CM challenge. The comparative gene expression profiling analysis (DESeq2) was performed using RNA-seq data for groups: CM + saline vs. Sham + saline and CM + NTCI vs CM + saline in both organs.