The Peptide Genomic Therapy Increases Antibacterial Immunity and Survival in Sepsis by Reprograming the Gene Orthologs of Human Immunodeficiencies in the Spleen and Lungs

Sepsis is a life-threatening complication of infections afflicting 49 million patients worldwide with 11 million sepsis-related deaths. In the USA, this growing public health problem concerns 1.7 million adult and pediatric patients. An estimated 1 million patients with asplenia or hyposplenia are particularly vulnerable to sepsis. As the spleen is a major blood-filtering immune organ, we show that its anti-bacterial immunity was increased 9 times by the Peptide Genomic Therapy with the cell-penetrating Nuclear Transport Checkpoint Inhibitor (NTCI) in the preclinical model. Likewise, the antibacterial immunity was increased in the lungs, the frequent site of bacterial infections in spleen-compromised hosts. We also show that the survival increased from 44% to 80%, when the NTCI was added to the antibiotic therapy. Strikingly, the NTCI reprogrammed the expression of the gene orthologs responsible for human immunodeficiencies, aka the Inborn Errors of Immunity (IEI). Among them, the 227 IEI genes were reprogrammed in the spleen and 215 in the lungs, while the mediators of inflammation in blood (IL-6, IL-10, TNFa, Interferon ?, and MCP1) were normalized. Thus, the antibacterial immunity in the spleen and lungs was dramatically increased by the Peptide Genomic Therapy with the NTCI that almost doubled survival in sepsis when added to the antibiotic. Overall design: We investigated the spleen's and lungs' genome response to polymicrobial sepsis. We also established an impact of nuclear import blockade on gene expression in sepsis. 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 spleen total RNA samples from mice euthanized at 26 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 Sham + saline.