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ORIGINAL RESEARCH article

Front. Immunol.

Sec. Molecular Innate Immunity

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1635081

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

Provisionally accepted
  • Vanderbilt University School of Medicine, Nashville, United States

The final, formatted version of the article will be published soon.

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. We show that the Peptide Genomic Therapy (PGT) with the cell-penetrating Nuclear Transport Checkpoint Inhibitor (NTCI) peptide increased 29 times bacterial clearance in the spleen, a major blood-filtering immune organ in the preclinical model of sepsis, when combined with the antibiotic. Likewise, the PGT with NTCI peptide increased antibacterial immunity in the lungs, the frequent site of bacterial infections in spleen-compromised hosts. The survival reached 80% when the NTCI peptide was added to antibiotic, compared to 44% with meropenem alone. The NTCI peptide reprogrammed the expression of the gene orthologs responsible for human immunodeficiencies, also referred to as the Inborn Errors of Immunity (IEI). 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, TNFα, Interferon γ, and MCP1) were normalized by the NTCI peptide. Thus, the PGT with NTCI peptide combined with antibiotic significantly increased the antibacterial immunity in the spleen and lungs and almost doubled survival in sepsis.

Keywords: inborn errors of immunity (IEI), nuclear transport checkpoint inhibitor (NTCI), Polymicrobial sepsis, cSN50.1, Cell-Penetrating Peptides, inflammatory regulome, Gene Expression, RNAseq

Received: 25 May 2025; Accepted: 10 Oct 2025.

Copyright: © 2025 Hawiger, Qiao, Zienkiewicz and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Jacek Hawiger, jack.hawiger@vanderbilt.edu

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