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

ABSTRACT: 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, TNFα, Interferon γ, 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE308045 | GEO | 2025/10/31

REPOSITORIES: GEO

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Project description:Sepsis is a life-threatening condition with multi-organ failure caused by a dysregulated host response to infection. Among different organs susceptible to infection, the lung is the main one leading to sepsis 4. Patients with severe sepsis are at a high risk of developing acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which occurs in up to 50% of patients. Myeloid C-type lectin domain family 5 member A (CLEC5A) is a pattern recognition receptor that participates in host defense against infection. Blockage of CLEC5A increased survival of mice with polymicrobial sepsis or endotoxemia, and protected the lungs against septic infection. To explore the underlying cellular and molecular mechanisms of CLEC5A in sepsis-induced lung injury, a comprehensive single-cell transcriptomics of CLEC5A-/- lungs was generated by scRNA-seq. Mice were subjected to cecal ligation and puncture (CLP), and the lungs were collected 12 h post-surgery. Single cell suspensions were prepared from lung tissues of three CLEC5A-/- mice and three WT littermates, and pooled cells from these mice were subjected to scRNA-seq processing using the 10×Genomics Chromium system. A total of 55,177 single cells, including 29,306 cells from WT lungs and 15,871 cells from CLEC5A-/- lungs, were obtained after removal of multiplets and filtration of low-quality cells. Total cells were grouped into 34 distinct clusters by Uniform Manifold Approximation and Projection, and a total of 14 distinct cell types were identified, including granulocytes, T cells, B cells, alveolar-macrophages (AM), monocytes, macrophages, natural killer T cells (NKT), mesothelium, natural killer cells (NK), endothelial cells, fibroblasts, dendritic cells (DC), epithelial cells, and smooth muscle cells (SMC).The scRNA-seq analysis implied the potential role of CLEC5A in endothelial cells regarding crosstalk with immune cells in septic lungs. Deletion of CLEC5A inhibited endothelial barrier dysfunction induced by sepsis, and decreased leukocyte-endothelial adhesion and transendothelial migration. The role of CLEC5A in pulmonary endothelial cells and the barrier function is identified for the first time, which contributes to the regulation of immunity/inflammation in the lungs under septic infection. This work extends the therapeutic potential of targeting CLEC5A in sepsis-induced endothelial barrier dysfunction and lung injury.

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

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