Survival, bacterial clearance and thrombocytopenia are improved in polymicrobial sepsis by targeting nuclear transport shuttles

• Published in: PloS one Vol. 12; no. 6; p. e0179468
• Main Authors: Veach, Ruth Ann, Liu, Yan, Zienkiewicz, Jozef, Wylezinski, Lukasz S, Boyd, Kelli L, Wynn, James L, Hawiger, Jacek
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.06.2017; Public Library of Science (PLoS)
• Subjects: Activator protein 1; Active Transport, Cell Nucleus - drug effects; alpha Karyopherins - antagonists & inhibitors; alpha Karyopherins - metabolism; Animals; Anti-Infective Agents - therapeutic use; Antiinfectives and antibacterials; Bacteria; beta Karyopherins; Biology and Life Sciences; Biophysics; Blood; Blood plasma; Care and treatment; Cell adhesion & migration; Cell-Penetrating Peptides - chemical synthesis; Cell-Penetrating Peptides - chemistry; Cell-Penetrating Peptides - pharmacology; Cellular signal transduction; Chemokines; Chemokines - blood; Coding; Critical care; Cytokines; Cytokines - blood; Death; Disease Models, Animal; E-selectin; Failure; Female; Genomes; Immunology; Immunotherapy; Infiltration; Inflammation; Injuries; Injury prevention; Inosine monophosphate; Kinases; L-selectin; Liver; Liver - immunology; Liver - metabolism; Liver - pathology; Lungs; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Microorganisms; Microvasculature; Mortality; Neutrophils - cytology; Neutrophils - immunology; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - metabolism; Nuclear transport; Nuclei; P-selectin; Physicians; Physiology; Plasma levels; Proteins; Selectins - blood; Sepsis; Sepsis - drug therapy; Sepsis - microbiology; Sepsis - mortality; Sepsis - pathology; Spleen; Stresses; Survival; Survival Rate; Therapy; Thrombocytopenia; Thrombocytopenia - pathology; Transcription Factor RelA - metabolism; Transcription factors; Transport; Tumor necrosis factor-TNF; Virulence; Virulence factors; United States > US; Nashville Tennessee
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0179468

The rising tide of sepsis, a leading cause of death in the US and globally, is not adequately controlled by current antimicrobial therapies and supportive measures, thereby requiring new adjunctive treatments. Severe microvascular injury and multiple organ failure in sepsis are attributed to a "genomic storm" resulting from changes in microbial and host genomes encoding virulence factors and endogenous inflammatory mediators, respectively. This storm is mediated by stress-responsive transcription factors that are ferried to the nucleus by nuclear transport shuttles importins/karyopherins. We studied the impact of simultaneously targeting two of these shuttles, importin alpha 5 (Imp α5) and importin beta 1 (Imp β1), with a cell-penetrating Nuclear Transport Modifier (NTM) in a mouse model of polymicrobial sepsis. NTM reduced nuclear import of stress-responsive transcription factors nuclear factor kappa B, signal transducer and activator of transcription 1 alpha, and activator protein 1 in liver, which was also protected from sepsis-associated metabolic changes. Strikingly, NTM without antimicrobial therapy improved bacterial clearance in blood, spleen, and lungs, wherein a 700-fold reduction in bacterial burden was achieved while production of proinflammatory cytokines and chemokines in blood plasma was suppressed. Furthermore, NTM significantly improved thrombocytopenia, a prominent sign of microvascular injury in sepsis, inhibited neutrophil infiltration in the liver, decreased L-selectin, and normalized plasma levels of E-selectin and P-selectin, indicating reduced microvascular injury. Importantly, NTM combined with antimicrobial therapy extended the median time to death from 42 to 83 hours and increased survival from 30% to 55% (p = 0.022) as compared to antimicrobial therapy alone. This study documents the fundamental role of nuclear signaling mediated by Imp α5 and Imp β1 in the mechanism of polymicrobial sepsis and highlights the potential for targeting nuclear transport as an adjunctive therapy in sepsis management.