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.