Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis

Abstract

Despite intensive clinical and scientific efforts, the mortality rate of sepsis remains high due to the lack of precise biomarkers for patient stratification and therapeutic guidance. Secreted human tryptophanyl-tRNA synthetase 1 (WARS1), an endogenous ligand for Toll-like receptor (TLR) 2 and TLR4 against infection, activates the genes that signify the hyperinflammatory sepsis phenotype. High plasma WARS1 levels stratified the early death of critically ill patients with sepsis, along with elevated levels of cytokines, chemokines, and lactate, as well as increased numbers of absolute neutrophils and monocytes, and higher Sequential Organ Failure Assessment (SOFA) scores. These symptoms were recapitulated in severely ill septic mice with hypercytokinemia. Further, injection of WARS1 into mildly septic mice worsened morbidity and mortality. We created an anti-human WARS1-neutralizing antibody that suppresses proinflammatory cytokine expression in marmosets with endotoxemia. Administration of this antibody into severe septic mice attenuated cytokine storm, organ failure, and early mortality. With antibiotics, the antibody almost completely prevented fatalities. These data imply that blood-circulating WARS1-guided anti-WARS1 therapy may provide a novel theranostic strategy for life-threatening systemic hyperinflammatory sepsis. Sepsis is a heterogeneous illness with limited options for personalized immunotherapy. Tryptophanyl-tRNA synthetase 1 may represent a theranostic target for identifying patients with sepsis who are at risk of hyperinflammatory mortality and help control inflammation.High plasma WARS1 levels are associated with inflammation, organ failure, and early mortality in critically ill patients with sepsis. WARS1 injection causes organ failure and mortality by increasing the expression of hyperinflammatory sepsis endotype genes in mice with sepsis. Administration of anti-WARS1 MAb alone or in combination with antibiotics provides protection against death in severely ill septic mice with hypercytokinemia. Sepsis is a heterogeneous illness with limited options for personalized immunotherapy. Tryptophanyl-tRNA synthetase 1 may represent a theranostic target for identifying patients with sepsis who are at risk of hyperinflammatory mortality and help control inflammation.