Reference Database

Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis.
Kim, Yoon Tae
Huh, Jin Won
Choi, Yun Hui
Yoon, Hee Kyeong
Nguyen, Tram Tt
Chun, Eunho
Jeong, Geunyeol
Park, Sunyoung
Ahn, Sungwoo
Lee, Won-Kyu
Noh, Young-Woock
Lee, Kyoung Sun
Ahn, Hee-Sung
Lee, Cheolju
Lee, Sang Min
Kim, Kyung Su
Suh, Gil Joon
Jeon, Kyeongman
Kim, Sunghoon
Jin, Mirim
EMBO Mol Med 2024 Jan;16(1): 40-63

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.

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