High-molecular-Weight Kininogen Is a Critical Component of Host Defense against Gram-negative Bacteria: Evidence from a Humanized HK Mouse Model
ISTH Academy. Yang A. Jul 10, 2019; 274059; OC 71.5 Topic: Contact Pathway
Aizhen Yang
Aizhen Yang
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OC 71.5

High-molecular-Weight Kininogen Is a Critical Component of Host Defense against Gram-negative Bacteria: Evidence from a Humanized HK Mouse Model

A. Yang1, Y. Wu1,2
1Soochow University, Suzhou, China, 2Temple University, Philadelphia, United States

Main Topic: Coagulation and Anticoagulation
Category: Contact Pathway

Background: Patients with gram-negative sepsis had an increase in activation of plasma contact activation system (CAS) and cleaved fragment of high-molecular-weight kininogen (HK). Injection of lipopolysaccharide (LPS) to healthy human subjects activated plasma CAS and induced the cleavage of HK. However, the physiological and pathophysiological relevance of these observations remains unknown.
Aims: To determine the role of plasma CAS and HK in host response to gram-negative bacterial infection.
Methods: Phenotypes of the mice lacking Factor XII, prekallikrein, and HK were compared in cecal ligation puncture (CLP) and peritoneal injection of E.coli models. Humanized HK (hKng1+/+/mKng1-/-) mice, whose Kng1 gene was replaced with human gene using CRISPR-Cas9 strategy, were used to evaluate the role of human HK.
Results: In both CLP and peritoneal injection of E.coli models, compared with wild-type mice, survival rate of Kng1-/- mice lacking HK was significantly decreased, but that of other CAS factors-deficient mice remained comparable, suggesting the selective role of HK in mice. To determine the role of human HK, hKng1+/+/mKng1-/-mice received peritoneal injection of E.coli. Compared with Kng1-/-mice, hKng1+/+/mKng1-/- mice showed a significant increase in survival rate, accompanied with lower plasma bacterial load and proinflammatory cytokines, and less lung and liver injury. I125- labeled human HK was intravenously injected to Kng1-/- mice bearing E.coli infection, it was rapidly recruited into the site of infection, shown by autoradiography. Human HK bound to E.coli dose-dependently, which was significantly blocked by LPS. The binding site of human HK to LPS was mapped to DHG15 a.a. in the domain 5. The DHG15 peptide had anti-bacterial effect in vitro and in vivo. In patients with gram-negative sepsis, the cleaved form of HK was increased in plasma, in consistence with an increase in circulating LPS levels.
Conclusions: Human HK is critical in host defense against gram-negative bacterial infection as a patter-recognition molecule and anti-bacterial protein.

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