High-molecular-weight kininogen is a critical component of host defense against <i>Escherichia coli</i> sepsis

High-molecular-weight kininogen (HK) is known to bind lipopolysaccharides (LPS) with high affinity and serves as a crucial LPS carrier in circulation, supporting endotoxemia. However, its role in host defense against Gram-negative bacterial infection remains unclear. Here we demonstrate that HK directly binds to <i>Escherichia coli</i> (<i>E. coli</i>) via LPS and rapidly localizes to sites of infection. HK-deficient mice (<i>Kng</i>1<i>^-</i>^/-) showed increased susceptibility to infection, with increased bacterial dissemination, lung injury, and proinflammatory cytokine production. In contrast, endogenous expression of human HK in <i>Kng</i>1<i>^-</i>^/- mice restored survival, limited bacterial spread, and reduced tissue damage. Mechanistically, HK promoted neutrophil antimicrobial responses by enhancing reactive oxygen species production and microbicidal activity. Consistently, liver-specific HK deficiency recapitulated the impaired bacterial clearance and reduced survival upon <i>E. coli</i> challenge, highlighting the importance of plasma HK. Together, these findings identify HK as a new soluble pattern recognition molecule that senses <i>E. coli</i> invasion and initiates neutrophil-mediated antimicrobial responses, revealing a previously unrecognized protective function of the contact system in innate immunity.