<i>Pasteurella multocida</i> infection disrupts airway epithelial barrier function by triggering the NF-κB–microtubule–STING pathway

ABSTRACT Zoonotic respiratory pathogens commonly disrupt epithelial barrier integrity across animal species and humans, yet the host mechanisms coupling immune activation to structural barrier failure remain elusive. Here, we report that Pasteurella multocida infection is associated with activation of an NF-κB–microtubule–STING signaling axis, which contributes to epithelial barrier dysfunction. Infection activated NF-κB, induced microtubule depolymerization, and impaired microtubule-dependent trafficking of STING, consistent with defective delivery to degradative compartments, accompanied by intracellular accumulation, enhanced TBK1–IRF3 signaling, excessive interferon-β production, and loss of junction proteins. STING inhibition restored barrier integrity in vitro and in vivo , while alleviating lung injury and improving survival in infected mice. These findings highlight STING as a potential host-directed therapeutic target for pasteurellosis. IMPORTANCE Pasteurella multocida is a zoonotic pathogen that causes respiratory diseases in livestock, poultry, and even humans, resulting in substantial economic losses and posing threats to public health. The mechanism by which its infection impairs the airway epithelial barrier function remains unclear. This study identifies the NF-κB–microtubule–STING pathway as critical: P. multocida infection activates NF-κB, disrupts microtubule integrity, and impairs STING trafficking, which leads to excessive IFN-β production and the degradation/loss of junctional proteins. Inhibition of STING can restore airway epithelial barrier function, alleviate lung injury in mice, and improve survival rates. These findings provide novel therapeutic targets for host-directed therapy against P. multocida infections, with clinical and veterinary application value.