Synergy of bacteriophage depolymerase with host immunity rescues sepsis mice infected with hypervirulent <i>Klebsiella pneumoniae</i> of capsule type K2

The hypervirulent Klebsiella pneumoniae (hvKp) with K1 and K2 capsular types causes liver abscess, pneumonia, sepsis, and invasive infections with high lethality. The presence of capsular polysaccharide (CPS) resists phagocytic engulfment and contributes to excessive inflammatory responses. Bacteriophage depolymerases can specifically target bacterial CPS, neutralizing its defense. Based on our previous research, we expressed and purified a bacteriophage depolymerase (Dep1979) targeting hvKp with capsule type K2. Interestingly, although Dep1979 lacked direct bactericidal activity in vitro, it exhibited potent antibacterial activity in vivo. Low-dose Dep1979 (0.1 mg/kg) improved the 7-day survival of immunocompetent mice to 100%. Even at 0.01 mg/kg, mice achieved 100% survival at 5 days, although efficacy sharply declined at doses as low as 0.001 mg/kg. Following Dep1979 treatment, reduced expression of inflammatory factors and no apparent tissue damage were observed. However, therapeutic efficacy significantly diminished in immunosuppressed mice. These findings underscore the critical role of Dep1979 in disarming CPS, which synergizes with host immunity to enhance antibacterial activity against hvKp.携带K1、K2荚膜型的高毒力肺炎克雷伯菌（hypervirulent Klebsiella pneumoniae, hvKp）可引发肝脓肿、肺炎、脓毒症及高致死性侵袭性感染。荚膜多糖（capsular polysaccharide, CPS）可抵御吞噬细胞的吞噬作用，并介导过度炎症反应。噬菌体解聚酶（bacteriophage depolymerases）可特异性靶向细菌荚膜多糖，中和其防御功能。基于本团队前期研究，我们表达并纯化了一株靶向K2型高毒力肺炎克雷伯菌的噬菌体解聚酶（Dep1979）。有趣的是，尽管Dep1979在体外不具备直接杀菌活性，但其在体内展现出强效抗菌活性。低剂量Dep1979（0.1 mg/kg）可使免疫健全小鼠的7天生存率提升至100%；即便剂量降至0.01 mg/kg，小鼠在5天时的生存率仍可达100%，但当剂量低至0.001 mg/kg时，其治疗效果则大幅下降。经Dep1979治疗后，可观察到炎症因子表达水平降低，且未出现明显组织损伤。然而，在免疫抑制小鼠中，其治疗效果显著减弱。本研究结果证实，Dep1979通过中和荚膜多糖发挥关键作用，并与宿主免疫协同增强抗高毒力肺炎克雷伯菌的抗菌活性。