Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL, United States.
Front Immunol. 2019 Apr 4;10:615. doi: 10.3389/fimmu.2019.00615. eCollection 2019.
Pore-forming toxin (PFT) induced necroptosis exacerbates pulmonary injury during bacterial pneumonia. However, its role during asymptomatic nasopharyngeal colonization and toward the development of protective immunity was unknown. Using a mouse model of () asymptomatic colonization, we determined that nasopharyngeal epithelial cells (nEC) died of pneumolysin (Ply)-dependent necroptosis. Mice deficient in MLKL, the necroptosis effector, or challenged with Ply-deficient showed less nEC sloughing, increased neutrophil infiltration, and altered IL-1α, IL-33, CXCL2, IL-17, and IL-6 levels in nasal lavage fluid (NALF). Activated MLKL correlated with increased presence of CD11c antigen presenting cells in -associated submucosa. Colonized MLKL KO mice and wildtype mice colonized with Ply-deficient produced less antibody against the bacterial surface protein PspA, were delayed in bacterial clearance, and were more susceptible to a lethal secondary challenge. We conclude that PFT-induced necroptosis is instrumental in the natural development of protective immunity against opportunistic PFT-producing bacterial pathogens.
成孔毒素 (PFT) 诱导的坏死性凋亡会加剧细菌性肺炎期间的肺损伤。然而，其在无症状鼻咽定植期间以及对保护性免疫的发展中的作用尚不清楚。我们使用无症状定植的小鼠模型，确定鼻咽上皮细胞 (nEC) 因肺炎球菌溶血素 (Ply) 依赖性坏死性凋亡而死亡。缺乏 MLKL（坏死性凋亡效应物）的小鼠或接受 Ply 缺陷型 挑战的小鼠，鼻咽上皮细胞脱落减少，中性粒细胞浸润增加，鼻洗液 (NALF) 中白细胞介素-1α、白细胞介素-33、CXCL2、白细胞介素-17 和白细胞介素-6 的水平发生改变。活化的 MLKL 与与 CD11c 抗原呈递细胞在 相关的粘膜下的存在增加相关。定植的 MLKL KO 小鼠和用 Ply 缺陷型 定植的野生型小鼠对细菌表面蛋白 PspA 的抗体产生减少，细菌清除延迟，对致命的二次 挑战更敏感。我们得出结论，PFT 诱导的坏死性凋亡是针对机会性产生 PFT 的细菌病原体自然产生保护性免疫的重要因素。
